BANZEL

PATIENT INFORMATION

BANZEL
(ban-‘zel)
[rufinamide]
Tablets and Oral Suspension

Read this Medication Guide before you start taking BANZEL and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.

What is the most important information I should know about BANZEL?

Do not stop taking BANZEL without first talking to your healthcare provider.

Stopping BANZEL suddenly can cause serious problems.

BANZEL can cause serious side effects, including:

1. Like other antiepileptic drugs, BANZEL may cause suicidal thoughts or actions in a very small number of people, about 1 in 500.

Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:

• thoughts about suicide or dying
• attempt to commit suicide
• new or worse depression
• new or worse anxiety
• feeling agitated or restless
• panic attacks
• trouble sleeping (insomnia)
• new or worse irritability
• acting aggressive, being angry, or violent
• acting on dangerous impulses
• an extreme increase in activity and talking (mania)
• other unusual changes in behavior or mood
• Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.

How can I watch for early symptoms of suicidal thoughts and actions?

• Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.
• Keep all follow-up visits with your healthcare provider as scheduled.

Call your healthcare provider between visits as needed, especially if you are worried about symptoms.

Do not stop BANZEL without first talking to a healthcare provider.

• Stopping BANZEL suddenly can cause serious problems. Stopping a seizure medicine suddenly in a patient who has epilepsy can cause seizures that will not stop (status epilepticus).

2. BANZEL may cause you to feel sleepy, tired, weak, dizzy, or have problems with coordination and walking.

What is BANZEL?

BANZEL is a prescription medicine used with other medicines to treat seizures associated with Lennox-Gastaut Syndrome (LGS) in adults and pediatric patients 1 year of age and older.

It is not known if BANZEL is safe and effective in the treatment of Lennox-Gastaut Syndrome in pediatric patients under 1 year of age.

Who should not take BANZEL?

Do not take BANZEL if you have a genetic condition called familial short QT syndrome, a problem that affects the electrical system of the heart.

What should I tell my healthcare provider before taking BANZEL?

Before you take BANZEL, tell your healthcare provider if you:

• have heart problems
• have liver problems
• have any other medical problems
• have or have had suicidal thoughts or actions, depression or mood problems
• are pregnant or plan to become pregnant. It is not known if BANZEL can harm your unborn baby. Tell your healthcare provider right away if you become pregnant while taking BANZEL. You and your healthcare provider will decide if you should take BANZEL while you are pregnant.
• BANZEL may make certain types of birth control less effective. Talk to your healthcare provider about the best birth control methods for you while you take BANZEL.
  • If you become pregnant while taking BANZEL, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic medicines during pregnancy.
• are breastfeeding or plan to breastfeed. It is not known if BANZEL will pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you take BANZEL.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.

Taking BANZEL with certain other medicines can cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider.

Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist each time you get a new medicine.

How should I take BANZEL?

• Take BANZEL exactly as your healthcare provider tells you. Your healthcare provider will tell you how much BANZEL to take.
• Your healthcare provider may change your dose. Do not change your dose of BANZEL without talking to your healthcare provider.
• Take BANZEL with food.
• BANZEL tablets can be swallowed whole, cut in half or crushed.
• If you take BANZEL Oral Suspension instead of BANZEL tablets, shake the bottle well before you take each dose. Measure your dose of BANZEL Oral Suspension using the bottle adapter and dosing syringes provided.

See the complete Instructions for Use below for information on how to use the dosing syringes and measure your dose of BANZEL Oral Suspension.

• If you take too much BANZEL, call your local Poison Control Center or get emergency medical help right away.

What should I avoid while taking BANZEL?

• Do not drink alcohol or take other medicines that make you sleepy or dizzy while taking BANZEL until you talk to your healthcare provider. BANZEL taken with alcohol or medicines that cause sleepiness or dizziness may make your sleepiness or dizziness worse.
• Do not drive, operate heavy machinery, or do other dangerous activities until you know how BANZEL affects you. BANZEL can slow your thinking and motor skills.

What are the possible side effects of BANZEL?

See “What is the most important information I should know about BANZEL?”

BANZEL may cause serious side effects including:

• BANZEL can also cause allergic reactions or serious problems which may affect organs and other parts of your body like the liver or blood cells. You may or may not have a rash with these types of reactions.

