Antiepileptic Drugs, 5th Edition

Drugs in Development



Mary Ann Karolchyk DO*

Dieter Schmidt MD**

* Global Head, Epilepsy Section, Department of Clinical Research and Development, Novartis Pharmaceuticals Corporation, Basel, Switzerland

** Head, Epilepsy Research Group Section, Berlin, Germany

Rufinamide (CGP33101; RUF331) is a triazole derivative synthesized by Novartis Pharma AG (Basel, Switzerland). It is structurally unrelated to other anticonvulsant drugs. The compound's effectiveness as an anticonvulsant was evaluated in standard animal screening models. It was chosen for further preclinical testing from a number of related compounds based on its favorable efficacy and side effect profile. Controlled clinical studies have shown rufinamide to be an effective and safe anticonvulsant in the treatment of inadequately controlled partial seizures in adults.


Rufinamide, 1-(2,6-difluorophenyl)methyl-1H-1,2,3-triazole-4-carboxamide, is a triazole derivative (Figure 97.1). This neutral compound has a molecular weight of 238.20, exists as a white to practically white crystalline powder, and melts at 240°C to 242°C. The solubility of rufinamide in water as well as in gastric and intestinal fluids is low (approximately 60 mg/L at 37°C).

Plasma and urine levels of rufinamide are determined by high-performance liquid chromatography. Concentrations down to 0.1 µg/mL can be detected with this methodology (1,2).


Anticonvulsant Activity

The anticonvulsant spectrum of activity and the side effect profile of rufinamide were evaluated internally by Novartis and externally through the National Institutes of Health-sponsored Antiepileptic Drug Development program. In this program, a compound's efficacy in electrically and chemically induced seizures in rodent species was evaluated in a blinded manner. In addition to measures of anticonvulsant activity, the Rotorod test was performed to assess toxicity. The protective index, the median toxic dose divided by the median effective dose (TD50/ED50), of the compound was then calculated. As a reference, four prototype antiepileptic drugs (AEDs), ethosuximide, phenobarbital, phenytoin, and valproic acid, were tested in the same manner. Results from these tests in mice are shown in Table 97.1 (3,4).

Kindled seizures can be regarded as an animal model of partial seizures evolving to generalized seizures (5). In fully kindled cats, oral rufinamide at doses of 100 and 300 mg/kg delayed kindling development and suppressed afterdischarges, as did carbamazepine (40 mg/kg) and sodium valproate (180 mg/kg). Unlike these two AEDs, however, rufinamide antagonized kindling without provoking motor disturbances. Another animal model of chronically recurring partial seizures (with or without generalization) is the rhesus monkey with an aluminum hydroxide implant in the motor cortex. Subchronic treatment with oral rufinamide (30 to 50 mg/kg/day for 15 days) reduced seizure frequency by 75% to 100%, without producing limiting side effects.


FIGURE 97.1. Chemical structure of rufinamide, 1-(2,6-difluorophenyl)methyl-1H-1,2,3-triazole-4-carboxamide.




TD50 (mgkg), i.p.

ED50 (mgkg) and PI, i.p.


Rotarod Test


s.c. PTZ

s.c. BIC

s.c. PIC

s.c. STR


>500, >1000

15.5, >32.2

54, >9.3

50.5, >9.9

76.3, >6.6

Max 37.5%b




130, 3.4

459, 1

243, 1.8

Max 62.5%b



21.8, 3.2

13.2, 5.2

37.7, 1.8

27.5, 2.5

95.3, 0.7



9.5, 6.9




Max 50%b

Sodium valproate


272, 1.6

149, 2.9

360, 1.2

387, 1.1

293, 1.5

a No protection.

b Indicates percentage protected at maximum dose; values cannot be calculated as not all animals were protected at the maximum dose.

BIC, bicuculline; ED50, median effective dose; i.p., intraperitoneally; MES, maximal electroshock; PI, protective index; PIC, picrotoxin; PTZ, pentylenetetrazol; s.c., subcutaneous; STR, strychmine; TD50, median toxic dose.

Rufinamide also has been evaluated in genetic animal models of epilepsy. All components of sound-induced seizures in the audiogenic seizure-susceptible DBA/2 mouse were suppressed at oral rufinamide doses of 7 to 45 mg/kg. Rufinamide was ineffective, however, in preventing absence seizures in WAG/Rij rats.

