1 INDICATIONS AND USAGE

BANZEL (rufinamide) is indicated for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in children 4years and older and adults.

2 DOSAGE AND ADMINISTRATION

BANZEL should be given with food. Tablets can be administered whole, as half tablets or crushed, for dosing flexibility.

BANZEL Oral Suspension should be shaken well before every administration. The provided adapter and calibrated oral dosing syringe should be used to administer the oral suspension. The adapter which is supplied in the product carton should be inserted firmly into the neck of the bottle before use and remain in place for the duration of the usage of the bottle. The dosing syringe should be inserted into the adapter and the dose withdrawn from the inverted bottle. The cap should be replaced after each use. The cap fits properly when the adapter is in place. See BANZEL Oral Suspension Dosing Instructions for complete instructions on how to properly dose and administer the BANZEL Oral Suspension.

2.1 Patient with Lennox-Gastaut Syndrome

Children four years and older with Lennox-Gastaut syndrome: Treatment should be initiated at a daily dose of approximately 10mg/kg/day administered in two equally divided doses. The dose should be increased by approximately 10mg/kg increments every other day to a target dose of 45mg/kg/day or 3200mg/day, whichever is less, administered in two equally divided doses. It is not known whether doses lower than the target doses are effective.

Adults with Lennox-Gastaut syndrome: Treatment should be initiated at a daily dose of 400-800mg/day administered in two equally divided doses. The dose should be increased by 400-800mg every other day until a maximum daily dose of 3200mg/day, administered in two equally divided doses is reached. It is not known whether doses lower than 3200mg are effective.

2.2 Patients with Renal Impairment

Renally impaired patients (creatinine clearance less than 30mL/min) do not require any special dosage change when taking BANZEL [see Clinical Pharmacology (12.3)]

2.3 Patients Undergoing Hemodialysis

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

2.4 Patients with Hepatic Disease

Use of BANZEL 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 Population (8.7)].

2.5 Patients on Antiepileptic Drugs (AEDs)

Patients on valproate should begin at a BANZEL dose lower than 10mg/kg/day (children) or 400mg/day (adults). For effects of other AEDs on BANZEL see Drug Interactions (7.2).

3 DOSAGE FORMS AND STRENGTHS

Film coated Tablets: 200mg (pink) and 400mg (pink). Tablets are scored on both sides.

Oral Suspension: 40mg/mL

4 CONTRAINDICATIONS

BANZEL is contraindicated in patients with Familial Short QT syndrome [see Warnings and Precautions, QT Shortening (5.3)]

5 WARNINGS AND PRECAUTIONS

5.1 Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including Banzel, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199placebo-controlled clinical trials (mono- and adjunctive therapy) of 11different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863AED-treated patients was 0.43%, compared to 0.24% among 16,029placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24weeks, the risk of suicidal thoughts or behavior beyond 24weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100years) in the clinical trials analyzed. Table1 shows absolute and relative risk by indication for all eva luated AEDs.

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing Banzel or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

5.2 Central Nervous System Reactions

Use of BANZEL has been associated with central nervous system-related adverse reactions. The most significant of these can be classified into two general categories:
1)somnolence or fatigue, and 2)coordination abnormalities, dizziness, gait disturbances, and ataxia [see Adverse Reactions (6.1)].

5.3 QT Shortening

Formal cardiac ECG studies demonstrated shortening of the QT interval (mean=20msec, for doses ≥2400mg twice daily) with BANZEL treatment. In a placebo-controlled study of the QT interval, a higher percentage of BANZEL-treated subjects (46% at 2400mg, 46% at 3200mg, and 65% at 4800mg) had a QT shortening of greater than 20msec at Tmax compared to placebo (5- 10%).

Reductions of the QT interval below 300msec were not observed in the formal QT studies with doses up to 7200mg/day. Moreover, there was no signal for drug-induced sudden death or ventricular arrhythmias.

The degree of QT shortening induced by BANZEL is without any known clinical risk. Familial Short QT syndrome is associated with an increased risk of sudden death and ventricular arrhythmias, particularly ventricular fibrillation. Such events in this syndrome are believed to occur primarily when the corrected QT interval falls below 300msec. Non-clinical data also indicate that QT shortening is associated with ventricular fibrillation.

Patients with Familial Short QT syndrome should not be treated with BANZEL. Caution should be used when administering BANZEL with other drugs that shorten the QT interval [see Contraindications (4)].