Call your healthcare provider right away if you have any of the following. Symptoms may include:

• swelling of your face, eyes, lips, or tongue
• trouble swallowing or breathing
• a skin rash
• hives
• fever, swollen glands, or sore throat that do not go away or come and go
• swollen glands
• yellowing of your skin or eyes
• dark urine
• unusual bruising or bleeding
• severe fatigue or weakness
• severe muscle pain
• your seizures happen more often or become worse

Call your healthcare provider right away if you have any of the symptoms listed above.

The most common side effects of BANZEL include:

• headache
• dizziness
• tiredness
• sleepiness
• nausea
• vomiting

Tell your healthcare provider about any side effect that bothers you or that does not go away. These are not all of the possible side effects of BANZEL. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store BANZEL?

• Store BANZEL tablets and oral suspension at 59°F to 86°F (15°C to 30°C).

Tablets

• Keep BANZEL tablets in a dry place.

Oral Suspension

• Replace the cap securely after opening.
• Keep BANZEL Oral Suspension in an upright position.
• Use BANZEL Oral Suspension within 90 days of first opening the bottle.

Keep BANZEL and all medicines out of the reach of children.

General Information about the safe and effective use of BANZEL

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use BANZEL for a condition for which it was not prescribed. Do not give BANZEL to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about BANZEL. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about BANZEL that is written for health professionals.

For more information, go to www.banzel.com or call 1-888-274-2378.

What are the ingredients in BANZEL?

Tablets

Active ingredient: rufinamide

Inactive ingredients: colloidal silicon dioxide, corn starch crosscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulphate, iron oxide red, polyethylene glycol, talc, and titanium dioxide.

Oral Suspension

Active ingredient: rufinamide

Inactive ingredients: microcrystalline cellulose and carboxymethylcellulose sodium, hydroxyethylcellulose, anhydrous citric acid, simethicone emulsion 30%, poloxamer 188, methylparaben, propylparaben, propylene glycol, potassium sorbate, noncrystallizing sorbitol solution 70%, orange flavor.

The oral suspension does not contain lactose or gluten and is dye-free. The oral suspension does contain carbohydrates.

Instructions for Use

BANZEL
(ban-‘zel)
[rufinamide]
Oral Suspension

Read the Instructions for Use before using BANZEL Oral Suspension and each time you get a refill. There may be new information. This leaflet does not take the place of talking with the doctor about your medical condition or treatment.

Prepare the BANZEL Oral Suspension dose

You will need the following supplies: See Figure A

• BANZEL Oral Suspension bottle
• Bottle adapter
• Dosing syringe (2 dosing syringes are included in the BANZEL Oral Suspension box)

Figure A

Your total daily dose of BANZEL Oral Suspension is ………. mL.

Take BANZEL in 2 equally divided doses:

Morning dose = ………. mL Evening dose = ………. mL

Note: The doctor may change your dose, especially when you are first starting BANZEL Oral Suspension.

If your morning and evening doses are more than 20 mL each, measure each dose using either:

• 2 syringes, or
• 1 syringe, taking two steps to draw up the medicine in that same syringe

Step 1. Remove the BANZEL Oral Suspension bottle, bottle adapter, and 2 syringes from the box. See Figure A

Step 2. Shake the bottle well before each use. See Figure B

Figure B

Step 3. Uncap the bottle and insert the bottle adapter into the bottle. See Figure C

Figure C

Once the bottle adapter is installed, it cannot be removed. See Figure D

Figure D

Step 4. Check the morning or evening dose in milliliters (mL) as prescribed by your doctor. Locate this number on the syringe. See Figure E

Figure E

Step 5. Insert the syringe into the upright bottle and push the plunger all the way down. See Figure F

Figure F

Step 6. With the syringe in place, turn the bottle upside down. Pull the plunger to the number of mL needed (the amount of liquid medicine in Step 4). See Figure G

Figure G

Measure the mLs of medicine from the white layer at the end of the plunger, not the black layer. See Figure H

Figure H

Step 7. If the dose is more than 20 mL, you can either use:

• 2 syringes, or
• 1 syringe, taking two steps to draw up the medicine in that same syringe

For example:

If your dose is 30 mL, draw up 20 mL in the first syringe and the remaining 10 mL in the second syringe.

or

If your dose is 30 mL, draw up 20 mL in the single syringe and squirt the medicine into your mouth, then draw up the remaining 10 mL in that same syringe.

