<P>BANZEL (rufinamide) BRIEF SUMMARY—See package insert for full Prescribing Information 1 INDICATIONS AND USAGE BANZEL (rufinamide) is indicated for adjunctive treatment of seizures associated with Lennox-Gastaut Syndrome in children 4 years 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 The dosing syringe should be inserted into the adapter and the dose withdrawn from the inverted bottle.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 (17.3) for complete instructions on how to properly dose and administer the BANZEL Oral Suspension. 2.1 Patients with Lennox-Gastaut Syndrome Children four years and older with Lennox-Gastaut Syndrome: Treatment should be initiated at a daily dose of approximately 10 mg/kg/day administered in two equally divided doses. The dose should be increased by approximately 10 mg/kg increments every other day to a target dose of 45 mg/kg/day or 3200 mg/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 400-800 mg/day administered in two equally divided doses. The dose should be increased by 400-800 mg every other day until a maximum daily dose of 3200 mg/day, administered in two equally divided doses is reached. It is not known whether doses lower than 3200 mg are effective. 2.2 Patients with Renal Impairment Renally impaired patients (creatinine clearance less than 30 mL/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 Populations, (8.7). 2.5 Patients on Antiepileptic Drugs (AEDs) Patients on valproate should begin at a BANZEL dose lower than 10 mg/kg/day (children) or 400 mg/day (adults). For effects of other AEDs on BANZEL see Drug Interactions (7.2). 4 CONTRAINDICATIONS BANZEL is contraindicated in patients with Familial Short QT syndrome see Warnings and Precautions (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 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different 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 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43, compared to 0.24 among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients 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 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks 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 (5-100 years) in the clinical trials analyzed. Table 1 shows absolute and relative risk by indication for all evaluated AEDs. Table 1: Absolute and Relative Risk of Suicidal Behavior and Ideation IndicationPlacebo Patients with Events Per 1000 Patients Drug Patientswith Events Per 1000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events Per 1000 Patients Epilepsy1.03.43.52.4 Psychiatric5.78.51.52.9 Other1.01.81.90.9 Total2.44.31.81.9 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 = 20 msec, for doses = 2400 mg twice daily) with BANZEL treatment. In a placebo-controlled study of the QT interval, a higher percentage of BANZEL-treated subjects (46 at 2400 mg, 46 at 3200 mg, and 65 at 4800 mg) had a QT shortening of greater than 20 msec at Tmax compared to placebo (5 – 10). Reductions of the QT interval below 300 msec were not observed in the formal QT studies with doses up to 7200 mg/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 300 msec. 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 day 29 of Banzel therapy and extending over a course of 30 days of continued Banzel therapy with resolution 11 days 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 12 years 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. In addition, rare cases of DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) and Stevens-Johnson syndrome have been reported in association with rufinamide therapy post marketing. If an antiepileptic drug hypersensitivity syndrome is suspected, rufinamide 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 64 patients 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 635 patients in the placebo-treated patients. 5.7 Laboratory Tests Leucopenia (white cell count < 3X109 L) 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 4 years 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 3200 mg/day) with a higher frequency than in placebo were: headache, dizziness, fatigue, somnolence, and nausea. Table 2 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 45 mg/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 2: Incidence () of Treatment-Emergent Adverse Reactions in all Pediatric Double-Blind Adjunctive Trials by Preferred Term at the Recommended Dose of 45 mg/kg/day (Adverse Reactions occurred in at least 3 of BANZEL-treated patients and occurred more frequently than in Placebo Patients) Preferred Term (BANZEL N=187 vs Placebo N=182) Somnolence (17 vs 9), vomiting (17 vs 7), headache (16 vs 8), fatigue (9 vs 8), dizziness (8 vs 6), nausea (7 vs 3), influenza (5 vs 4), nasopharyngitis (5 vs 3), decreased appetite (5 vs 2), rash (4 vs 2), ataxia (4 vs 1), diplopia (4 vs 1), bronchitis (3 vs 2), sinusitis (3 vs 2), psychomotor hyperactivity (3 vs 1), abdominal pain upper (3 vs 2), aggression (3 vs 2), ear infection (3 vs 1), disturbance in attention (3 vs 1), and pruritis (3 vs 0) Table 3 lists treatment-emergent adverse reactions that occurred in at least 3 of adult patients with epilepsy treated with BANZEL (up to 3200 mg/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 3200 mg/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. Table 3: Incidence () of Treatment-Emergent Adverse Reactions in all Adult Double-Blind Adjunctive Trials (up to 3200 mg/day) by Preferred Term (Adverse Reactions occurred in at least 3 of BANZEL-treated patients and occurred more frequently than in Placebo Patients) Preferred Term (BANZEL N=823 vs Placebo N=376) Headache (27 vs 26), dizziness (19 vs 12), fatigue (16 vs 10), nausea (12 vs 9), somnolence (11 vs 9), diplopia (9 vs 3), tremor (6 vs 5), nystagmus (6 vs 5), vision blurred (6 vs 2), vomiting (5 vs 4), ataxia (4 vs 0), abdominal pain upper (3 vs 2), anxiety (3 vs 2), constipation (3 vs 2), dyspepsia (3 vs 2), back pain (3 vs 1), gait disturbance (3 vs 1), and vertigo (3 vs 1) 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 Table 4. Table 4: Adverse Reactions Most Commonly Leading to Discontinuation in Double-Blind Adjunctive Trials (At The Recommended Dose of 45 mg/kg/day) in Pediatric Patients Preferred Term (BANZEL N=187 vs Placebo N=182) 04-11321R1BANBSUpdate.indd 17/30/13 3:07 PM K Cosmos Communications 1 9 js 28374a07.10.14133 Q1Q2</p> <UL><LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/1/1/">Front-Cover</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/2/2/">Inside-Front-Cover</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/3/3/">Page-3</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/4/4/">Page-4</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/5/5/">Page-5</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/6/6/">Page-6</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/7/7/">Page-7</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/8/8/">Page-8</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/9/9/">Page-9</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/10/10/">Page-10</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/11/11/">Page-11</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/12/12/">Page-12</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/13/13/">Page-13</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/14/14/">Page-14</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/15/15/">Page-15</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/16/16/">Page-16</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/17/17/">Page-17</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/18/18/">Page-18</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/19/19/">Page-19</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/20/20/">Page-20</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/21/21/">Page-21</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/22/22/">Page-22</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/23/23/">Page-23</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/24/24/">Page-24</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/25/25/">Page-25</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/26/26/">Page-26</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/27/27/">Page-27</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/28/28/">Page-28</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/29/29/">Page-29</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/30/30/">Page-30</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/31/31/">Page-31</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/32/32/">Page-32</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/33/33/">Page-33</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/34/34/">Page-34</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/35/35/">Page-35</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/36/36/">Page-36</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/37/37/">Page-37</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/38/38/">Page-38</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/39/39/">Back-Cover</a></LI> <LI><a href="http://www.mzines.net/publications/704/x/sitemap.xml" target="_blank">site map</a></LI> </UL>

 

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