5.4 Multi-organ Hypersensitivity Reactions

Multi-organ hypersensitivity syndrome, a serious condition sometimes induced by antiepileptic drugs, has occurred in association with BANZEL therapy in clinical trials. One patient experienced rash, urticaria, facial edema, fever, elevated eosinophils, stuperous state, and severe hepatitis, beginning on day29 of Banzel therapy and extending over a course of 30days of continued Banzel therapy with resolution 11days after discontinuation. Additional possible cases presented with rash and one or more of the following: fever, elevated liver function studies, hematuria, and lymphadenopathy. These cases occurred in children less than 12years of age, within four weeks of treatment initiation, and were noted to resolve and/or improve upon BANZEL discontinuation. This syndrome has been reported with other anticonvulsants and typically, although not exclusively, presents with fever and rash associated with other organ system involvement. Because this disorder is variable in its expression, other organ system signs and symptoms not noted here may occur. If this reaction is suspected, BANZEL should be discontinued and alternative treatment started.

All patients who develop a rash while taking BANZEL must be closely supervised.

5.5 Withdrawal of AEDs

As with all antiepileptic drugs, BANZEL should be withdrawn gradually to minimize the risk of precipitating seizures, seizure exacerbation, or status epilepticus. If abrupt discontinuation of the drug is medically necessary, the transition to another AED should be made under close medical supervision. In clinical trials, BANZEL discontinuation was achieved by reducing the dose by approximately 25% every two days.

5.6 Status Epilepticus

Estimates of the incidence of treatment emergent status epilepticus among patients treated with BANZEL are difficult because standard definitions were not employed. In a controlled Lennox-Gastaut syndrome trial, 3 of 74 (4.1%) BANZEL-treated patients had episodes that could be described as status epilepticus in the BANZEL-treated patients compared with none of the 64patients in the placebo-treated patients. In all controlled trials that included patients with different epilepsies, 11 of 1240 (0.9%) BANZEL-treated patients had episodes that could be described as status epilepticus compared with none of 635patients in the placebo-treated patients.

5.7 Laboratory Tests

Leucopenia (white cell count <3×109L) was more commonly observed in BANZEL-treated patients (43 of 1171, 3.7%) than placebo-treated patients (7 of 579, 1.2%) in all controlled trials.

6 ADVERSE REACTIONS

6.1 Controlled Trials

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.

Placebo-controlled double-blind studies were performed in adults and in pediatric patients, down to age of 4, in other forms of epilepsy, in addition to the trial in Lennox-Gastaut syndrome. Data on CNS Reactions [see Warnings and Precautions (5.2)] from the Lennox-Gastaut study are presented first. Because there is no reason to suspect that adverse reactions would substantially differ between these patient populations, safety data from all of these controlled studies are then presented. Most of these adverse reactions were mild to moderate and transient in nature.

Common central nervous system reactions in the controlled trial of patients 4years or older with Lennox-Gastaut syndrome treated with BANZEL as adjunctive therapy [see Warnings and Precautions (5.2)]

Somnolence was reported in 24.3% of BANZEL-treated patients compared to 12.5% of placebo patients and led to study discontinuation in 2.7% of treated patients compared to 0% of placebo patients. Fatigue was reported in 9.5% of BANZEL-treated patients compared to 7.8% of placebo patients. It led to study discontinuation in 1.4% of treated patients and 0% of placebo patients.

Dizziness was reported in 2.7% of BANZEL-treated patients compared to 0% of placebo patients, and did not lead to study discontinuation.

Ataxia and gait disturbance were reported in 5.4% and 1.4% of BANZEL-treated patients, respectively, and in no placebo patients. Balance disorder and abnormal coordination were each reported in 0% of BANZEL-treated patients and 1.6% of placebo patients. None of these reactions led to study discontinuation.

All Adverse Reactions for All Treated Patients with Epilepsy, Double-blind Adjunctive Therapy Studies: The most commonly observed (≥10%) adverse reactions in BANZEL-treated patients, when used as adjunctive therapy at all doses studied (200 to 3200mg/day) with a higher frequency than in placebo were: headache, dizziness, fatigue, somnolence, and nausea.

Table2 lists treatment-emergent adverse reactions that occurred in at least 3% of pediatric patients with epilepsy treated with BANZEL in controlled adjunctive studies and were numerically more common in patients treated with BANZEL than placebo.

At the target dose of 45mg/kg/day for adjunctive therapy in children, the most commonly observed (≥3%) adverse reactions with an incidence greater than in placebo, for BANZEL were somnolence, vomiting and headache.

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

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

Discontinuation in Controlled Clinical Studies

In controlled double-blind adjunctive clinical studies, 9.0% of patients receiving BANZEL as adjunctive therapy and 4.4% receiving placebo discontinued as a result of an adverse reaction. The adverse reactions most commonly leading to discontinuation of BANZEL (>1%) used as adjunctive therapy were generally similar in adults and children.

