Summary Basis of Decision for Banzel ™
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
BanzelTM
Rufinamide, 100 mg, 200 mg, 400 mg, Tablet, Oral
Eisai Ltd.
Submission control no: 139913
Date issued: 2011-10-12
Foreword
Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.
Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.
The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).
For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.
Other Policies and Guidance
Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.
1 Product and submission information
Brand name:
Manufacturer/sponsor:
Medicinal ingredient:
International non-proprietary Name:
Strength:
Dosage form:
Route of administration:
Drug identification number(DIN):
- 02369613 - 100 mg
- 02369621 - 200 mg
- 02369648 - 400 mg
Therapeutic Classification:
Non-medicinal ingredients:
Film-coating: hypromellose, iron oxide red, polyethylene glycol, talc and titanium dioxide
Submission type and control no:
Date of Submission:
Date of authorization:
2 Notice of decision
On June 22, 2011, Health Canada issued a Notice of Compliance to Eisai Limited for the drug product, Banzel.
Banzel contains the medicinal ingredient rufinamide which is an antiepileptic drug.
Banzel is indicated for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in children 4 years and older and adults. Banzel is not indicated for the treatment of any other type of seizure disorder.
The precise mechanism(s) by which rufinamide exerts its antiepileptic effect in humans is unknown. The results of in vitro studies suggest that rufinamide may prolong the inactive state of plasma membrane sodium channels.
The market authorization was based on quality, non-clinical, and clinical information submitted. The efficacy of Banzel as adjunctive treatment for the seizures associated with LGS was established in a single multicentre, double-blind, placebo-controlled, randomized, parallel-group study. A total of 138 male and female patients (between 4 and 37 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 antiepileptic drugs. Compared to placebo, Banzel-treated patients demonstrated significant improvements in the number of total seizures, drop attacks, and seizure severity. Overall, Banzel was generally well-tolerated.
Banzel (100 mg, 200 mg and 400 mg rufinamide) is presented in tablet form. For children and adults less than 30 kg, treatment should be initiated at a daily dose of 200 mg administered in two equally divided doses. For adults and children 30 kg or over, treatment should be initiated at a daily dose of 400 mg administered in two equally divided doses. For both groups, according to clinical response and tolerability, the dose should be increased at 5 mg/kg/day every two weeks. Titration should be stopped after a satisfactory control of seizures is obtained. The maximum recommended dose and dosing guidelines are available in the Product Monograph.
Banzel is contraindicated for patients with Familial Short QT syndrome, family history of short QT syndrome, presence, or history of short QT interval; and patients who are hypersensitive to rufinamide, triazole derivatives or any of the excipients. Banzel should be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of Banzel are described in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Banzel is favourable for adjunctive treatment of seizures associated with LGS in children 4 years and older and adults.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Rufinamide, the medicinal ingredient of Banzel, belongs to the class of antiepileptic drugs. The precise mechanism(s) by which rufinamide exerts its antiepileptic effect in humans is unknown. The results of in vitro studies suggest that rufinamide may prolong the inactive state of plasma membrane sodium channels.
Manufacturing Process and Process Controls
Rufinamide is manufactured via a multi-step synthesis. Each step of the manufacturing process is considered to be controlled within acceptable limits:
- The sponsor has provided information on the quality and controls for all materials used in the manufacture of the drug substance;
- The drug substance specifications are found to be satisfactory; and
- The processing steps have been evaluated and the appropriate ranges for process parameters have been established.
Characterization
Detailed characterization studies were performed to provide assurance that rufinamide consistently exhibits the desired characteristic structure and biological activity.
Impurities arising from manufacturing and/or storage were reported and characterized. The proposed limits are considered adequately qualified that is (i.e.) within International Conference of Harmonisation (ICH) limits and/or qualified from toxicological studies.
Control of Drug Substance
Copies of the analytical methods and, where appropriate, validation reports were provided and are considered satisfactory for all analytical procedures used for release and stability testing of rufinamide.
Batch analysis results were reviewed and all results comply with the specifications and demonstrate consistent quality of the batches produced.
The drug substance packaging is considered acceptable.
Stability
Based on the long-term, real-time, and accelerated stability data submitted, the proposed retest period and storage conditions for the drug substance were supported and are considered satisfactory.