Repeat Steps 4 through 6 when drawing up the remaining dose of medicine, if your dose is more than 20 mL.

Step 8. Remove the syringe from the bottle adapter.

Step 9. Slowly squirt BANZEL directly into the corner of your mouth. If you need 2 syringes for your dose, slowly squirt the medicine from the first syringe into your mouth, then slowly squirt the medicine from the second syringe into your mouth. See Figure I

Figure I

Step 10. Rinse the syringe (or syringes) with tap water after each use. See Figure J

• Fill a cup with water
• Pull back on the plunger and draw the water from the cup into the syringe
• Push on the plunger to release the water into the sink

Figure J

DESCRIPTION

Banzel (rufinamide) is a triazole derivative structurally unrelated to currently marketed antiepileptic drugs (AEDs). Rufinamide has the chemical name 1-[(2,6-difluorophenyl)methyl]-1H-1,2,3-triazole-4 carboxamide. It has an empirical formula of C₁₀H₈F₂N₄O 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.

INDICATIONS

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.

DOSAGE AND ADMINISTRATION

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.

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 INFORMATION].

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 [see CLINICAL PHARMACOLOGY].

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 Populations].

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 INTERACTIONS].

HOW SUPPLIED

Dosage Forms And Strengths

Film-Coated Tablets

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

Oral Suspension

40 mg/mL.

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).

Storage And Handling

Store the tablets at 25°C (77°F); excursions permitted to 15°- 30°C (59°F – 86°F). Protect from moisture. Replace cap securely after opening.

Store the oral suspension at 25°C (77°F); excursions permitted to 15°- 30°C (59°F – 86°F). Replace cap securely after opening. The cap fits properly in place when the adapter is in place.

SIDE EFFECTS

The following serious adverse reactions are described below and elsewhere in the labeling:

• Suicidal Behavior and Ideation [see WARNINGS AND PRECAUTIONS]
• Central Nervous System Reactions [see WARNINGS AND PRECAUTIONS]
• QT Shortening [see WARNINGS AND PRECAUTIONS]
• Multi-Organ Hypersensitivity/Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see WARNINGS AND PRECAUTIONS]
• Leukopenia [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

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.

Adverse Reactions In Adult And Pediatric Patients Ages 3 To 17 Years Of Age

In the pooled, double-blind, adjunctive therapy studies in adult and pediatric patients ages 3 to 17 years of age, the most common (≥10%) adverse reactions in BANZEL-treated patients, in all doses studied (200 to 3200 mg per day) with a higher frequency than in patients on placebo were: headache, dizziness, fatigue, somnolence, and nausea.

Table 2 lists adverse reactions that occurred in at least 3% of pediatric patients (ages 3 to less than 17 years) with epilepsy treated with BANZEL in controlled adjunctive studies and were numerically more common in patients treated with BANZEL than in patients on placebo.

At the target dose of 45 mg/kg per day for adjunctive therapy in pediatric patients (ages 3 to less than 17 years), the most common (≥3%) adverse reactions with an incidence greater than in placebo for BANZEL were somnolence, vomiting, and headache.

Table 2: Adverse Reactions in Pediatric Patients (Ages 3 to less than 17 years) in Pooled Double-Blind Adjunctive Trials

Adverse Reaction	BANZEL (N=187) %	Placebo (N=182) %
Somnolence	17	9
Vomiting	17	7
Headache	16	8
Fatigue	9	8
Dizziness	8	6
Nausea	7	3
Influenza	5	4
Nasopharyngitis	5	3
Decreased Appetite	5	2
Rash	4	2
Ataxia	4	1
Diplopia	4	1
Bronchitis	3	2
Sinusitis	3	2
Psychomotor Hyperactivity	3	1
Upper Abdominal Pain	3	2
Aggression	3	2
Ear Infection	3	1
Disturbance in Attention	3	1
Pruritis	3	0

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

At all doses studied of up to 3200 mg per day given as adjunctive therapy in adults, the most common (≥ 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: Adverse Reactions in Adults in Pooled Double-Blind Adjunctive Trials

