<P>Convulsion (2 vs 1), rash (2 vs 1), fatigue (2 vs 0), and vomiting (1 vs 0) In adult double-blind adjunctive clinical studies (up to 3200 mg/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 Table 5. Table 5: Adverse Reactions Most Commonly Leading to Discontinuation in Double-Blind Adjunctive Trials (up to 3200 mg/day) in Adult Patients Preferred Term (BANZEL N=823 vs Placebo N=376) Dizziness (3 vs 1), fatigue (2 vs 1), headache (2 vs 1), nausea (1 vs 0), and ataxia (1 vs 0) Other Adverse Events Observed During Clinical Trials: BANZEL has been administered to 1978 individuals 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 3 times 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 1/100 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 Post-marketing Experience Decreased weight has been reported in patients receiving rufinamide both in the presence and absence of gastrointestinal symptoms. 7 DRUG INTERACTIONS Based on in vitro studies, rufinamide shows little or no inhibition of most cytochrome P450 enzymes at clinically relevant concentrations, with weak inhibition of CYP 2E1. Drugs that are substrates of CYP 2E1 (e.g. chlorzoxazone) may have increased plasma levels in the presence of rufinamide, but this has not been studied. Based on in vivo drug interaction studies with triazolam and oral contraceptives, rufinamide is a weak inducer of the CYP 3A4 enzyme and can decrease exposure of drugs that are substrates of CYP 3A4 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. Table 6: Summary of drug-drug interactions of BANZEL with other antiepileptic drugs AED Co-administeredInfluence of Rufinamide on AED concentrationa)Influence of AED on Rufinamide concentration CarbamazepineDecrease by 7 to 13b)Decrease by 19 to 26 Dependent on dose of carbamazepine LamotrigineDecrease by 7 to 13b)No Effect PhenobarbitalIncrease by 8 to 13b)Decrease by 25 to 46c),d) Independent of dose or concentration of phenobarbital PhenytoinIncrease by 7 to 21b)Decrease by 25 to 46c),d) Independent of dose or concentration of phenytoin TopiramateNo EffectNo Effect ValproateNo EffectIncrease by <16 to 70c) Dependent on concentration of valproate PrimidoneNot InvestigatedDecrease by 25 to 46c),d) Independent of dose or concentration of primidone Benzodiazepinese)Not InvestigatedNo Effect a) Predictions are based on BANZEL concentrations at the maximum recommended dose of BANZEL. b) Maximum changes predicted to be in children and in patients who achieve significantly higher levels of BANZEL, as the effect of rufinamide on these AEDs is concentration-dependent. c) Larger effects in children 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 BANZEL clearance. e) All compounds of the benzodiazepine class were pooled to examine for ‘class effect on BANZEL clearance. Phenytoin: The decrease in clearance of phenytoin estimated at typical levels of rufinamide (Cavss 15 µg/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 Table 6). 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 10 mg/kg/day (children) or 400 mg/day (adults) see Dosage and Administration (2.5). 7.3 Effects of BANZEL on other Medications Hormonal contraceptives: Co-administration of BANZEL (800 mg bid for 14 days) 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 (400 mg bid) resulted in a 37 decrease in AUC and a 23 decrease in Cmax of triazolam, a CYP 3A4 substrate. Olanzapine: Co-administration and pre-treatment with BANZEL (400 mg bid) resulted in no change in AUC and Cmax of olanzapine, a CYP 1A2 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 300 mg/kg/day and to rabbits at doses of 30, 200, and 1000 mg/kg/day during the period of organogenesis (implantation to closure of the hard palate); the high doses are associated with plasma AUCs ˜2 times the human plasma AUC at the maximum recommended human dose (MRHD, 3200 mg/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 highest dose tested in rabbits was associated with abortion. The no-effect doses for adverse effects on rat and rabbit embryo-fetal development (20 and 30 mg/kg/day, respectively) were associated with plasma AUCs ˜ 0.2 times that in humans at the MRHD. In a rat pre- and post-natal development study (dosing from implantation through weaning) conducted at oral doses of 5, 30, and 150 mg/kg/day (associated with plasma AUCs up to ˜1.5 times that in humans at the MRHD), decreased offspring growth and survival were observed at all doses tested. A no-effect dose for adverse effects on pre- and post-natal development was not established. The lowest dose tested was associated with plasma AUC < 0.1 times that in humans at the MRHD. Pregnancy Registry To provide information regarding the effects of in utero exposure to BANZEL, physicians are advised to recommend that pregnant patients taking BANZEL enroll in the North American Antiepileptic Drug Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/. 8.2 Labor and Delivery The effect of BANZEL on labor and delivery in humans is not known. 8.3 Nursing Mothers Rufinamide is likely to be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from BANZEL, a decision should be made whether to discontinue nursing or discontinue the drug taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness in patients with Lennox-Gastaut Syndrome have not been established in children less than 4 years. The pharmacokinetics of rufinamide in the pediatric population (age 4-17 years) is similar to that in the adults see Clinical Pharmacology (12.3). 8.5 Geriatric Use Clinical studies of BANZEL did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Pharmacokinetics of rufinamide in the elderly are similar to that in the young subjects see Clinical Pharmacology (12.3). 8.6 Renal Impairment: Rufinamide pharmacokinetics in patients with severe renal impairment (creatinine clearance <30 mL/min) was similar to that of healthy subjects. Dose adjustment in patients undergoing dialysis should be considered see Dosage and Administration (2.3) and Clinical Pharmacology (12.3). 8.7 Hepatic Impairment: There have been no specific studies investigating the effect of hepatic impairment on the pharmacokinetics of rufinamide. 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 Dosage and Administration (2.4). 9 DRUG ABUSE AND DEPENDENCE The abuse and dependence potential of BANZEL has not been evaluated in human studies. 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/day BANZEL 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 BANZEL. 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 patients clinical state. 17 PATIENT COUNSELING INFORMATION Patients should be informed of the availability of a Medication guide and they should be instructed to read the Medication Guide prior to taking BANZEL. Patients should be instructed to take BANZEL only as prescribed. 17.1 Suicidal Thinking and Behavior Patients, their caregivers, and families should be informed that antiepileptic drugs 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. As with all centrally acting medications, alcohol in combination with BANZEL may cause additive central nervous system effects. Patients should be advised to notify their physician if they experience a rash associated with fever. BANZEL should be taken with food. Patients should be advised about the potential for somnolence or dizziness and advised not to drive or operate machinery until they have gained sufficient experience on BANZEL to gauge whether it adversely affects their mental and/or motor performance. 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 see Drug Interactions (7.3). Additional non-hormonal forms of contraception are recommended when using BANZEL. Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. They should also be encouraged to enroll in the North American Antiepileptic Drug Pregnancy Registry if they become pregnant. To enroll, patients can call the toll free number 1-888-233-2334 see Use in Specific Populations (8.1). Patients should be advised to notify their physician if they are breast-feeding or intend to breast-feed. Patients who are prescribed the oral suspension should be advised to shake the bottle vigorously before every administration and to use the adaptor and oral dosing syringe. When applicable patients should be advised that BANZEL oral suspension does not contain lactose or gluten and is dye-free. The oral suspension does contain carbohydrates. Distributed by Eisai Co., Ltd. © 2013 Eisai Inc. Printed in U.S.A. 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