3.1.2 Drug Product
Description and Composition
Banzel tablets are film-coated, pink in colour, ovaloid in shape with a slightly convex face, and contain 100 mg, 200 mg, or 400 mg of rufinamide. Each tablet is scored on both sides. On one side of the tablet is a symbol that looks similar to a rounded "E". On the same side, the 100 mg, 200 mg, and 400 mg tablets also have engravings of 261, 262, and 263, respectively. The 100 mg and 200 mg strengths are available in bottles of 30 and blister strips of 10 tablets each, while the 400 mg strength is available in bottles of 120 and blister strips of 10 tablets each.
The non-medicinal ingredients in the tablet core are colloidal silicon dioxide, corn starch, croscarmellose 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.
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of rufinamide with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
Pharmaceutical Development
Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review.
Manufacturing Process and Process Controls
The method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.
Control of Drug Product
Banzel is tested to verify that its identity, appearance, content uniformity, assay, dissolution, levels of drug-related impurities and microbiological impurities are within acceptance criteria. The test specifications and analytical methods are considered acceptable; the shelf-life and the release limits, for individual and total degradation products are within acceptable limits. The validation process is considered to be complete.
Data from final batch analyses were reviewed and are considered to be acceptable according to the specifications of the drug product.
Stability
Based on the real-time, long-term, and accelerated stability data submitted, the proposed 36-month shelf-life at 15-30°C for Banzel is considered acceptable when the product is packaged in the proposed container.
The compatibility of the drug product with the container closure system was demonstrated through stability studies. The container closure system met all validation test acceptance criteria.
3.1.3 Facilities and Equipment
The design, operations, and controls of the facility and equipment that are involved in the production of Banzel are considered suitable for the activities and products manufactured.
All of the proposed manufacturing sites comply with the requirements of Division 2 of the Food and Drug Regulations.
3.1.4 Adventitious Agents Safety Evaluation
Lactose monohydrate used in the manufacture of Banzel is sourced from animal origin (cows) that is not susceptible to transmissible spongiform encephalopathy (TSE). A signed certificate has been provided for lactose monohydrate stating that the milk used in manufacture of this excipient is sourced from healthy animals in the same conditions as milk is collected for human consumption.
The magnesium stearate used in the manufacture of Banzel is obtained exclusively from vegetable sources.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Banzel has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.
3.2 Non-Clinical Basis for Decision
3.2.1 Pharmacodynamics
Primary Pharmacodynamics
- In vitro studies in rat and mouse neurons demonstrated that rufinamide limits the frequency of firing of sodium-dependent action potentials by interacting with the inactivated state of the sodium channel and slowing conversion to the active state thereby reducing the frequency of action potentials. This indicates that anticonvulsant activity arises from direct inhibition of sodium channels and is different from other anticonvulsant drugs.
- Rufinamide did not interact significantly with other neurotransmitter systems, including gamma-aminobutyric acid (GABA), benzodiazepine, monoaminergic and cholinergic binding sites, N-methyl-D-aspartate (NMDA) and other excitatory amino acid binding sites. A weak interaction at β-adrenergic receptor sites occurred at a high concentration.
- Rufinamide was particularly effective in the maximal electroshock (MES) induced generalized tonic-clonic seizures models in mice and rats and relatively less effective in the chemically-induced seizure models in the rat.
- Rufinamide had a relatively long duration of action consistent with its pharmacokinetics.
- Additive anticonvulsant activity was observed with other anticonvulsant drugs in the MES test with no potentiation or antagonistic activity observed.
- No tolerance developed to anticonvulsant activity in the MES test after 5 days of rufinamide dosing.
- The protective index and safety ratio of rufinamide was comparable or better than other antiepileptic drugs tested.
- Rufinamide, overall, displayed a profile of anticonvulsant activity which differed somewhat from comparator drugs, but most resembled phenobarbital and valproic acid.
- A reduction in seizure frequency was observed in epileptic rhesus monkeys with chronically recurring partial seizures after treatment with rufinamide at 30-50 mg/kg daily for 15 days.
Secondary Pharmacodynamics
- Rufinamide appeared to enhance cognitive function at anticonvulsant doses and had an analgesic effect on neuropathic pain consistent with other anticonvulsant drugs.