Proposed Mechanism of Action

The anticonvulsant activity of rufinamide is mediated, at least in part, through prolongation of the inactivation phase of voltage-dependent sodium channels. In cultured mouse neurons, rufinamide limited the frequency of firing of sodium-dependent action potentials at a median inhibitory concentration of 2 × 10-7 g/mL. This effect could contribute to blocking the spread of seizure activity from an epileptogenic focus (6,7). Radioligand studies were performed to assess binding to other neurotransmitter sites. Concentrations of 10 µmol/L rufinamide showed no affinity for 5-hydroxytryptophan type 1 (5-HT1), 5-HT2, α1-, α2-, and β-adrenergic receptors; histamine-1 and cholinergic muscarinic agonist and antagonist sites also were not affected at this concentration. Rufinamide at concentrations of 10 to 100 µmol/L had no effect on [3H]flunitrazepam and [3H]γ-aminobutyric acid receptor binding. No binding to the N-methyl-D-aspartate, strychnine-insensitive glycine, and α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)/kainate receptors was detected at rufinamide concentrations up to 100 µmol/L.

General Pharmacology

Rufinamide at doses up to 10 mg/kg intravenously in dogs did not significantly affect cardiovascular or respiratory function, as assessed by changes in systolic and diastolic blood pressure, blood flow, respiratory rate, and tidal volume. In these animals, rufinamide produced a slight increase in heart rate that was apparent at 1 and 10 mg/kg, but not at 3 mg/kg.

In mice, sedation was noted at oral rufinamide doses of 900 mg/kg and 1,200 mg/kg. Rufinamide was effective in enhancing learning and memory in mice at and below effective anticonvulsant doses. At doses between 0.3 and 30 mg orally and intraperitoneally, learning performance in the stepdown passive avoidance paradigm was enhanced and electroshock-induced amnesia was partially counteracted.

There is neither physical nor psychological dependence liability associated with rufinamide. In a test of physical dependence, cynomolgus monkeys given 400 mg/kg/day oral rufinamide did not have withdrawal signs when the benzodiazepine antagonist Ro15-1788 was administered. No drug-seeking behavior was seen when increasing doses of rufinamide (5, 10, and 20 mg/kg) were administered to monkeys with implanted intragastric cannulae connected to injection devices to assess psychological dependence.


The acute (single-dose) toxicology of orally administered rufinamide was evaluated in the mouse, rat, and dog. In mice and rats, rufinamide was well tolerated after administration of doses up to 5,000 mg/kg. There was a 200- to 800-fold separation between the LD50 (median lethal dose) and ED50 in mice and rats, respectively. Doses up to 2,000 mg/kg were well tolerated in the dog; further dose increases were limited by emesis.

During chronic (≥6 months) oral rufinamide administration in the mouse, rat, dog, and monkey, several findings involving the bone, biliary system, and thyroid axis were reported. All findings occurred in a species-specific manner and were not considered to be relevant to humans.

Rufinamide showed no evidence of teratogenicity in mice, rats, or rabbits at oral doses of 300 to 1,000 mg/kg, administered during the period of organogenesis. There was


no impairment of general reproductive performance and fertility when rufinamide was orally administered to rats doses up to 150 mg/kg. Increased postnatal pup mortality rates were seen in some rat reproductive studies. This finding was further investigated with two cross-fostering studies. Both studies suggested the mortality rates to be related to late in utero effects secondary to maternal toxicity. This perinatal effect was not noted in other animals, including the mouse, thus confirming a species-specific finding.

The mutagenic potential of rufinamide was evaluated in a battery of in vitro and in vivo studies. Neither rufinamide nor its metabolites showed mutagenic potential in any study.

In a 104-week mouse carcinogenicity study, species-specific findings of an increased incidence of benign and malignant liver tumors and benign osteomas were noted at rufinamide doses of 400 mg/kg. The pathogenesis of both findings are linked to metabolism specific to the mouse: In particular, the liver findings are consistent with those produced by phenobarbital-type microsomal enzyme inducers, whereas the bone findings result from latent retrovirus activation by fluoride released from the rufinamide molecule during oxidative metabolism. In a rat carcinogenicity study of identical duration, a species-specific finding of an increased incidence of thyroid follicular adenomas at rufinamide doses of 60 mg/kg was noted. Liver tumors were not present in the rat.

