rufinamide 200 MG Oral Tablet [Banzel]
Generic Name: RUFINAMIDE
Brand Name: Banzel
- Substance Name(s):
- RUFINAMIDE
DRUG INTERACTIONS
7 D RUG INTERACTION S Patients on valproate should begin at a BANZEL dose lower than 10 mg/kg per day (pediatric patients) or 400 mg per day (adults) ( 7.2 ) Hormonal contraceptives may be less effective with BANZEL; use additional non-hormonal forms of contraception ( 7.3 ) 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 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 BANZEL with other AEDs.
Table 6: Summary of drug-drug interactions of BANZEL 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 BANZEL concentrations at the maximum recommended dose of BANZEL.
b) Maximum changes predicted to be in pediatric patients and in adult patients who achieve significantly higher levels of BANZEL, 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 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 (C avss 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 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 per day (pediatric patients) or 400 mg per day (adults) [ see Dosage and Administration ( 2.5 ) , Clinical Pharmacology ( 12.3 ) ] .
7.3 Effects of BANZEL on Hormonal Contraceptives 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 Use in Specific Populations ( 8.3 ), Clinical Pharmacology ( 12.3 ) and Patient Counseling Information ( 17 ) ] .
OVERDOSAGE
10 O VERDOSAGE 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 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 patient’s clinical state.
DESCRIPTION
11 BANZEL (rufinamide) is a triazole derivative structurally unrelated to currently marketed antiepileptic drugs (AEDs).
Rufinamide has the chemical name 1-[(2,6-difluorophenyl)methyl]-1 H -1,2,3-triazole-4 carboxamide.
It has an empirical formula of C 10 H 8 F 2 N 4 O and a molecular weight of 238.2.
The drug substance is a white, crystalline, odorless, and slightly bitter tasting neutral powder.
Rufinamide is practically insoluble in water, slightly soluble in tetrahydrofuran and in methanol, and very slightly soluble in ethanol and in acetonitrile.
BANZEL is available for oral administration in film-coated tablets, scored on both sides, containing 200 and 400 mg of rufinamide.
Inactive ingredients are colloidal silicon dioxide, corn starch crosscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulphate.
The film coating contains hypromellose, iron oxide red, polyethylene glycol, talc, and titanium dioxide.
BANZEL is also available for oral administration as a liquid containing rufinamide at a concentration of 40 mg/mL.
Inactive ingredients include microcrystalline cellulose and carboxymethylcellulose sodium, hydroxyethylcellulose, anhydrous citric acid, simethicone emulsion 30%, poloxamer 188, methylparaben, propylparaben, propylene glycol, potassium sorbate, noncrystallizing sorbitol solution 70%, and an orange flavor.
BANZEL (rufinamide)
CLINICAL STUDIES
14 Adult and Pediatric Patients ages 4 years and older The effectiveness of BANZEL as adjunctive treatment for the seizures associated with Lennox-Gastaut Syndrome (LGS) in adult and pediatric patients ages 4 years and older was established in a single multicenter, double-blind, placebo-controlled, randomized, parallel-group study (N=138).
Male and female patients (between 4 and 30 years of age) were included if they had a diagnosis of inadequately controlled seizures associated with LGS (including both atypical absence seizures and drop attacks) and were being treated with 1 to 3 concomitant stable dose AEDs.
Each patient must have had at least 90 seizures in the month prior to study entry.
After completing a 4-week Baseline Phase on stable therapy, patients were randomized to have BANZEL or placebo added to their ongoing therapy during the 12 -week Double-blind Phase.
The Double-blind Phase consisted of 2 periods: the Titration Period (1 to 2 weeks) and the Maintenance Period (10 weeks).
During the Titration Period, the dose was increased to a target dosage of approximately 45 mg/kg per day (3200 mg in adults of > 70 kg), given on a twice daily schedule.
Dosage reductions were permitted during titration if problems in tolerability were encountered.
Final doses at titration were to remain stable during the maintenance period.
Target dosage was achieved in 88% of the BANZEL-treated patients.
The majority of these patients reached the target dose within 7 days, with the remaining patients achieving the target dose within 14 days.
The primary efficacy variables were: The percent change in total seizure frequency per 28 days; The percent change in tonic-atonic (drop attacks) seizure frequency per 28 days; Seizure severity from the Parent/Guardian Global Evaluation of the patient’s condition.
This was a 7-point assessment performed at the end of the Double-blind Phase.
A score of +3 indicated that the patient’s seizure severity was very much improved, a score of 0 that the seizure severity was unchanged, and a score of -3 that the seizure severity was very much worse.
The results of the three primary endpoints are shown in Table 7 below.