Safety Pharmacology
- Central nervous system (CNS) studies identified relatively minor effects on behaviour, locomotor activity, motor coordination and drug-induced sleep time in mice. In monkeys, mild symptoms of CNS depression were observed following a high dose of rufinamide and these effects were transient.
- In a human Ether-à-go-go Related Gene (hERG) assay, the inhibition of hERG induced tail currents was 35.9% with 100 μmol/L rufinamide and 31.6% with the 1% dimethylsulfoxide vehicle. The positive control exhibited a significant 87.1% inhibition of hERG current.
- No liability was identified in a dog cardiovascular study at intravenous (IV) doses up to 10 mg/kg. In this study, the magnitude of heart rate decrease observed in rufinamide-treated dogs was not as pronounced as the heart rate decrease seen in controls given the 30% polyethylene glycol 400 in saline vehicle.
- In a respiratory evaluation in dogs, a very slight increase in tidal volume that lasted approximately 30 minutes occurred after the highest IV dose of 10 mg/kg.
- In a renal study conducted in female rats given single oral rufinamide doses up to 300 mg/kg, the only statistically significant effect was an increase in urine potassium excretion 6 hours after dosing at 300 mg/kg. Rufinamide had no effect on plasma electrolyte levels at 6 hours after dosing.
- In an evaluation of potential effects on blood glucose levels in male rats, a transient increase in blood glucose after a single 100 mg/kg rufinamide dose was not considered of toxicologic significance, as the effect was of a small magnitude (6%) and effects on blood glucose were not seen in numerous toxicology studies.
3.2.2 Pharmacokinetics
Absorption
The extent of absorption was variable across the test species and generally decreased in proportion at very high doses. The less than dose proportional increase in systemic exposure showed no pronounced gender differences. There was no significant accumulation with repeated dosing. Systemic exposure in young and mature dogs was similar for the same rufinamide dose.
Distribution
Radiolabelled rufinamide was distributed throughout the body in rats, and there was no evidence of a peculiar or persistent affinity to specific organs and tissues. A marked to moderate and reversible transfer of rufinamide and/or its metabolites to the embryo/foetal compartment was observed in rats and rabbits, respectively. Radiolabelled rufinamide was distinctly taken up into the mammary glands indicating that rufinamide and/or its metabolites could be excreted with the milk.
Binding of rufinamide to serum proteins in all species was low (23-35%).
Metabolism
Rufinamide was extensively metabolized in all species. The main metabolite was the carboxylic acid derivative formed by hydrolysis of the carboxylamide group, which presumably is catalyzed by carboxyesterase(s). Oxidative metabolism was minor and appeared to be more pronounced in rodents than in dogs or primates.
Rufinamide weakly induced drug-metabolizing enzymes in rat and mouse liver in a qualitatively similar manner to carbamezapine or phenobarbital. The effect was reversible in mice. Rufinamide showed no significant capacity to inhibit the activity of relevant human cytochrome P450 (CYP) enzymes, did not appear to be a substrate for P-glycoprotein (Pgp), and was a potentially weak inhibitor of digoxin transport in vitro. Collectively these studies do not predict significant drug-drug interactions involving rufinamide.
Excretion
Excretion of the rufinamide metabolites was in the urine and faeces with very little unchanged rufinamide excreted into the urine.
3.2.3 Toxicology
Single-Dose Toxicity
Rufinamide has a low acute toxicity with no mortality in mice and rats at oral doses up to 5,000 mg/kg and in dogs up to 2,000 mg/kg. Clinical signs at high doses were generally CNS-related and included hypoactivity, ataxia, irregular respiration, muscular hypertonia, piloerection, and hypothermia in rodents and slight trembling in dogs.
Repeat-Dose Toxicity
Treatment-related histopathologic changes were present in the liver of rats and mice and in the pituitary, thyroid and kidney of rats. Increased liver weight and hepatocellular centrilobular hypertrophy related to enzyme induction were present at doses of ≥200 mg/kg in mice and ≥60 mg/kg in rats. Liver histopathologic changes in mice (including hepatcellular hypertrophy and single cell necrosis) were accompanied by increased alanine aminotrasferase (ALT), aspartate aminotrasferase (AST) and alkaline phosphatase (ALP) activities; serum enzyme increases were not present in rats. Liver enzyme induction was manifest in rats, evidenced by increased hepatic thyroxine (T4) uridine diphosphate-glucuronyl transferase (UDP-GT) activity, total cytochrome P450, and aminopyrine N-demethylase activities. The liver findings in mice and rats and the pituitary and thyroid findings in rats represent a well recognized rodent phenomenon not considered relevant for human risk assessment.