Phase I investigations included approximately 85 healthy subjects who received oral rufinamide at doses up to 2,100 mg/day in single-dose and multiple-dose, double-blind, placebo-controlled studies. The most common adverse events in the rufinamide-treated subjects were headache, fatigue, and concentration difficulties. There were no clinically relevant abnormalities of laboratory parameters, electrocardiogram (ECG), and vital signs in rufinamide-treated subjects.


Absorption, Distribution, Metabolism, and Elimination Profile

Absorption of orally administered [14C]-labeled rufinamide was determined in the mouse, rat, dog, monkey, and baboon (8). In all species, absorption was near complete at low doses and decreased with the highest doses tested. The rate of absorption usually was slow in all species, with the exception of the immature rat. The absolute bioavailability of the compound in dogs and baboons was assessed using a [14C]-labeled intravenous formulation of the compound; plasma concentrations between the intravenous and oral formulations were comparable, indicating little or no first-pass metabolism.

The distribution of the radiolabel in most organs of the mouse and rat was similar to that in the blood and plasma, with the highest levels in the liver and the lowest levels in white fat. Serum protein binding was low (23% to 29%) in all species tested.

In all investigated animal species, the radiolabel excreted with the urine was predominantly due to inactive metabolites; less than 13% was the parent compound. No active metabolites were identified. The major urinary metabolite in all species, accounting for 50% to 90% of urinary radioactivity, was CGP47292, formed by hydrolysis of the carboxylamide group. Prominent (10% to 40% of urinary radioactivity) in the mouse and rat was 2,6-difluorobenzoic acid, CGP47291, a metabolite formed by oxidative cleavage at the benzylic carbon atom. Fifty percent to 65% of systemically available radioactivity was excreted within 7 days in the urine of tested animals. Rufinamide and it metabolites were eliminated predominantly renally, with low biliary/fecal elimination.

A single 600-mg dose of radiolabeled rufinamide was administered to three healthy human subjects (9). Thirty-four percent of rufinamide was protein bound, predominantly to albumin. The parent compound accounted for approximately 80% of the total plasma radioactivity. Less than 2% of the dose was recovered unchanged in urine, indicating extensive metabolism. As in animal studies, the major biotransformation pathway was hydrolysis of the carboxylamide group to CGP47292. This metabolite accounted for approximately 78% of the urinary radioactivity. There was no indication for involvement of oxidizing cytochrome P450 (CYP) enzymes or glutathione in the biotransformation process. Renal excretion was predominant, accounting for 84.7% of the dose.

Human Pharmacokinetic Studies

The onset of rufinamide absorption was rapid under both fed and fasted conditions in single-dose studies in healthy subjects and patients with epilepsy. Pharmacokinetic profiles in healthy volunteers were similar under both singleand multiple-dose (28 days) administration. In multiple-dose studies in patients with epilepsy, the plasma area under the curve (AUC) increased less than proportionally with individual doses greater than 400 mg, probably because of dose-limited absorption behavior. In one large population pharmacokinetics study in patients with epilepsy, the AUC at a dose of 1,600 mg/day (800 mg twice daily) was 73% greater than that of 800 mg/day (400 twice daily) (10). Food increased the extent of rufinamide absorption by approximately 40%.

A formulation change from dry compaction to the final market image (FMI) was made during the course of development. Twenty-four healthy volunteers participated in a three-way, crossover bioavailability/food effect study comparing the dry compaction tablet in the fed state and the FMI tables in both the fed and the fasting states. The FMI tablet had a 22% higher AUC and 34% higher maximal


plasma concentration (Cmax) than the dry compaction tablet. Similar to the dry compaction tablet, administration of the FMI tablet with food increased the AUC, although to a lesser extent (34%). Plasma parameters from this study are shown in Table 97.2.



Dry Compaction Formulation, Fed State (n = 24)

FMI Formulation, Fed State (n = 24)

FMI Formulation, Fasting State (n = 24)

Mean AUC (γg/mL · h)




Mean half-life (h)




Mean Cmax (γg/mL)




Median Tmax (h)




AUC, area under the curve; Cmax, maximum concentration; FMI, final market image; Tmax, time to maximum plasma concentration.