Adverse Reaction	Dizziness	Placebo (N=376) %
Headache	27	26
Dizziness	19	12
Fatigue	16	10
Nausea	12	9
Somnolence	11	9
Diplopia	9	3
Tremor	6	5
Nystagmus	6	5
Blurred Vision	6	2
Vomiting	5	4
Ataxia	4	0
Upper Abdominal Pain	3	2
Anxiety	3	2
Constipation	3	2
Dyspepsia	3	2
Back Pain	3	1
Gait Disturbance	3	1
Vertigo	3	1

Discontinuation In Controlled Clinical Studies

In controlled, double-blind, adjunctive clinical studies, 9% of pediatric and adult patients receiving BANZEL as adjunctive therapy and 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 pediatric patients.

In pediatric patients (ages 4 to less than 17 years) double-blind adjunctive clinical studies, 8% of patients receiving BANZEL as adjunctive therapy (at the recommended dose of 45 mg/kg per day) and 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: Most Common Adverse Reactions Leading to Discontinuation in Pediatric Patients (Ages 4 to less than 17 years) in Pooled Double-Blind Adjunctive Trials

Adverse Reaction	BANZEL (N=187) %	Placebo (N=182) %
Convulsion	2	1
Rash	2	1
Fatigue	2	0
Vomiting	1	0

In adult double-blind, adjunctive clinical studies, 10% of patients receiving BANZEL as adjunctive therapy (at doses up to 3200 mg per day) and 6% 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: Most Common Adverse Reactions Leading to Discontinuation in Adult Patients in Pooled Double-Blind Adjunctive Trials

Adverse Reaction	BANZEL (N=823) %	Placebo (N=376) %
Dizziness	3	1
Fatigue	2	1
Headache	2	1
Nausea	1	0
Ataxia	1	0

Pediatric Patients Ages 1 To Less Than 4 Years

In a multicenter, parallel group, open-label study comparing BANZEL (45 mg/kg per day) adjunctive treatment (n=25) to the adjunctive treatment with an AED of the investigator’s choice (n=11) in pediatric patients (1 year to less than 4 years of age) with inadequately controlled Lennox-Gastaut Syndrome, the adverse reaction profile was generally similar to that observed in adults and pediatric patients 4 years of age and older treated with BANZEL. Adverse reactions that occurred in at least 2 (8%) BANZEL-treated patients and with a higher frequency than in the AED comparator group were: vomiting (24%), somnolence (16%), bronchitis (12%), constipation (12%), cough (12%), decreased appetite (12%), rash (12%), otitis media (8%), pneumonia (8%), decreased weight (8%), gastroenteritis (8%), nasal congestion (8%), and pneumonia aspiration (8%).

Other Adverse Reactions Observed During Clinical Trials

BANZEL has been administered to 1978 individuals during all epilepsy clinical trials (placebo-controlled and open-label). Adverse reactions 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 reactions, 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.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of BANZEL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

DRUG INTERACTIONS

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-administered	Influence of Rufinamide on AED concentrationa)	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
Benzodiazepinese)	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 (phenobarbitaltype 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.

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, CLINICAL PHARMACOLOGY].

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, CLINICAL PHARMACOLOGY and PATIENT INFORMATION].

OVERDOSE

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.

CONTRAINDICATIONS

BANZEL is contraindicated in patients with Familial Short QT syndrome [see WARNINGS AND PRECAUTIONS].

CLINICAL PHARMACOLOGY

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 (EC₅₀ of 3.8 μM).

Pharmacokinetics

Overview

BANZEL oral suspension is bioequivalent on a mg per mg basis to BANZEL tablets. BANZEL is well absorbed after oral administration. However, the rate of absorption is relatively slow and the extent of absorption is decreased as dose is increased. The pharmacokinetics does not change with multiple dosing. Most elimination of rufinamide is via metabolism, with the primary metabolite resulting from enzymatic hydrolysis of the carboxamide moiety to form the carboxylic acid. This metabolic route is not cytochrome P450 dependent. There are no known active metabolites. Plasma half-life of rufinamide is approximately 6-10 hours.