In pediatric double-blind adjunctive clinical studies, 8.0% of patients receiving BANZEL as adjunctive therapy and 2.2% receiving placebo discontinued as a result of an adverse reaction. The adverse reactions most commonly leading to discontinuation of BANZEL (>1%) used as adjunctive therapy are presented in Table4.

In adult double-blind adjunctive clinical studies (up to 3200mg/day), 9.5% of patients receiving BANZEL as adjunctive therapy and 5.9% receiving placebo discontinued as a result of an adverse reaction. The adverse reactions most commonly leading to discontinuation of BANZEL (>1%) used as adjunctive therapy are presented in Table5.

Other Adverse Events Observed During Clinical Trials:

BANZEL has been administered to 1978individuals during all epilepsy clinical trials (placebo-controlled and open-label). Adverse events 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 events, 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 3times are also included based on their medical significance. Because the reports include events observed in open-label, uncontrolled observations, the role of BANZEL 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 1/100patients; infrequent adverse events- those occurring in 1/100 to 1/1000patients; rare- those occurring in fewer than 1/1000patients.

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.

7 DRUG INTERACTIONS

Based on invitro studies, rufinamide shows little or no inhibition of most cytochrome P450 enzymes at clinically relevant concentrations, with weak inhibition of CYP2E1. Drugs that are substrates of CYP2E1 (e.g.chlorzoxazone) may have increased plasma levels in the presence of rufinamide, but this has not been studied.

Based on invivo drug interaction studies with triazolam and oral contraceptives, rufinamide is a weak inducer of the CYP3A4 enzyme and can decrease exposure of drugs that are substrates of CYP3A4 [see Drug Interactions (7.3)].

Rufinamide is metabolized by carboxylesterases. Drugs that may induce the activity of carboxylesterases may increase the clearance of rufinamide. Broad-spectrum inducers such as carbamazepine and phenobarbital may have minor effects on rufinamide metabolism via this mechanism. Drugs that are inhibitors of carboxylesterases may decrease metabolism of rufinamide.

7.1 Effects of BANZEL on other AEDs

Population pharmacokinetic analysis of average concentration at steady state of carbamazepine, lamotrigine, phenobarbital, phenytoin, topiramate, and valproate showed that typical rufinamide Cavss 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 BANZEL with other AEDs.

Phenytoin: The decrease in clearance of phenytoin estimated at typical levels of rufinamide (Cavss 15μg/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 BANZEL

Potent cytochrome P450 enzyme inducers, such as carbamazepine, phenytoin, primidone, and phenobarbital appear to increase the clearance of BANZEL (see Table6). Given that the majority of clearance of BANZEL 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: Based on a population pharmacokinetic analysis, rufinamide clearance was decreased by valproate. In children, valproate administration may lead to elevated levels of rufinamide by up to 70%. Patients stabilized on BANZEL 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 BANZEL dose lower than 10mg/kg/day (children) or 400mg/day (adults) [see Dosage and Administration (2.5)].

7.3 Effects of BANZEL on other Medications

Hormonal contraceptives: Co-administration of BANZEL (800mg BID for 14days) and Ortho-Novum 1/35® resulted in a mean decrease in the ethinyl estradiol AUC0-24 of 22% and Cmax by 31% and norethindrone AUC0-24 by 14% and Cmax by 18%, respectively. The clinical significance of this decrease is unknown. Female patients of childbearing age should be warned that the concurrent use of BANZEL with hormonal contraceptives may render this method of contraception less effective. Additional non-hormonal forms of contraception are recommended when using BANZEL [see Information for Patients (17)].

Triazolam: Co-administration and pre-treatment with BANZEL (400mg bid) resulted in a 37% decrease in AUC and a 23% decrease in Cmax of triazolam, a CYP3A4 substrate.

Olanzapine: Co-administration and pre-treatment with BANZEL (400mg bid) resulted in no change in AUC and Cmax of olanzapine, a CYP1A2 substrate.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. BANZEL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Rufinamide produced developmental toxicity when administered orally to pregnant animals at clinically relevant doses.

Rufinamide was administered orally to rats at doses of 20, 100, and 300mg/kg/day and to rabbits at doses of 30, 200, and 1000mg/kg/day during the period of organogenesis (implantation to closure of the hard palate); the high doses are associated with plasma AUCs ≈2times the human plasma AUC at the maximum recommended human dose (MRHD, 3200mg/day). Decreased fetal weights and increased incidences of fetal skeletal abnormalities were observed in rats at doses associated with maternal toxicity. In rabbits, embryo-fetal death, decreased fetal body weights, and increased incidences of fetal visceral and skeletal abnormalities occurred at all but the low dose. The