Neither sex nor age (14 to 64 years) had a significant influence on steady-state AUC(0-12h), Cmax, and minimum plasma concentration (Cmin) of rufinamide (10). To evaluate the profile in pediatric patients with epilepsy, 16 children aged 2 through 17 years were enrolled in a 2-week, open-label, ascending-dose study stratified by age (2 to 6 years, 7 to 12 years, and 13 to 17 years) (11). Rufinamide was administered orally in equally divided twice-daily doses of 10 mg/kg/day in week 1 and 30 mg/kg/day in week 2. There were no significant differences in plasma pharmacokinetic parameters as a function of age. On a milligram per kilogram per day basis, the AUC(0-12h), Cmax, and Cmin of rufinamide in this study were similar to data from adult pharmacokinetic studies.

The pharmacokinetic profile of rufinamide in the elderly was assessed in nine healthy elderly subjects and nine sexmatched younger adult subjects under both single- (400 mg) and multiple-dose (800 mg/day × 4 days) conditions (12,13). No significant pharmacokinetic differences were found between the groups.

Drug Interactions

In vitro, rufinamide demonstrated little or no competitive or mechanism-based inhibition of the following human CYP enzymes: CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and CYP4A9/11 (14). The Ki values were ≥450 µmol/L and at least 40 times the trough plasma levels (10.6 µmol/L) after daily administration of 800 mg rufinamide for 12 weeks.

In vivo interaction studies were conducted to assess any potential pharmacokinetic effect of rufinamide on concomitant drug administration. The effect of repeated-dose rufinamide on the AUC, Cmax, and time to maximum plasma concentration (Tmax) of hormonal components [ethinyl estradiol (EE) and norethindrone (NED)] of the low-dose contraceptive Ortho-Novum 1/35 (Ortho McNeil, Raritan., NJ) was determined in an open-label study in healthy subjects (15). Rufinamide, 1,600 mg/day, was administered for 14 consecutive days; 24-hour NED and EE levels were measured at the end of the rufinamide dosing cycle and compared with baseline values. Coadministration of rufinamide resulted in an approximately 22% and 14% decrease in EE and NED AUCs, respectively. A decrease in the Cmax of 31% (NED) and 18% (EE) also was seen; there was no significant difference in Tmax. There were no reported cases of breakthrough bleeding during coadministration of rufinamide. Although this interaction was statistically significant, the clinical significance is unknown because markers of ovulation were not assessed.

Two healthy-subject, open-label interaction studies were performed with the specific CYP substrates olanzapine (CYP1A2) (16) and triazolam (CYP3A4). In both studies, pharmacokinetic parameters were assessed after single-dose administration of the substrate and again after 11 days of rufinamide (800 mg/day) dosing. Pretreatment with rufinamide had no effect on the pharmacokinetic parameters of olanzapine; however, the triazolam AUC(0-∞) and Cmax were decreased by approximately 37% and 23%, respectively. This interaction may be significant only for those concomitantly administered drugs that are metabolized predominantly through the CYP3A4 pathway.

Potential interactions with concomitantly administered AEDs were assessed in 471 rufinamide-treated patients who participated in the trials described by Stefan et al. (17). All patients had inadequately controlled partial seizures and were taking one, two, or three fixed-dose concomitant AEDs. In this population pharmacokinetics analysis, valproate and lamotrigine decreased the plasma clearance of rufinamide by 22% (10), whereas any combination of phenytoin, phenobarbital, and primidone increased the clearance by approximately 25% (10). Because rufinamide has a wide therapeutic window, these changes are not expected to be clinically significant. Although it is known that valproate is a broad-spectrum inhibitor of hepatic metabolism and phenytoin and phenobarbital/primidone are known inducers of CYP isoenzymes,


the mechanism of these interactions with rufinamide have not been fully elucidated. Other AEDs, including carbamazepine, vigabatrin, oxcarbazepine, and clobazam, did not modify the plasma pharmacokinetics of rufinamide. Similarly, rufinamide did not influence the trough levels of the most commonly coadministered AEDs in this study, including carbamazepine, valproate, phenytoin, clobazam, phenobarbital, primidone, oxcarbazepine, and clonazepam.



To date, more than 1,500 patients with epilepsy have been treated with rufinamide during the course of clinical studies. Table 97.3 lists the completed efficacy studies in adult patients.

The study of Pålhagen et al. provided the first proof of anticonvulsant effect in humans (18). It was a multicenter, double-blind, placebo-controlled, weekly rising dose study in patients with epilepsy on one or two fixed-dose concomitant AEDs to investigate the pharmacokinetic and safety profile of rufinamide in single- (open-label) and multiple-dose (double-blind) administration. Fifty patients with inadequately controlled partial or generalized seizures were equally randomized to rufinamide or placebo treatment groups. Weekly ascending doses of 400, 800, 1,200, and 1,600 mg/day of rufinamide or matching placebo were administered in a twice-daily dosing regimen.