The main finding in the dog studies of 3 months or longer duration was hepatobiliary toxicity/cholestasis at rufinamide dose levels as low as 5 mg/kg and exposures well below those in humans at therapeutic doses. ALT and ALP activity were often, but not always, increased in dogs with microscopic findings. Hepatobiliary effects of reduced severity persisted through 4-week recovery periods.
In the 13-week monkey study, rufinamide at 300 mg/kg/day caused statistically significant decreases in QT interval at Day 28 and 86 that were potentially treatment-related, but unlikely of toxicologic significance due to the small magnitude (9 and 12 msec, respectively) of change.
In the 13-week monkey study, rufinamide resulted in the formation of choleliths and associated inflammation of gall bladder epithelium at 100-300 mg/kg, and increased ALT, AST and ALP activities at 60-300 mg/kg. In the 26/52 week monkey study, increased liver weight and hepatocellular hypertrophy were observed at 60 and 200 mg/kg and choleliths were observed at 200 mg/kg. Exposures at these dose levels were comparable to and above those at the maximum recommended human dose (MRHD). Exposure at the no-observed-effect-levels (NOELs) (20 and 35 mg/kg) was less than that at the MRHD. The choleliths were partially reversible after a 4-week recovery period and were composed primarily of an insoluble cysteine conjugate of the hydroxylated metabolite of rufinamide assumed to have been formed by the enzymatic degradation of the corresponding glutathione and precipitation in bile. The sponsor stated that the cysteine conjugate of hydroxylated metabolite is not formed in humans and therefore cholelith formation may not be relevant to human safety.
Carcinogenicity
In the mouse carcinogenicity study:
- Mild increases in hepatocellular adenomas and carcinomas in both sexes at the high dose (400 mg/kg) were accompanied by hepatocellular hypertrophy and increases in serum liver enzymes. The tumorigenic effects observed in mouse liver can be reasonably considered to represent an adaptive rodent-specific phenomenon related to microsomal enzyme induction and are not considered to represent a significant risk for human safety.
- Increases in the incidence of osteomas occurred at all dose levels (40, 120 and 400 mg/kg). The sponsor proposed that the induction of the tumours and related non-neoplastic findings in mouse bone (hyperostosis) were due to the metabolism of rufinamide-releasing fluoride, causing retroviral activation in bone cells and, as such, rufinamide-induced increases in osteoma in mice were not relevant for human safety since a similar metabolism causing fluoride release has not been observed in humans. However, the potential relevance of rufinamide induced osteoma for human risk/safety estimation cannot be ruled out with certainty.
In the rat carcinogenicity study:
- Increased incidence of thyroid follicular adenomas occurred at 60 and 200 mg/kg.
Treatment-related non-neoplastic findings in liver included centrilobular hepatocellular hypertrophy (60 and 200 mg/kg) and pigmented hepatic macrophages, apoptosis and megalocytosis (200 mg/kg in females only).
- The mechanism underpinning the development of proliferative lesions of thyroid caused by agents that produce induction of hepatic drug metabolizing enzyme activity is well established for male rats. There is substantial evidence that humans are less sensitive than rodents to the tumour-inducing effects of long-term derangement of thyroid status.
Mutagenicity
Rufinamide was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay and in the in vitro mammalian cell point mutation assay. Rufinamide was not clastogenic in the in vitro Chinese hamster ovary cell chromosome aberration assay and in the in vivo rat bone marrow micronucleus study, and did not increase sister chromatid exchange in rats or the frequency of nuclear anomalies in hamster bone marrow cells.
Reproductive and Developmental Toxicity
A full series of developmental/reproductive toxicity studies in rats and rabbits demonstrated embryo-foetal toxicity, including increased pre- and post-implantation loss, increased structural anomalies and variations, and early pup mortality at systemic exposures less than that of the Maximum Recommended Human Dose (MRHD). Therefore, rufinamide should not be taken by pregnant women or those planning to become pregnant.
Findings in juvenile animals were generally similar to those in adults and included hepatobiliary effects in young dogs.
