• Withdrawal of AEDs. BANZEL should be withdrawn gradually to
`
`
`minimize the risk of precipitating seizures, seizure exacerbation, or
`status epilepticus. (5.5)
`Status Epilepticus (5.6)
`
`
`
`
`•
`
`------------------------------ADVERSE REACTIONS-------------------------------
`
`In all patients with epilepsy treated with BANZEL in double-blind,
`•
`adjunctive therapy studies, the most commonly observed adverse
`reactions (≥ 10% and greater than placebo) were headache, dizziness,
`fatigue, somnolence, and nausea (6.1)
`
`
`
`
`
`
`•
`
`
`•
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Eisai, Inc. at
`1-888-274-2378 or www.banzel.com or FDA at 1-800-FDA-1088 or
`
`
`www.fda.gov/medwatch.
`
`
`------------------------------DRUG INTERACTIONS-------------------------------
`See Full Prescribing Information for effects of BANZEL on other AEDs (7.1),
`effects of other AEDs on BANZEL (7.2), and effects of BANZEL on other
`medication (7.3)
`
`
`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 on
`
`valproate should begin at a BANZEL dose lower than 10 mg/kg/day
`(children) or 400 mg/day (adults). (7.2)
`
`
`
`Other AEDs can influence rufinamide concentrations. This effect is
`
`more pronounced in children than adults (7.1)
`
`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. (7.3)
`
`
`•
`
`
`-----------------------USE IN SPECIFIC POPULATIONS------------------------
`
`Pregnancy: To enroll in the North American Antiepileptic Drug
`
`•
`Pregnancy Registry call 1-888-233-2334, toll free (8.1)
`Renal impairment: Renally impaired patients (creatinine clearance less
`
`than 30 mL/min) do not require any specific dosage change. (2.2)
`
`
`Adjusting the BANZEL dose for the loss of drug upon dialysis should be
`considered. (8.6)
`
`• Hepatic impairment: Use in patients with severe hepatic impairment is
`
`
`not recommended. Caution should be exercised in treating patients with
`
`mild to moderate hepatic impairment. (8.7)
`
`
`for PATIENT COUNSELING
`17
`See
`MEDICATION GUIDE
`
`
`
`
`
`-----------------------WARNINGS AND PRECAUTIONS-----------------------­
`
`Suicidal behavior and ideation. (5.1)
`
`•
`Patients should be advised that BANZEL can cause Central Nervous
`•
`System Reactions (5.2)
`
`
`
`Caution should be used when administering BANZEL with other drugs
`that shorten the QT interval. (5.3)
`
`• Multi-organ Hypersensitivity Reactions have occurred in association
`with BANZEL. If this reaction is suspected, BANZEL should be
`discontinued and alternative treatment started. (5.4)
`______________________________________________________________________________________________________________________________________
`
`INFORMATION
`
`and
`
`
`
`Revised: October 2010
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`8.2 Labor and Delivery
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Renal Impairment
`8.7 Hepatic Impairment
`
`9 DRUG ABUSE AND DEPENDENCE
`
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`12.3 Pharmacokinetics
`
`13 NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`14 CLINICAL STUDIES
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`
`17.1 Suicidal Thinking and Behavior
`
`
`
`
`
`
`
`*Sections or subsections omitted from the full prescribing information are not
`listed
`
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`
` BANZEL® safely and effectively. See full prescribing information for
`BANZEL®.
`
`
`BANZEL® (rufinamide) Tablet, Film Coated for Oral Use
`
`
`Initial U.S. Approval: 2008
`
`----------------------------INDICATIONS AND USAGE---------------------------
`BANZEL (rufinamide) is an anti-epileptic drug indicated for:
`
`
`Adjunctive treatment of seizures associated with Lennox-Gastaut
`•
`
`syndrome (LGS) in children 4 years and older and adults. (1)
`
`
`•
`
`
`•
`
`
`
`----------------------DOSAGE AND ADMINISTRATION-----------------------
`
`BANZEL should be given with food. Tablets can be administered whole, as
`
`half tablets, or crushed. (2)
`
`Children four years and older with LGS: 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. (2.1)
`
`Adults with LGS: 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
`
`dose of 3200 mg/day, administered in two equally divided doses is
`
`
`
`reached. (2.1)
`See Full Prescribing Information for dosing in patients with renal
`
`
`impairment, (2.2), hemodialysis (2.3), hepatic impairment, (2.4), and for
`
`those patients on valproate. (2.5)
`
`
`---------------------DOSAGE FORMS AND STRENGTHS----------------------
`
`200 mg (pink), 400 mg (pink), film-coated tablets with a score on both
`
`
`
`
`•
`sides. (3)
`
`
` ---------------------CONTRAINDICATIONS----------------------
`
`
`BANZEL is contraindicated in patients with Familial Short QT
`•
`syndrome. (4)
`
`
`
`
`
`
`
`•
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`1
`INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Patients with Lennox-Gastaut Syndrome
`2.2 Patients with Renal Impairment
`2.3 Patients Undergoing Hemodialysis
`2.4 Patients with Hepatic Disease
`2.5 Patients on AEDs
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Suicidal Behavior and Ideation
`
`5.2 Central Nervous System Reactions
`5.3 QT Shortening
`5.4 Multi-organ Hypersensitivity Reactions
`5.5 Withdrawal of AEDs
`5.6 Status Epilepticus
`
`6 ADVERSE REACTIONS
`6.1 Controlled Trials
`6.2 Laboratory Tests
`
`7 DRUG INTERACTIONS
`7.1 Effects of BANZEL on other AEDs
`7.2 Effects of other AEDs on BANZEL
`7.3 Effects of BANZEL on other Medications
`
`
`Reference ID: 2857297
`
`1
`
`ARGENTUM Exhibit 1209
`Argentum Pharmaceuticals LLC v. Research Corporation Technologies, inc.