The efficacy analyses used the following standard parameters: seizure frequency ratio, as defined as the seizure frequency per 28 days during treatment divided by the baseline seizure frequency, as the primary variable; and the 25% and 50% responder rates as secondary variables. Patients who received rufinamide had a statistically significant decrease in seizure frequency ratio relative to the placebo treatment group (p = .0397; Wilcoxon ranksum test). The 25% responder rate was significantly higher in rufinamide-treated patients than in placebo-treated patients (52% versus 16%, p = .014; chi-square test); the 50% responder rate also showed a trend toward significance in rufinamide-treated patients (39% versus 16%, p = .096; chi-square test) despite the small sample size.



Study Description/Population

Number of Patients Per Treatment

RFA Dose (mg/day)

Results of Primary Analysis

Pålhagen et al., 2001 (18)

4-week rising-dose study in adults with partial/generalized seizures

RFA: n = 25
PLB: n = 25

Week 1: 400
Week 2: 800
Week 3: 1,200
Week 4: 1,600

Decrease in seizure frequency ratio relative to PLB (p = .0397)

Stefan et al., 2000 (17)

12-week, 5-arm dose-ranging study in adults with partial seizures

RFA: n = 514
PLB: n = 133

Four treatment arms: 200, 400, 800, 1,600

Significant linear trend of dose-response for seizure frequency (p = .003)

Vazquez et al., 2000 (19)

13-week study in adults with partial seizures

RFA: n = 156
PLB: n = 157


Decrease in partial seizure frequency relative to PLB (p = .0158)

PLB, placebo; RFA, rufinamide.

After this proof-of-concept study, a large, double-blind, placebo-controlled, dose-ranging study was conducted in patients with partial seizures inadequately controlled with one, two, or three fixed-dose concomitant AEDs (17). Six hundred forty-seven patients with inadequately controlled partial seizures were randomized to one of the four rufinamide treatment groups (200, 400, 800, or 1,600 mg/day administered twice daily) or placebo. After a prospective 12-week baseline phase, patients entered a 13-week treatment phase; study drug was initiated at the randomized dose without titration. The primary outcome, the linear trend of dose response for seizure frequency per 28 days in the treatment phase, was statistically significant in favor of rufinamide (p = .003; linear regression). A secondary efficacy variable compared the seizure frequency ratio of each treatment group with that of placebo (Wilcoxon rank-sum tests). The seizure frequency ratio was statistically significantly lower for the 400, 800, and 1,600 mg/day treatment groups compared with placebo (all p ≤ .0274). These significant differences corresponded to a reduction in median seizure frequency ratio of 12%, 17%, and 18%, respectively, relative to placebo (Figure 97.2). A key secondary variable, the linearity of dose response of 50% responders, was statistically significant (p = .0319; logistic regression). At daily doses of 400 to 1,600 mg, the 50% responder rates ranged between 11.6% and 16.0%, relative to a placebo rate of 9.0%.

A second double-blind, placebo-controlled study was conducted in a similar population. A total of 313 adult patients with inadequately controlled partial seizures receiving one to two fixed-dose concomitant AEDs were randomized to rufinamide treatment (3,200 mg/day, administered twice daily) or placebo. After a prospective 8-week


baseline phase, patients entered a 13-week treatment phase; study drug was titrated to 3,200 mg/day over a 1- to 2-week period. The primary efficacy variable, percentage change in partial seizure frequency during the treatment phase relative to the baseline phase, was statistically significant in favor of the rufinamide treatment group (p = .0158; Wilcoxon ranksum test). Rufinamide-treated patients had a 20.4% median reduction in partial seizure frequency, whereas placebo-treated patients had a 1.6% median increase. The percentage of patients who responded to treatment was significantly greater in the rufinamide treatment group than in the placebo treatment group. Of the rufinamide-treated patients, 28.2% experienced at least a 50% reduction in seizure frequency per 28 days relative to baseline, compared with 18.6% of the placebo-treated patients (p = .0381; logistic regression).


FIGURE 97.2. Median seizure frequency ratios. The results of Wilcoxon rank-sum tests were used to compare the seizure frequency ratio of each rufinamide treatment group with placebo; significant values are marked with an asterisk (all p ≤ .0274).

