Banzel - Scientific Information
|Condition:||Epilepsy, Lennox-Gastaut Syndrome, Seizures (Convulsions)|
|Ingredients:||rufinamide, 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.|
|Chemical name:||1-[(2,6-difluorophenyl)methyl]-1H-1,2,3-triazole-4 carboxamide|
|Molecular formula and molecular mass:||C10H8F2N4O 238.2|
|Physicochemical properties:||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.|
The efficacy of BANZEL as adjunctive treatment for the seizures associated with Lennox-Gastaut syndrome (LGS) was established in a single multicenter, double-blind, placebo-controlled, randomized, parallel-group study (74 rufinamide, 64 placebo). 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 Anti-Epileptic Drugs (AEDs). Number of seizures experienced by patients in the 28 days prior to study entry ranged between 21 and 109,714 in the placebo arm and 48 to 53,760 in the rufinamide group.
After completing a 4-week Baseline Phase on stable AED therapy, patients were randomized to have BANZEL or placebo added to their ongoing therapy during the 12-week Double-blind (Treatment) Phase. The Treatment 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/day (3200 mg in adults of ≥ 70 kg), given on a b.i.d schedule. Dosage reductions were permitted during the Titration Period if problems in tolerability were encountered. Final doses achieved at the end of Titration Period were to remain stable/fixed during the Maintenance Period. Target dosage was achieved in 88% of the BANZEL-treated patients. Of the 74 patients who received rufinamide and of the 64 patients who received placebo, 64 (86.5%) and 59 (92.2%), respectively, completed the study.
The co-primary efficacy end-points 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;
- 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 indicated that the seizure severity was unchanged, and a score of -3 indicated that the seizure severity was very much worse.
A significant improvement was observed for all three co-primary end-points (Table 1).
Treatment Phase (Titration + Maintenance)
(n = 64)
(n = 74)
|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)|
Mechanism of Action
The precise mechanism(s) by which rufinamide exerts its antiepileptic effect is unknown. The results of in vitro studies suggest that rufinamide may prolong the inactive state of plasma membrane sodium channels.
Studies carried out in vitro show that rufinamide acts to limit the frequency of firing of sodium-dependent action potentials in rat and mouse neurons, an effect that may contribute to blocking the spread of seizure activity from an epileptogenic focus. Rufinamide did not significantly interact with a number of neurotransmitter systems, including: GABA, benzodiazepine, monoaminergic and cholinergic binding sites, NMDA and other excitatory amino acid binding sites.
In vivo anti-convulsant studies examined the ability of rufinamide to suppress both electrically and chemically-induced seizures as well as partial seizures. Following oral or intraperitoneal administration, rufinamide potently suppressed maximal electroshock-induced tonic-clonic seizures in rodents. No development of tolerance occurred during a 5-day treatment period in mice and rats. Rufinamide was also effective, but comparably less potent, in antagonizing chemically-induced clonic seizures. In Rhesus monkeys with chronically recurring partial seizures, rufinamide reduced seizure frequency. The protective index and safety ratio of rufinamide were comparable to or better than other AEDs.
To assess the effects of rufinamide on learning and memory, the electroshock-induced amnesia test and the step-down passive avoidance test were performed in mice. A reduction in electro-shock induced amnesia and an improvement in learning were observed in each respective test. These effects of rufinamide showed an inverted U-shaped dose-response relationship.
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 transient symptoms of CNS depression were seen after a high dose of rufinamide.
In a hERG assay, the 35.9% inhibition of hERG induced tail currents with 100 µmol/L rufinamide was comparable to the 31.6% inhibition seen with the 1% dimethylsulfoxide vehicle indicating rufinamide had no significant inhibitory effects. 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% PEG 400 in saline vehicle. A very slight increase in tidal volume lasting about 30 minutes was observed in dogs 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 significant effect was an increase in urine potassium excretion 6 hours after 300 mg/kg, with no concomitant effect on plasma electrolyte levels.
Rufinamide was of low acute toxicity with approximate lethal doses of more than 5000 mg/kg (p.o.) in mice, 5000 mg/kg (p.o.) and 1000 mg/kg i.p. in rats and more than 2000 mg/kg (p.o.) in dogs. The majority of observations were CNS related.
Repeated Dose Toxicity
In rats studied for up to 52 weeks at doses of up to 600 mg/kg by gavage or diet, centrilobular hypertrophy and thyroid follicular hypertrophy were observed along with related effects on the pituitary at ≥60 mg/kg. Cytoplasmic vacuolation of cells of the anterior pituitary which were positive for thyroid stimulating hormone (TSH) were observed. The effect of liver enzyme induction that disrupts the pituitary-thyroid axis is a well-established species sensitive phenomenon in the rat and therefore the relevance of these findings in humans is limited.
In dog studies, rufinamide at doses up to 600 mg/kg by oral capsule administration was well tolerated clinically for up to 52 weeks, except for two moribund cases in a 13-week study that were accompanied by anemia and bone marrow changes at 200 and 600 mg/kg; however these findings were not seen in any other subsequent study in dogs, indicating that a direct relationship to rufinamide was unlikely. Histopathological evidence of hepatobiliary toxicity/cholestatsis were observed at dose levels at and above 20 mg/kg/day and were accompanied by increased ALP, AST, and ALT at a dose of 200 mg/kg/day. These microscopic findings were not seen in rodents or monkeys.