Table 7: Lennox-Gastaut Syndrome Trial Seizure Frequency Primary Efficacy Variable Results Variable Placebo Rufinamide Median percent change in total seizure frequency per 28 days -11.7 -32.7 (p=0.0015) Median percent change in tonic-atonic seizure frequency per 28 days 1.4 -42.5 (p<0.0001) Improvement in Seizure Severity Rating from Global Evaluation 30.6 53.4 (p=0.0041) Pediatric Patients ages 1 to less than 4 years The effectiveness of BANZEL as adjunctive treatment for the seizures associated with Lennox-Gastaut Syndrome in pediatric patients ages 1 year to less than 4 years was established based on a single multi-center, open-label, active-controlled, randomized, pharmacokinetic bridging study.
The pharmacokinetic profile of BANZEL is not significantly affected by age either as a continuous covariate (1 to 35 years) or as a categorical covariate (age categories: 1 to less than 4 years and 4 years of age and older), after body weight is taken into consideration.
HOW SUPPLIED
16 H OW S UPPLIED /S TORAGE AND H ANDLING Tablet Imprint 16.1 How Supplied BANZEL 200 mg tablets (containing 200 mg rufinamide) are pink in color, film-coated, oblong-shape tablets, with a score on both sides, imprinted with “ 262” on one side.
They are available in bottles of 120 (NDC 62856-582-52).
BANZEL 400 mg tablets (containing 400 mg rufinamide) are pink in color, film-coated, oblong-shape tablets, with a score on both sides, imprinted with “ 263” on one side.
They are available in bottles of 120 (NDC 62856-583-52).
BANZEL oral suspension is an orange flavored liquid supplied in a polyethylene terephthalate (PET) bottle with child-resistant closure.
The oral suspension is packaged with a dispenser set which contains a calibrated oral dosing syringe and an adapter.
Store the oral suspension in an upright position.
Use within 90 days of first opening the bottle, then discard any remainder.
The oral suspension is available in bottles of 460 mL (NDC 62856-584-46).
16.2 Storage and Handling Store the tablets at 25ºC (77ºF); excursions permitted to 15º- 30ºC (59ºF – 86ºF).
Protect from moisture.
Replace cap securely after opening.
Store the oral suspension at 25ºC (77ºF); excursions permitted to 15º- 30ºC (59ºF – 86ºF).
Replace cap securely after opening.
The cap fits properly in place when the adapter is in place.
GERIATRIC USE
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 [ s ee Clinical Pharmacology ( 12.3 ) ] .
DOSAGE FORMS AND STRENGTHS
3 Film-coated Tablets: 200 mg (pink) and 400 mg (pink).
Tablets are scored on both sides.
Oral Suspension: 40 mg/mL.
White to off-white opaque liquid.
Film-coated tablets: 200 mg (pink), 400 mg (pink) ( 3 ) Oral suspension: 40 mg/mL ( 3 )
MECHANISM OF ACTION
12.1 Mechanism of Action The precise mechanism(s) by which rufinamide exerts its antiepileptic effect is unknown.
The results of in vitro studies suggest that the principal mechanism of action of rufinamide is modulation of the activity of sodium channels and, in particular, prolongation of the inactive state of the channel.
Rufinamide (≥ 1 μM) significantly slowed sodium channel recovery from inactivation after a prolonged prepulse in cultured cortical neurons, and limited sustained repetitive firing of sodium-dependent action potentials (EC 50 of 3.8 μM).
INDICATIONS AND USAGE
1 I NDICATIONS AND USAGE BANZEL is indicated for adjunctive treatment of seizures associated with Lennox-Gastaut Syndrome in pediatric patients 1 year of age and older and in adults.
BANZEL 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 ( 1 )
PEDIATRIC USE
8.4 Pediatric Use Safety and effectiveness have been established in pediatric patients 1 to 17 years of age.
The effectiveness of BANZEL in pediatric patients 4 years of age and older was based upon an adequate and well-controlled trial of BANZEL 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 [see Dosage and Administration ( 2.1 ), Adverse Reactions ( 6.1 ), and Clinical Studies ( 14 )].
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 [ see Clinical Pharmacology ( 12.3 ) ] .
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.
PREGNANCY
8.1 P regnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, such as BANZEL, during pregnancy.
Encourage women who are taking BANZEL 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 BANZEL in pregnant women.
In animal reproduction studies, oral administration of rufinamide resulted in developmental toxicity in pregnant rats and rabbits at clinically relevant doses [see Data ] .
In the U.S.
general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, 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.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Monitor patients for new or worsening depression, suicidal thoughts/behavior, and unusual changes in mood or behavior ( 5.1 ) Central nervous system reactions can occur ( 5.2 ) Use caution when administering BANZEL with other drugs that shorten the QT interval ( 5.3 ) Discontinue BANZEL if multi-organ hypersensitivity reaction occurs ( 5.4 ) Withdraw BANZEL gradually to minimize the risk of precipitating seizures, seizure exacerbation, or status epilepticus ( 5.5 ) 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 1 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 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 Risk Difference: Additional Drug Patients with Events Per 1000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 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.