Absorption And Distribution

Following oral administration of BANZEL, peak plasma concentrations occur between 4 and 6 hours (Tmax) both under fed and fasted conditions. BANZEL tablets display decreasing bioavailability with increasing dose after single and multiple dose administration. Based on urinary excretion, the extent of absorption was at least 85% following oral administration of a single dose of 600 mg rufinamide tablet under fed conditions.

Multiple dose pharmacokinetics can be predicted from single dose data for both rufinamide and its metabolite. Given the dosing frequency of every 12 hours and the half-life of 6 to 10 hours, the observed steady-state peak concentration of about two to three times the peak concentration after a single dose is expected.

Food increased the extent of absorption of rufinamide in healthy volunteers by 34% and increased peak exposure by 56% after a single dose of 400 mg tablet, although the Tmax was not elevated [see DOSAGE AND ADMINISTRATION].

Only a small fraction of rufinamide (34%) is bound to human serum proteins, predominantly to albumin (27%), giving little risk of displacement drug-drug interactions. Rufinamide was evenly distributed between erythrocytes and plasma. The apparent volume of distribution is dependent upon dose and varies with body surface area. The apparent volume of distribution was about 50 L at 3200 mg per day.

Metabolism

Rufinamide is extensively metabolized but has no active metabolites. Following a radiolabeled dose of rufinamide, less than 2% of the dose was recovered unchanged in urine. The primary biotransformation pathway is carboxylesterase(s) mediated hydrolysis of the carboxamide group to the acid derivative CGP 47292. A few minor additional metabolites were detected in urine, which appeared to be acyl-glucuronides of CGP 47292. There is no involvement of oxidizing cytochrome P450 enzymes or glutathione in the biotransformation process.

Rufinamide is a weak inhibitor of CYP 2E1. It did not show significant inhibition of other CYP enzymes. Rufinamide is a weak inducer of CYP 3A4 enzymes.

Rufinamide did not show any significant inhibition of P-glycoprotein in an in vitro study.

Elimination/Excretion

Renal excretion is the predominant route of elimination for drug related material, accounting for 85% of the dose based on a radiolabeled study. Of the metabolites identified in urine, at least 66% of the rufinamide dose was excreted as the acid metabolite CGP 47292, with 2% of the dose excreted as rufinamide.

The plasma elimination half-life is approximately 6-10 hours in healthy subjects and patients with epilepsy.

Special Populations

Age

Pediatrics

Based on a population analysis which included a total of 115 patients, including 85 pediatric patients (24 patients ages 1 to 3 years, 40 patients ages 4 to 11 years, and 21 patients ages 12 to 17 years), the pharmacokinetics of rufinamide was similar across all age groups.

Elderly

The results of a study evaluating single-dose (400 mg) and multiple dose (800 mg per day for 6 days) pharmacokinetics of rufinamide in 8 healthy elderly subjects (65-80 years old) and 7 younger healthy subjects (18-45 years old) found no significant age-related differences in the pharmacokinetics of rufinamide.

Sex

Population pharmacokinetic analyses of females show a 6-14% lower apparent clearance of rufinamide compared to males. This effect is not clinically important.

Race

In a population pharmacokinetic analysis of clinical studies, no difference in clearance or volume of distribution of rufinamide was observed between the black and Caucasian subjects, after controlling for body size. Information on other races could not be obtained because of smaller numbers of these subjects.

Renal Impairment

Rufinamide pharmacokinetics in 9 patients with severe renal impairment (creatinine clearance < 30 mL per min) was similar to that of healthy subjects. Patients undergoing dialysis 3 hours post rufinamide dosing showed a reduction in AUC and Cmax by 29% and 16%, respectively.

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 a population pharmacokinetic analysis, rufinamide clearance was decreased by valproate. In pediatric patients, valproate administration may lead to elevated levels of rufinamide by up to 70% [see DRUG INTERACTIONS].

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.

• Co-administration and pre-treatment of BANZEL (400 mg twice daily) and triazolam resulted in a 37% decrease in AUC and a 23% decrease in Cmax of triazolam, a CYP 3A4 substrate.
• Co-administration of BANZEL (800 mg twice daily 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 [see DRUG INTERACTIONS and Use In Specific Populations].

Rufinamide is metabolized by carboxylesterases. Drugs that may induce the activity of carboxylesterases may increase the clearance of rufinamide. Broadspectrum 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.

Clinical Studies

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.