Non-human primate studies were performed in the baboon (1-month duration only) and the Cynomolgus monkey by oral administration at up to 300 mg/kg for up to 52 weeks. No test-article related deaths occurred, and the major finding was the formation of choleliths in the gall bladder. These were composed mainly of an insoluble cysteine conjugate of a hydroxylated metabolite of rufinamide, which is not formed in humans. A human radiotracer study showed that this metabolic pathway was not relevant in humans. This finding, therefore, is not likely relevant to human risk assessment. Reversible liver weight increases and reversible adaptive hepatocellular hypertrophy were observed.
These findings are presented side by side with drug exposure levels in Table 2.
|Reduced body weight gain and food consumption. Increased T4. Histopathological changes in liver, pituitary and thyroid.||60||NA (<1.0)||NA (<1.0)|
|Dogs||Histopathological changes in liver.||20||734 (0.4)||352 (0.2)|
|Increased ALP||200||991 (0.5)||3580 (1.9)|
|Cynomolgus Monkeys||None (NOAEL)||60||1690 (0.9)||2290 (1.2)|
|Increased AST and ALP.
Histopathological changes in liver.
|200||3190 (1.7)||3060 (1.6)|
NP= not performed
NA= not available (ratio to human exposure estimated)
* Ratios to human levels of the maximum clinical dose (3200 mg/day or 1923 µmol.hr/L) are presented in the parentheses.
Carcinogenesis and Mutagenesis
Rufinamide was given in the diet to mice at 40, 120, and 400 mg/kg/day and to rats at 20, 60, and 200 mg/kg/day for two years. The doses in mice were associated with plasma AUCs 0.1 to 1 times the human plasma AUC at the maximum recommended human dose (MRHD, 3200 mg/day). Increased incidences of tumors (benign bone tumors (osteomas) and/or hepatocellular adenomas and carcinomas) were observed in mice at all doses. Increased incidences of thyroid follicular adenomas were observed in rats at all but the low dose; the low dose is <0.1 times the MRHD on a mg/m2 basis.
Rufinamide was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay or the in vitro mammalian cell point mutation assay. Rufinamide was not clastogenic in the in vitro mammalian cell chromosomal aberration assay or the in vivo rat bone marrow micronucleus assay.
Developmental and Reproductive Studies
Oral administration of rufinamide (doses of 20, 60, 200, and 600 mg/kg/day) to male and female rats prior to mating and throughout mating, and continuing in females up to Day 6 of gestation resulted in increased post-implantation losses at all dose levels, decreased fertility index, conception rate, numbers of corpora lutea, implantations, and live embryos at 200 and 600 mg/kg and reduced mating index, sperm count, and sperm motility at 600 mg/kg. Therefore a NOAEL was not identified at dose levels as low as 20 mg/kg at which systemic exposure would have been well below that at the MRHD.
Rufinamide was administered orally to rats at doses of 20, 100, and 300 mg/kg/day and to rabbits (in 2 studies) at doses of 30, 200, and 700 or 1000 mg/kg/day during the period of organogenesis (implantation to closure of the hard palate); the high doses are associated with plasma AUCs 1.5 to 2 times the human plasma AUC at the maximum recommended human dose (MRHD, 3200 mg/day). Decreased fetal weights and increased incidences of fetal skeletal abnormalities were observed in rats at dose levels of 100 and 200 mg/kg that were associated with maternal toxicity. Dose-dependent increases in skeletal variations were seen at all dose levels, although the effect was mild at the low dose and thus 20 mg/kg is considered a NOAEL for the offspring. In rabbits, embryo-fetal death, decreased fetal body weights, and increased incidences of fetal visceral and skeletal abnormalities occurred at all but the low dose (30 mg/kg). The highest dose (1000 mg/kg) tested in rabbits was associated with abortion. The no-effect doses for adverse effects on rat and rabbit embryo-fetal development (20 and 30 mg/kg/day, respectively) were associated with plasma AUCs ≈ 0.2 times that in humans at the MRHD).
In a rat pre- and post-natal development study (dosing from implantation through weaning) conducted at oral doses of 5, 30, and 150 mg/kg/day (associated with plasma AUCs up to ≈1.5 times that in humans at the MRHD), decreased offspring growth and survival were observed at all doses tested. A no-effect dose for adverse effects on pre- and post-natal development was not established. The lowest dose tested was associated with plasma AUC <0.1 times that in humans at the MRHD.
Repeat-dose toxicity studies have been performed in the neonate and/or juvenile rat and dog and findings were generally similar to those in adult/older animals. In the pivotal rat study, pre-weaning weight reductions were observed. Post-weaning, body weight reductions were seen at 150 mg/kg/day, along with reversible, adaptive centrilobular hepatocellular hypertrophy. At 50 and 150 mg/kg/day, pituitary cytoplasmic vacuolation was observed, with some reversibility. This finding is related to the hepatocellular hypertrophy/liver enzyme induction, and both findings in the rat are not considered toxicologically important to humans, in view of the species-sensitivity at the liver and thyroid-pituitary axis. The NOAEL of this study was 15 mg/kg/day. In the pivotal juvenile dog study, significant findings were an increase in ALT and pigment deposition in centrilobular and midzonal hepatocytes and bile canaliculi; lipofuscin-containing dark brown pigment in Kupffer cells after a 4-week reversal period; and primary focal neutrophilic infiltrates surrounding intrahepatic bile ducts or that were perivascular at the highest dose (200 mg/kg). The NOAEL of this study was 5 mg/kg/day, at which systemic exposure would have been about 1/20th that at the MRHD. There were no effects on behavioural or physical development at any dose level.