3.2.4 Summary and Conclusion
Overall, the non-clinical studies for this drug submission are considered acceptable. Rufinamide was generally well-tolerated in the repeat-dose animal studies, with the hepatobiliary system being a common target. The effects differed in each species due to variations of metabolic pathways. The toxicity findings were in most cases considered not relevant to humans, being recognized as species-specific. However, rufinamide did produce developmental toxicity when administered orally to pregnant animals at clinically relevant doses. Therefore, pregnant women or women planning to become pregnant should not use Banzel. Appropriate warnings and precautionary measures are in place in the Product Monograph to address the identified safety concerns. Overall, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product for the requested indication.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
Population pharmacokinetic/pharmacodynamic modelling demonstrated that in the Lennox-Gastaut study, the reduction of total and tonic-clonic seizure frequencies, the improvement of the global evaluation of seizure severity and rate of reduction of seizure frequency by >50% were dependent on rufinamide concentrations.
A study in healthy volunteers evaluated the effects of a single oral dose of 800 mg rufinamide on acoustically evoked potentials. Results found a statistically significant increase of the N100 amplitude with rufinamide compared to placebo. As the N100 likely reflects early attentional and orienting processes, the increase in N100 suggests an intensified attentional focusing on target stimuli.
3.3.2 Pharmacokinetics
Absorption
Maximum plasma levels of rufinamide were reported approximately 6 hours following oral administration. Intake of food increased the absorption of rufinamide. The drug exposure [area under the curve (AUC)] levels and the maximum plasma drug concentration (Cmax) values were increased by 34% and 56%, respectively. Bioavailability of this drug was inversely proportional to the dose.
Distribution
In humans, approximately 34% of rufinamide is bound to serum proteins.
The apparent volume of distribution is dependent upon dose and varies with body surface area. The apparent volume of distribution was approximately 50 L at 3,200 mg/day.
Metabolism
Rufinamide is extensively metabolized by hydrolysis of its carboxide group to a pharmacologically inactive (carboxylic acid derivative) metabolite, which is mainly excreted through kidneys.
In vivo data indicate that rufinamide does not inhibit cytochrome P450 enzymes: 1A2; 2A6; 2C9; 2C19; 2D6; 3A4/5; or 4A9/11-2.
Excretion
Renal excretion accounts for approximately 85% of the rufinamide dose with about 66% of the drug excreted as the carboxylic acid derivative and <2% as unchanged drug. The plasma elimination half-life was approximately 6-10 hours in healthy and epileptic subjects.
3.3.3 Clinical Efficacy
The safety and efficacy of Banzel were evaluated as add-on treatment in a single, multicentre, double-blind, randomized, placebo-controlled 16-week study, in inadequately controlled LGS patients. After a 4-week baseline period, eligible patients were randomized into a placebo group or a Banzel group. Patients then entered into a titration period of 2 weeks, during which each patient was titrated up to their maximum tolerated dose (maximum of 45 mg/kg/day, 3,200 mg/day in adults of ≥70 kg), followed by a maintenance period of 10 weeks, during which each patient received their maximum tolerated dose as established in the titration period. There were 74 patients in the Banzel group and 64 patients in the placebo group (total 138 patients). The ages of the patients ranged from 4 to 37 years, with more than 70% of the patients <17 years old.
The three co-primary endpoints were:
- the median percent change in total seizure frequency per 28 days;
- the median percent change in tonic-atonic seizure frequency (drop attacks) per 28 days; and
- seizure severity from the Parent/Guardian Global Evaluation of the patient’s condition.
The Parent/Guardian Global Evaluation was a 7-point assessment performed at the end of the double-blind phase. Scores ranged from +3: seizure severity very much improved; to -3: seizure severity very much worse. Zero (0) represented no change.
All three co-primary end-points in the Banzel group were both statistically and clinically significantly improved as compared to those in the placebo group.
3.3.4 Clinical Safety
The safety of Banzel was primarily based on the pivotal study described in section 3.3.3 Clinical Efficacy. The safety evaluation included data from the 138 patients that received at least one dose of either treatment. The adverse events reported for Banzel were similar to those of other antiepileptic drugs [for example (e.g.) dizziness, somnolence, diplopia, blurred vision]. Other events included rash (7% in the Banzel group, 2% in placebo); and nystagmus (4%), ataxia (5%) and status epilepticus (4%) all in the Banzel group versus (vs.) none in the placebo group. Somnolence was reported in 24% of Banzel-treated patients compared to 13% of placebo patients. Two of the cases in the Banzel group were rated as severe. There were no severe cases in the placebo group. Vomiting was reported in 22% of Banzel-treated patients compared to 6% of placebo patients.
