| Active Ingredient | RUFINAMIDE |
|---|
| Drug Name | FDA Application No. | Company | Dosage Form;Route | Strength | RLD Strength | Original Approval or Tentative Approval Date |
Exclusivity Expiration (NCE) |
Exclusivity Expiration (ODE) |
Chemical Type |
Review Classification |
Marketing Status |
TE Code |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| BANZEL | (NDA) 021911 | EISAI INC | TABLET;ORAL | 200MG, 400MG | 200MG, 400MG (RS) | November 14, 2008 | - | - | 1 New molecular entity (NME) | S Standard review drug | Prescription | None |
| Parameters | Details |
|---|---|
| Structural Formula |
 |
| Chemical Name | 1-[(2,6-difluorophenyl)methyl]-1H-1,2,3-triazole-4 carboxamide |
| CAS No | 106308-44-5 |
| Molecular Formula | C10H8F2N4O |
| Molecular Weight | 238.2 |
| Appearance | white, crystalline, odorless, and slightly bitter tasting neutral powder |
| Solubility | The active substance is chemically stable and neutral - rufinamide does not act as a base or acid in aqueous solution (not dissociating). Rufinamide is practically insoluble in water, aqueous solvent and in gastric and intestinal fluid, slightly soluble in tetrahydrofuran and in methanol, and very slightly soluble in ethanol and in acetonitrile. |
| Water Solubility | 0.642 mg/mL (Predicted) |
| Polymorphism | There are four known polymorphic forms. |
| pKa (Strongest Acidic) | 12.69 (Predicted) |
| pKa (Strongest Basic) | (Predicted) -1.1 |
| Log P | 0.835 |
| Identification | TLC, HPLC-PDA |
| Degradation | Photostability studies were conducted in the upright position, performed using 1.2 million lux hours on bottles without a cover. No changes were observed in the suspension exposed to light. |
| Hygroscopic | Not hygroscopic |
| Photostability study | Photo stable |
| Melting Point | - |
| BCS Class | III |
| Manufacture of API | - |
| Parameters | Details |
|---|---|
| Indications 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. |
| Dosage and Administration |
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. 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. |
| 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). |
| Absorption |
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. 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 Effect | 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. |
| Distribution | 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 invitro study. |
| Elimination | 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. |
| Peak plasma time (Tmax) | 4 and 6 hours |
| Half life | 6- 10 hours |
| Bioavailability | - |
| Age, gender |
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. 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. Population pharmacokinetic analyses of females show a 6-14% lower apparent clearance of rufinamide compared to males. This effect is not clinically important. |
| DMF | Status | Type | Submit Date | Holder |
|---|---|---|---|---|
| 25676 | A | II | January 4, 2012 | AMINO CHEMICALS LTD |
| 26209 | A | II | October 23, 2012 | GLENMARK PHARMACEUTICALS LTD |
| 26316 | A | II | September 10, 2012 | LUPIN LTD |
| 26385 | A | II | September 29, 2012 | MSN LABORATORIES PRIVATE LTD |
| 28284 | I | II | May 9, 2014 | ZHEJIANG JIUZHOU PHARMACEUTICAL CO LTD |
| 29034 | A | II | March 27, 2015 | APOTEX PHARMACHEM INC |
| Parameters | Details | ||
|---|---|---|---|
| Strength | 200MG | 400MG | |
| Excipients used | colloidal silicon dioxide (18mg), corn starch (50mg), crosscarmellose sodium (15mg), hypromellose, lactose monohydrate (100mg), magnesium stearate (7.5mg), microcrystalline cellulose (500mg), and sodium lauryl sulphate (7.5mg) | colloidal silicon dioxide, corn starch crosscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulphate | |
| Composition of coating material | hypromellose, iron oxide red, polyethylene glycol, talc, and titanium dioxide. | ||
| Composition of caspule shell | - | ||