`IPR2016-00204
`
`Page 00001
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`

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`
`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.
`
`
`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 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 Population,
`(8.7)].
`
`
`
`2.5 Patients on 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).
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
` 200 mg (pink) and 400 mg (pink) film-coated tablets. Tablets are scored on both sides.
`
`
`4 CONTRAINDICATIONS
`
`
`
`
`
`
`Reference ID: 2857297
`
`
`
`2
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` 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 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
`
`
`
`
`
`
`Indication
`
`Epilepsy
`Psychiatric
`Other
`Total
`
`Placebo
`Patients
`with Events
`Per
`1000 Patients
`
`
`
`
`
`Drug
`Patients
`with Events
`Per
`1000 Patients
`
`Relative Risk:
`Incidence of
`Events in Drug
`Patients/Incidence
`in Placebo Patients
`
`1.0
`5.7
`1.0
`2.4
`
`3.4
`8.5
`1.8
`4.3
`
`3.5
`1.5
`1.9
`1.8
`
`Risk
`Difference:
`Additional
`Drug Patients
`with Events
`Per 1000
`Patients
`2.4
`2.9
`0.9
`1.9
`
`
`
`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.
`
`Reference ID: 2857297
`
`
`
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`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
`
`
`
`
`
`Reference ID: 2857297
`
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`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 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
`
`
`
`
`
`Reference ID: 2857297
`
`
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`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
`
`Somnolence
`Vomiting
`Headache
`Fatigue
`Dizziness
`Nausea
`Influenza
`Nasopharyngitis
`Decreased Appetite
`Rash
`Ataxia
`Diplopia
`Bronchitis
`Sinusitis
`Psychomotor Hyperactivity
`Abdominal Pain Upper
`Aggression
`Ear Infection
`
`
`BANZEL
`(N=187)
`%
`
`17
`17
`16
`9
`8
`7
`5
`5
`5
`4
`4
`4
`3
`3
`3
`3
`3
`3
`
`Placebo
`(N=182)
`%
`
`9
`7
`8
`8
`6
`3
`4
`3
`2
`2
`1
`1
`2
`2
`1
`2
`2
`1
`
`Reference ID: 2857297
`
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`3
`3
`
`1
`0
`
`Disturbance in Attention
`Pruritis
`
`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 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 3200mg/day) by Preferred Term (Adverse Reactions occurred in at
`least 3% of BANZEL-treated patients and occurred more frequently than in Placebo Patients)
`
`
`Placebo
`(N=376)
`%
`
`26
`12
`10
`9
`9
`3
`5
`5
`2
`4
`0
`2
`2
`2
`2
`1
`1
`1
`
`
`BANZEL
`(N=823)
`%
`
`27
`19
`16
`12
`11
`9
`6
`6
`6
`5
`4
`3
`3
`3
`3
`3
`3
`3
`
`Preferred Term
`
`Headache
`Dizziness
`Fatigue
`Nausea
`Somnolence
`Diplopia
`Tremor
`Nystagmus
`Vision Blurred
`Vomiting
`Ataxia
`Abdominal Pain Upper
`Anxiety
`Constipation
`Dyspepsia
`Back Pain
`Gait Disturbance
`Vertigo
`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.
`
`
`Reference ID: 2857297
`
`
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`
`
`
`
`Preferred Term
`
`Table 4: Adverse Reactions Most Commonly Leading to Discontinuation in Double-Blind
`Adjunctive Trials (At The Recommended Dose of 45mg/kg/day) in Pediatric Patients
`Placebo
`BANZEL
`
`(N=182)
`(N=187)
`%
`%
`2
`1
`2
`1
`2
`0
`1
`0
`
`Convulsion
`Rash
`Fatigue
`Vomiting
`
`Preferred Term
`
`Dizziness
`Fatigue
`Headache
`Nausea
`Ataxia
`
`Placebo
`(N=376)
`%
`
`1
`1
`1
`0
`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
`BANZEL
`
`(N=823)
`%
`
`3
`2
`2
`1
`1
`
`
`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.
`
`
`
`7 DRUG INTERACTIONS
`
`
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`Reference ID: 2857297
`
`
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`8
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`Page 00008
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`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
`
`Influence of AED on Rufinamide
`concentration
`
`Decrease by 19 to 26%
`Dependent on dose of carbamazepine
`No Effect
` d)
`Decrease by 25 to 46%c)
`’
`Independent of dose or concentration of
`phenobarbital
`
` d)
`Decrease by 25 to 46%c)
`’
`Independent of dose or concentration of
`phenytoin
`
`No Effect
`Increase by <16 to 70%c)
` Dependent on concentration of valproate
` d)
`Decrease by 25 to 46%c)
`’
`Independent of dose or concentration of
`primidone
`No Effect
`
`
`
`AED
`Co-administered
`Carbamazepine
`
` Influence of Rufinamide on
`
`
` AED concentrationa)
`Decrease by 7 to 13%b)
`
`
`Lamotrigine
`
`Decrease by 7 to 13%b)
`
`
`Phenobarbital
`
`Increase by 8 to 13%b)
`
`
`
`Phenytoin
`
`Increase by 7 to 21%b)
`
`
`
`No Effect
`
`No Effect
`
`Not Investigated
`
`
`Not Investigated
`
`
`
`Topiramate
`
`Valproate
`
`Primidone
`
`Benzodiazepines e)
`
`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.
`
`
`Reference ID: 2857297
`
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` 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 (400mg 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
`
`Reference ID: 28572