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, consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
5.2 C entral Nervous System Reactions Use of BANZEL has been associated with central nervous system-related adverse reactions in the controlled clinical trial of patients 4 years or older with Lennox-Gastaut Syndrome.
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.
Somnolence was reported in 24% of BANZEL-treated patients compared to 13% of patients on placebo, and led to study discontinuation in 3% of BANZEL-treated patients compared to 0% of patients on placebo.
Fatigue was reported in 10% of BANZEL-treated patients compared to 8% of patients on placebo.
It led to study discontinuation in 1% of BANZEL-treated patients and 0% of patients on placebo.
Dizziness was reported in 2.7% of BANZEL-treated patients compared to 0% of patients on placebo, and did not lead to study discontinuation.
Ataxia and gait disturbance were reported in 5.4% and 1.4% of BANZEL-treated patients, respectively, compared to no patient on placebo.
None of these reactions led to study discontinuation.
Accordingly, patients should be advised not to drive or operate machinery until they have gained sufficient experience on BANZEL to gauge whether it adversely affects their ability to drive or operate machinery.
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.
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 T max 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 per 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 /Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multi-organ hypersensitivity, has been reported in patients taking antiepileptic drugs, including BANZEL.
DRESS may be fatal or life-threatening.
DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection.
Eosinophilia is often present.
It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident.
Because this disorder is variable in its expression, other organ systems not noted here may be involved.
All cases of DRESS identified in clinical trials with BANZEL occurred in pediatric patients less than 12 years of age, occurred within 4 weeks of treatment initiation, and resolved or improved with BANZEL discontinuation.
DRESS has also been reported in adult and pediatric patients taking BANZEL in the postmarketing setting.
If DRESS is suspected, the patient should be evaluated immediately, BANZEL should be discontinued, and alternative treatment should be started.
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 2 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 Leukopenia BANZEL has been shown to reduce white cell count.
Leukopenia (white cell count < 3X10 9 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.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Medication Guide and Instructions for Use ).
Administration Information Advise patients to take BANZEL with food [see Dosage and Administration ( 2.2 )] .
Advise patients who are prescribed the oral suspension to shake the bottle vigorously before every administration and to use the adaptor and oral dosing syringe [see Dosage and Administration ( 2.2 )] .
Suicidal Thinking and Behavior Inform patients, their caregivers, and families 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 [see Warnings and Precautions ( 5.1 )] .
Central Nervous System Reactions Inform patients about the potential for somnolence or dizziness and advise them 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 [see Warnings and Precautions ( 5.2 )] .
Multi-Organ Hypersensitivity Reactions Advise patients to notify their physician if they experience a rash associated with fever [see Warnings and Precautions ( 5.4 )] .
Drug Interactions Inform female patients of childbearing age that the concurrent use of BANZEL with hormonal contraceptives may render this method of contraception less effective.
Recommend patients use additional non-hormonal forms of contraception when using BANZEL [see Drug Interactions ( 7.3 ) and Use in Specific Populations ( 8.3 ) ] .
Inform patients that alcohol in combination with BANZEL may cause additive central nervous system effects.
Pregnancy Advise patients to notify their physician if they become pregnant or intend to become pregnant during therapy.
Encourage patients 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 ) ] .
Breast-feeding Advise patients to notify their physician if they are breast-feeding or intend to breast-feed [see Use in Specific Populations ( 8.2 )] .
DOSAGE AND ADMINISTRATION
2 BANZEL should be given with food.
Tablets can be administered whole, as half tablets, or crushed ( 2.2 ) Measure oral suspension using provided adapter and dosing syringe ( 2.2 ) Pediatric patients 1 year and older: Starting daily dose: 10 mg/kg per day in two equally divided doses ( 2.1 ) Increase by 10 mg/kg increments every other day to maximum dose of 45 mg/kg per day, not to exceed 3200 mg per day, in two divided doses ( 2.1 ) Adults: Starting daily dose: 400-800 mg per day in two equally divided doses ( 2.1 ) Increase by 400-800 mg every other day until a maximum dose of 3200 mg per day, in two divided doses, is reached ( 2.1 ) 2.1 Dosage Information Pediatric patients ( 1 year to less than 17 years) The recommended starting daily dose of BANZEL 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 BANZEL 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 400-800 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.
2.2 Administration Information Administer BANZEL with food.
BANZEL film-coated tablets can be administered whole, as half tablets or crushed.
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 Patient Counseling Information ( 17 )] .
2.
3 Dosing in 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 [s ee Clinical Pharmacology ( 12.3 ) ] .
2.
4 Dosing in 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 s ( 8.7 ) ] .
2.
5 Dosing in Patients Taking Valproate Patients taking valproate should begin BANZEL at a dose lower than 10 mg/kg per day in pediatric patients or 400 mg per day in adults [ see Drug Int eractions ( 7.2 ) ] .