London, 24 June 2021 – Hikma Pharmaceuticals PLC (Hikma), the multinational pharmaceutical company, announces it launched Rufinamide Tablets, the generic equivalent of Banzel® , through its US affiliate, Hikma Pharmaceuticals USA Inc. The company has launched 200mg and 400mg doses.
24 June 2021
Product, Press Release
Rufinamide is indicated for adjunctive treatment of seizures associated with Lennox-Gastaut Syndrome in paediatric patients 1 year of age and older and in adults.
According to IQVIA, US sales of Rufinamide Tablets, 200mg and 400mg, were approximately $285 million in the 12 months ending April 2021.
“We are proud to be among the first wave of generics to provide this important medicine,” said Brian Hoffmann, President of Hikma Generics. “Hikma also markets Rufinamide Oral Suspension and we are pleased to add this new formulation to our portfolio. This launch demonstrates our ability to successfully deliver on our pipeline and launch new products, improving patients’ access to high-quality generic medicines.”
 Banzel® is a registered trademark of Novartis AG.
Important Safety Information for Rufinamide Tablets, 200mg and 400mg:
Rufinamide is contraindicated in patients with Familial Short QT syndrome and in patients with known hypersensitivity to rufinamide or to any of the excipients used in the formulation.
WARNINGS AND PRECAUTIONS
- Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including rufinamide, 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; median treatment duration of 12 weeks) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk of suicidal thinking or behavior compared to patients randomized to placebo. There were four suicides in the 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.
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 rufinamide or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. For more information, see the full Prescribing Information for rufinamide tablets.
- Central Nervous System Reactions
Use of rufinamide has been associated with central nervous system-related adverse reactions in a 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 disturbance and ataxia.
Patients should be advised not to drive or operate machinery until they have gained sufficient experience on rufinamide to gauge whether it adversely affects their ability to drive or operate machinery
- QT Shortening
Formal cardiac ECG studies demonstrated shortening of the QT interval (mean=20 msec, for doses ≥2400 mg twice daily) with rufinamide.
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 rufinamide 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 rufinamide. Use caution when administering rufinamide with other drugs that shorten the QT interval.
- Multi-organ Hypersensitivity/Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
DRESS, also known as multi-organ hypersensitivity, has been reported in patients taking antiepileptic drugs, including rufinamide. DRESS may be fatal or life-threatening. It is important to note that early manifestations of hypersensitivity may be present even though symptoms are not evident.
If DRESS is suspected, the patient should be evaluated immediately, rufinamide should be discontinued and alternative treatment should be started.
- Withdrawal of AEDs
As with all antiepileptic drugs, rufinamide 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.
- Status Epilepticus
Estimates of the incidence of treatment-emergent status epilepticus among patients treated with rufinamide are difficult because standard definitions were not employed.
In all controlled trials that included patients with different epilepsies, 11 of 1240 (0.9%) rufinamide-treated patients had episodes that could be described as status epilepticus, compared with none of the 635 placebo-treated patients.
Rufinamide has been shown to reduce white cell count.
The following serious adverse reactions are described in the full Prescribing Information for rufinamide tablets:
- Suicidal Behavior and Ideation
- Central Nervous System Reactions
- QT Shortening
- Multi-Organ Hypersensitivity/Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
In the pooled, double-blind, adjunctive therapy studies in adult and pediatric patients ages 3 to 17, the most common (≥10%) adverse reactions in rufinamide-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. For more information, see the full Prescribing Information for rufinamide tablets.
- Effects of Rufinamide 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.
The decrease in clearance of phenytoin estimated at typical rufinamide levels is predicted to increase plasma levels of phenytoin by 7% to 21%. As phenytoin is known to have non-linear pharmacokinetics, it is possible that exposure will be greater than the model prediction.
For more information about the effects of rufinamide on other AEDs, see the full Prescribing Information for rufinamide tablets.
- Effects of Other AEDs on Rufinamide
Potent cytochrome P450 enzyme inducers, such as carbamazepine, phenytoin, primidone and phenobarbital, appear to increase the clearance of rufinamide. Any effects, where they occurred, were likely to be more marked in the pediatric population.
Patients stabilized on rufinamide before being prescribed valproate should begin valproate therapy at a low dose. Similarly, patients on valproate should begin rufinamide therapy at a dose lower than 10 mg/kg/day (pediatric patients) or 400 mg/day (adults).
For more information about the effects of other AEDs on rufinamide, see the full Prescribing Information for rufinamide tablets.
- Effects of Rufinamide on Hormonal Contraceptives
Female patients of childbearing age should be warned that the concurrent use of rufinamide with hormonal contraceptives may render this method of contraception less effective. Additional non-hormonal forms of contraception are recommended when using rufinamide.
USE IN SPECIFIC POPULATIONS
There are no adequate data on the developmental risks associated with use of rufinamide in pregnant women. Encourage women who are taking rufinamide during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 1-888-233-2334 or visiting https://www.aedpregnancyregistry.org/ .
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 rufinamide and any potential adverse effects on the breastfed infant from rufinamide or from the underlying maternal condition.
- Females and Males of Reproductive Potential
Use of rufinamide may reduce the effectiveness of hormonal contraceptives containing ethinyl estradiol or norethindrone. Advise women of reproductive potential taking rufinamide who are using a contraceptive containing ethinyl estradiol and norethindrone to use an additional non-hormonal form of contraception.
The effect of rufinamide on fertility in humans has not been established.
- Pediatric Use
Safety and effectiveness have been established in pediatric patients 1 to 17 years of age. Safety and effectiveness in pediatric patients younger than 1 year have not been established.
- Geriatric Use
Clinical studies of rufinamide did not include sufficient number 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 rufinamide 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.
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 of rufinamide 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 rufinamide. 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.
DOSAGE AND ADMINISTRATION
Paediatric Patients (1 year and older):
The recommended starting daily dose of rufinamide in paediatric 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.
The recommended starting daily dose of rufinamide 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 to 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 rufinamide with food.
- Dosing in Patients Undergoing Dialysis
Consider adjusting the rufinamide dose during hemodialysis, as the dialysis process may reduce exposure to a limited (about 30%) extent.
- Dosing in Patients with Hepatic Disease
The use of rufinamide in patients with severe hepatic impairment is not recommended. Use caution when treating patients with mild to moderate hepatic impairment.
- Dosing in Patients Taking Valproate
Patients taking valproate should begin rufinamide at a lower dose (<10 mg/kg per day in pediatric patients; 400 mg/day in adults).
For more information, please see the full Prescribing Information and Medication Guide.
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit https://www.fda.gov/medwatch or call 1-800-FDA-1088.
Manufactured by: West-Ward Columbus Inc., Columbus, OH 43228
Distributed by: Hikma Pharmaceuticals USA Inc., Berkeley Heights, NJ 07922