| Pharmaceutical Development | A critical aspect in product manufacture is product homogeneity throughout the whole manufacturing process and for administration (dose uniformity) of the dosage form. A relative bioavailability study confirmed bioequivalence between 400 mg tablets and 10 mL of suspensions with different particle sizes and dissolution rates. These results indicated that particle size and dissolution rate is not critical to the bioavailability. The dissolution method has been optimised and shown to be discriminatory. Further, a correlation between particle size and dissolution has been established and only dissolution testing will be used as a finished product control method. Particle size will be checked at the end of the drug substance homogenization process by laser diffraction as an in-process test. | ||
| Manufacture of the product | A risk assessment was performed for the manufacturing process. Risk levels were assigned by process development studies. Proven acceptable ranges (PARs) and proposed operating conditions for the homogenization process, final mixing, filtration process and mixing before filling were evaluated and established. The risk levels were mitigated by setting PARs for each critical process parameters (CPPs) or by setting the CPPs to constant values based on the process development studies. Results of the comparative bioavailability study with the tablets also contributed to mitigate the risk level by a decrease of the severity level of particle size and dissolution rate. Bulk holding time was determined by an appropriate study. | ||
| Tablet / Capsule Image |
|
|
|
| Appearance | pink in color, film-coated, oblong-shape tablets, with a score on both sides, imprinted with “ Є 262” on one side and blank on the other side | pink in color, film-coated, oblong-shape tablets, with a score on both sides, imprinted with “ Є 263” on one side and blank on the other side | |
| Imprint code / Engraving / Debossment | score on both sides, imprinted with “ Є 262” on one side and blank on the other side | score on both sides, imprinted with “ Є 263” on one side and blank on the other side | |
| Score | 2 pieces | 2 pieces | |
| Color | PINK | PINK | |
| Shape | Oblong | Oblong | |
| Dimension | 15mm | 18mm | |
| Mfg by | Eisai Inc. (EU) | ||
| Mfg for | - | ||
| Marketed by | Eisai Inc. (US, EU) | ||
| Distributed by | Eisai Inc. (US) | ||
| Application No. | Prod No | Patent No | Patent Expiration | Drug Substance Claim | Drug Product Claim | Patent Use Code | Delist Requested | Link |
|---|---|---|---|---|---|---|---|---|
| N021911 | 2 | 6740669 | November 14, 2022 | Y | Y | - | - | Download |
| N021911 | 2 | 6740669*PED | May 14, 2023 | - | - | - | - | |
| N021911 | 2 | 7750028 | October 19, 2018 | - | - | U - 106 | - | Download |
| N021911 | 2 | 7750028*PED | April 19, 2019 | - | - | - | - | |
| N021911 | 2 | 8076362 | June 8, 2018 | - | Y | - | - | Download |
| N021911 | 2 | 8076362*PED | December 8, 2018 | - | - | - | - |
| USP Apparatus | Speed (RPMs) | Medium | Volume (mL) | Recommended Sampling Times (minutes) | Date Updated |
|---|---|---|---|---|---|
| - | - | Refer to USP | - | - | 15 August, 2013 |
| Label | Link |
|---|---|
| FDA label | Download |
| FDA chemistry review | Download |
| FDA Pharmacology Review(s) | Download |
| FDA Clinical Pharmacology Biopharmaceutics Review(s) | Download |
| FDA BE Recommendation | Download |
| European Public Assessment Report | Download |
| Territory | Brand name / Generic company name | Link |
|---|---|---|
| EU | INOVELON | Download |
| UK | INOVELON | Download |
| US | BANZEL | Download |
| US | GLENMARK GENERICS (ANDA #205075)* | Download |
| US | MYLAN PHARMS INC (ANDA #205095)* | Download |
| US | WEST-WARD PHARMS INT (ANDA #204988)* | Download |
| PEDIATRIC EXCLUSIVITY EXPIRATION- May 14, 2016 Inovelon tablet 100MG is also approved by EU and UK in addition to 200MG and 400MG strength. |
| www.accessdata.fda.gov, www.drugbank.ca, www.ema.europa.eu, www.medicines.org.uk, dailymed.nlm.nih.gov |