No deaths occurred during the study. Approximately 86% and 92% of the patients in Banzel and placebo groups, respectively, completed the study. Discontinuation due to lack of efficacy was 5% in the Banzel group vs. 1.5% in the placebo group. Six patients in the Banzel group discontinued due to adverse events (AEs) vs. none in the placebo group. The daily dose at the onset of the events that led to discontinuation was 100 and 400 and 1,400 mg in one patient each, and 800 mg in 3 patients. Some of the AEs which led to withdrawal were somnolence, rash, and vomiting in 2 patients each. A serious case of rash occurred in a 12-year old male that received Banzel.
Long-term Safety
In a 36-month observational open-label study, 124 patients (age range: 4 to 37 years) with LGS were treated with Banzel; 71.8% were between 4 and 16 years of age. The median daily dose of Banzel during therapy was 1,800 mg/day ranging from 103 to 4,865 mg/day. The median duration of exposure to Banzel was 432 days (range 10-1,149 days). Thirty-four percent of patients completed the study. The four most frequent AEs observed during Banzel treatment in this study were vomiting (31%), pyrexia (26%), upper respiratory tract infection (22%) and somnolence (21%). Seventeen patients (16 were paediatrics) experienced serious adverse events (SAEs); for example, rash, espophagitis, status epilepticus, vomiting, and lethargy. Approximately 41% (or 49 patients) discontinued the study due to lack of efficacy and approximately 10% (12 patients) due to AEs. Three patients experienced status epilepticus (all serious) none of whom had a previous history of this event. Of the twelve patients that withdrew due to AEs, rash was reported in 4 of these patients. Except for one, all of the cases were considered to be mild or moderate in severity.
Safety Issues of Interest
QTc Shortening
Formal cardiac electrocardiogram studies demonstrated shortening of the QT interval (mean approximately 20 msec, for doses >2,400 mg twice daily) with Banzel treatment. In a placebo-controlled study of the QT interval, a higher percentage of Banzel-treated subjects (46% at 2,400 mg, 46% at 3,200 mg, and 65% at 4,800 mg daily) had a QT shortening of greater than 20 msec at the time to reach the maximum plasma concentration (Tmax) 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 7,200 mg/day.
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.
Use of Banzel is contraindicated in patients with Familial Short QT syndrome or patients with a family history of short QT syndrome, as well as patients with the presence of, or history of, short QT interval. In addition to the contraindication, a warning statement has been added to the Product Monograph to address the QT shortening effect of Banzel.
Status Epilepticus
In the pivotal LGS study described in section 3.3.3 Clinical Efficacy, 3 patients in the Banzel group (4%) experienced status epilepticus vs. none in the placebo group. In all double-blind studies (various epilepsy-related indications), 11 Banzel-treated patients (1%) including 4 paediatric patients experienced status epilepticus vs. none in placebo. Since the International Birth Date (IBD) for rufinamide through July 29, 2011, seven post-marketing reports of status epilepticus during Banzel therapy have been received. A warning statement was added to the Product Monograph to warn prescribers of the possible association of Banzel with status epilepticus.
Hepatic-related Events
Based on all controlled clinical studies (LGS and other epilepsy-related indications), there were a total of 26 hepatic-related AEs in 1,240 patients treated with Banzel compared to 10 cases in 635 placebo-treated patients. In 10 of the 26 cases, patients entered the study with normal liver enzymes and had elevated values after Banzel treatment (no clear trend for dose). In 5 of the 10 cases, there was either a temporal relationship between Banzel therapy and the elevation of liver enzymes or a positive de-challenge upon Banzel discontinuation.