Two addition double-blind, placebo-controlled, adjunctive-therapy studies, one in primary generalized tonic-clonic seizures (n = 153, rufinamide dose 800 mg/day) and one in partial seizures in children 4 to 16 years of age (n = 269, rufinamide dose approximately 45 mg/kg/day), assessed rufinamide's safety and efficacy. The primary efficacy variable in both studies was the percentage change in seizure frequency (primary, generalized, tonic-clonic, and partial, respectively) during treatment relative to baseline. Although rufinamide decreased the respective seizure frequency in both studies, the primary efficacy analyses did not reach statistical significance.


Rufinamide as adjunctive therapy in patients with epilepsy was safe and well tolerated.

In the study of Stefan et al. (17), the most frequently reported adverse events were related to the nervous system; these events were more common in patients who received rufinamide than placebo (52.9 % versus 40.6%, respectively). The most frequent (incidence of ≥10% in any treatment group) were headache, fatigue, dizziness, viral infection, somnolence, nausea, and diplopia. Most adverse events were mild to moderate in severity and were transient; there was no evidence of a dose-response relationship for any adverse event. The incidence of adverse events was generally similar in patients who received rufinamide 200, 400, and 800 mg/day and placebo. At the 1,600-mg/day dose, only dizziness, somnolence, and diplopia occurred with a frequency at least twice that with placebo. Rufinamide had no significant adverse effects on pulse rate or blood pressure compared with placebo, and there were no clinically relevant changes in laboratory parameters. The percentage of patients who discontinued the study prematurely because of adverse events was similar between treatments (10.3% rufinamide all doses; 6.8% placebo), although slightly higher at the top dose of rufinamide (12.0%). The incidence of serious adverse events (SAEs) was low and similar in the rufinamide-treated (n = 21; 4.1%) and the placebo-treated (n = 5; 3.8%), patients, and there were no fatal or life-threatening events.

The rufinamide dose (3,200 mg/day) in the subsequent study of Vazquez et al. (18) was twice that of the highest dose in the Stefan et al. study (17); in addition, the more bioavailable FMI formulation was used in this study. As in the Stefan et al. study (17), the most frequently reported adverse events (serious and nonserious) were central nervous system related and were more common in rufinamidethan in placebo-treated patients (80.8% versus 58.6%). Adverse events with an incidence of at least 10% were similar to the previous study; the only additional adverse events occurring with a frequency of at least 10% were ataxia, vomiting, and abnormal vision. Most adverse events in the rufinamide-treatment group were transient and mild to moderate in severity, and had onset in the titration period of the study. Although the adverse event rates were in general higher than those in the previous study, the percentage


of patients who discontinued the study prematurely because of adverse events (13.5%) was similar to that in the highest dose group (12%) in the Stefan et al. study (17). The incidence of SAEs was low in both the rufinamide-treated (n = 8; 5.1%) and the placebo-treated (n = 4; 2.5%) patients. Three fatal adverse events occurred during the study: two of the patients received rufinamide and one received placebo. None of these events was suspected to be related to the study drug. As in the previous study, no treatment-emergent changes in laboratory parameters, vital signs, ECG, or physical examination results were evident.

In the two additional adjunctive therapy studies conducted in patients with primary generalized tonic-clonic seizures and in children, the most common treatment-emergent adverse events were related to the nervous system (headache and somnolence) and the gastrointestinal system (vomiting). The overall safety profile was similar to that seen in previous studies.

In all studies, rufinamide did not have a significant effect on the levels of concomitantly administered AEDs.

To date, patients have been treated with rufinamide for greater than 5 years in ongoing extension studies. No new safety findings have been noted with long-term therapy.


Well controlled studies completed to date show rufinamide to be efficacious as an adjunctive treatment of partial seizures in adults. Rufinamide was effective over the dose range of 400 to 3,200 mg/day in patients with partial seizures inadequately controlled with one, two, or three concomitantly administered AEDs. Rufinamide was safe and well tolerated over the entire dose range. Although adverse events increased in frequency at the highest doses tested, the types of adverse events were similar over the entire dose range. At the highest dose (3,200 mg/day), most adverse events occurred during titration, were mild to moderate in severity, and were transient.

Based on its favorable preclinical pharmacologic, toxicologic, and pharmacokinetic profiles in humans, and proven efficacy and safety in patients with inadequately controlled partial seizures, rufinamide may be considered to be a valuable addition to currently available therapies.


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