BANZEL® (rufinamide)

BANZEL® (rufinamide)

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BANZEL® (rufinamide)

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.

Indication

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

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 M) 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 M).

Dosage and administration

  • BANZEL should be given with food. Tablets can be administered whole, as half tablets, or crushed
  • Measure oral suspension using provided adapter and dosing syringe

Pediatric patients 1 year and older:

  • Starting daily dose: 10 mg/kg per day in two equally divided doses
  • 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

Adults:

  • Starting daily dose: 400-800 mg per day in two equally divided doses
  • Increase by 400-800 mg every other day until a maximum dose of 3200 mg per day, in two divided doses, is reached

Contraindication

BANZEL is contraindicated in patients with Familial Short QT syndrome.

Warnings and precautions

  • 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.
  • Monitor patients for new or worsening depression, suicidal thoughts/behavior, and unusual changes in mood or behavior
  • Central nervous system reactions can occur
  • Use caution when administering BANZEL with other drugs that shorten the QT interval
  • Discontinue BANZEL if multi-organ hypersensitivity reaction occurs
  • Withdraw BANZEL gradually to minimize the risk of precipitating seizures, seizure exacerbation, or status epilepticus.
  • Leukopenia. BANZEL has been shown to reduce white cell count. Leukopenia (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.

Adverse reactions

Most common adverse reactions (≥ 10% and greater than placebo) were headache, dizziness, fatigue, somnolence, and nausea

Drug interaction

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

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)

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.

Use in specific populations

Pregnancy: 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.

Lactation: There are no data on the presence of rufinamide in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for BANZEL and any potential adverse effects on the breastfed infant from BANZEL or from the underlying maternal condition.

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. 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

Safety and effectiveness in pediatric patients below the age of 1 year has not been established.

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.

Renal Impairment: Rufinamide pharmacokinetics in patients with severe renal impairment (creatinine clearance < 30 mL/min) was similar to that of healthy subjects. Dose adjustment in patients undergoing dialysis should be considered

Hepatic Impairment: Use of BANZEL in patients with severe hepatic impairment (Child-Pugh score 10 to 15) is not recommended. Caution should be exercised in treating patients with mild (Child-Pugh score 5 to 6) to moderate (Child-Pugh score 7 to 9) hepatic impairment.

Overdosage

Because strategies for the management of overdose are continually evolving, it is advisable to contact a Certified Poison Control Center to determine the latest recommendations for the management of an overdose of any drug.

One overdose of 7200 mg 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.

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.

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