The post-marketing data showed 8 spontaneous reports of hepatic-related events (5 considered “serious”) including hepatitis, increased liver enzymes and one case of hepatic failure. Three of the cases occurred in paediatric patients. In one case, a 9-year-old male patient with LGS was receiving rufinamide (450-600 mg/day) for approximately two months when he was hospitalized for persistent vomiting (4-5 days) and volume depletion. The patient experienced both renal and hepatic failure. Renal failure was traced to an infection, and was treated with an antibiotic; hepatic failure resolved (while hospitalized) upon withdrawal of all antiepileptic agents. In the case report it is unclear whether a re-challenge was attempted.
Rufinamide is metabolized in the liver independent of any of the CYP P450 family of enzymes. It is difficult to know, with certainty, if rufinamide is associated with liver injury. Furthermore, there are no liver injury or hepatotoxicity signals in the animal-related data. However, due to a number of reported cases of hepatic-related events in clinical trials, the sponsor has been asked to provide semi-annual reports of hepatic-related events to Health Canada, in addition to the regular/normal surveillance.
Rash and Hypersensitivity
The sponsor stated that the majority of anti-epileptic medications are associated with rash, or other skin manifestations of an immune mediated response, and some are also associated with the 'anti-epileptic drug hypersensitivity syndrome'. Serious antiepileptic drug hypersensitivity syndrome has occurred in association with rufinamide therapy. Signs and symptoms of this disorder were diverse; however, patients typically, although not exclusively, were presented with fever, and rash was associated with other organ system involvement.
In the pivotal LGS study, 2% of the placebo-treated patients and 7% of those that received Banzel therapy, experienced “rash”. This 3.5-fold difference between placebo and drug therapy is significant. When considering all of the double-blind, controlled clinical studies of Banzel, “rash” was also reported by 4% of the Banzel-treated paediatric patients (placebo: 2%). In one patient, after nearly 4 weeks of rufinamide therapy, rash, urticaria, facial edema, elevated eosinophils, fever, stuporous state and severe hepatitis were reported. Symptoms resolved 11 days after rufinamide discontinuation. Rash was present in 4 other cases with one or more of the following: fever, elevated liver enzymes, hematuria, and lymphadenopathy. A warning statement is provided in the Product Monograph to address rash-related events in the context of multi-organ hypersensitivity syndrome.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Lennox-Gastaut Syndrome (LGS) is one of the most devastating childhood epilepsies, with some patients experiencing thousands of seizures per month, and many children do not survive to adolescence or adulthood. The incidence of LGS is approximately 0.5-2 per 10,000. Patients are difficult to recruit, diagnose, and carry to study completion and follow-up. Due to these limitations, only a single safety and efficacy study has been conducted with Banzel in LGS patients. In this pivotal study, Banzel showed both statistically and clinically significant improvement over placebo.
Banzel has been available in Europe since January 2007 and in the United States since November 2008, and there have been no post-marketing safety signals to date. Patients with LGS are inevitably under close supervision by their physician in charge, due to the severe nature of the disease and to the fact that patients are usually taking 2-3 additional drugs which have their own spectrum of sometimes severe adverse effects that need to be monitored.
At this time, the benefit/risk ratio for Banzel (rufinamide), when prescribed under the conditions of use recommended in the Product Monograph, is favourable.
A mutually acceptable Product Monograph has been agreed upon with the sponsor. The sponsor has complied with all the Risk Management Plan post-marketing commitments required by Health Canada.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and efficacy, Health Canada considers that the benefit/risk profile of Banzel is favourable in the adjunctive treatment of seizures associated with Lennox-Gastaut Syndrome (LGS) in children 4 years and older and adults. Banzel is not indicated for the treatment of any other type of seizure disorder. The New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations.
4 Submission Milestones
Submission Milestones: BanzelTM
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2010-02-02 |
| Submission filed: | 2010-07-06 |
| Screening | |
| Screening Acceptance Letter issued: | 2010-08-25 |
| Review | |
| Biopharmaceutics Evaluation complete: | 2011-06-08 |
| Quality Evaluation complete: | 2011-06-14 |
| Clinical Evaluation complete: | 2011-06-15 |
| Labelling Review complete: | 2011-06-20 |
| Notice of Compliance issued by Director General: | 2011-06-22 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| BANZEL | 02369621 | EISAI LIMITED | RUFINAMIDE 200 MG |
| BANZEL | 02369648 | EISAI LIMITED | RUFINAMIDE 400 MG |
| BANZEL | 02369613 | EISAI LIMITED | RUFINAMIDE 100 MG |