Epilepsy: A Comprehensive Textbook
2nd Edition
© 2008 Lippincott Williams & Wilkins
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Chapter 157
Rufinamide
Tracy A. Glauser
Meir Bialer
Introduction
Rufinamide is a broad-spectrum antiepileptic drug (AED) with documented ability to block sodium (Na) channels.24,34 Following discovery of antiepileptic activity in animal models, it has been undergoing Phase II and III clinical trials. Rufinamide has demonstrated efficacy against partial seizures in adults and generalized seizures in patients with the Lennox-Gastaut syndrome (LGS).5,10,14 Clinical trials have reported a good tolerability profile. Rufinamide is currently under evaluation by the European Medicines Agency and the United States Food and Drug Administration (FDA).
Chemistry
Rufinamide (1–(2,6–difluorophenyl)methyl-IH-I,2,3triazole-4–carboxamide) (Fig. 1) is a triazole derivative structurally dissimilar to currently marketed AEDs.2,17 Rufinamide is a lipophilic compound with a partition coefficient (logP = 0.88) and solubility in water and in gastric and intestinal fluids of 40 to 70 mg/L.9 There are no currently marketed formulations of this compound. In clinical trials, film-coated tablets have been used.9
Plasma concentrations for rufinamide and its inactive carboxylic acid major metabolite (Fig. 1) are determined using high-performance liquid chromatography (HPLC).27 The limit of quantification of this validated HPLC assay is 25 ng/mL for rufinamide in plasma, 2.5 μg/mL for rufinamide in urine, and 5 μg/mL for rufinamide’s carboxylic acid major metabolite in urine.27
Pharmacology
Activity in Experimental Models of Seizures/Epilepsy
Rufinamide exhibits broad-spectrum anticonvulsant properties at nontoxic doses.34 In animal models, rufinamide’s protective index (PI = TD50/ED50) was superior to AEDs such as phenobarbital, phenytoin, ethosuximide, and valproic acid.2,34
The maximal electroshock (MES) test can identify AEDs with potential efficacy against partial seizures and generalized tonic–clonic seizures.20,22,26 Rufinamide given orally was protective against MES-induced tonic–clonic seizures in both mice and rats with an ED50 of 23.9 mg/kg and 6.1 mg/kg, respectively. Rufinamide’s anticonvulsant potency in the MES test was comparable to standard AEDs (Table 1).9 In rats and mice, tolerance was not noted over 5 days.34
The subcutaneous pentylenetetrazole (PTZ) test can identify AEDs with potential efficacy against clonic or absence seizures.20,22,26 Rufinamide’s efficacy in the subcutaneous PTZ test was species and route dependent. In mice, rufinamide suppressed PTZ-induced seizures with an ED50 of 45.8 mg/kg.34 Although orally administered rufinamide’s ED50 is less potent than phenobarbital’s ED50 (12.6 mg/kg), it is lower than the ED50 values for ethosuximide, valproic acid, and phenytoin9 (Table 2). Intraperitoneal rufinamide suppressed PTZ-induced clonus with an ED50 of 54.5mg/kg in mice.34 In rats, oral rufinamide was inactive against subcutaneous-induced PTZ seizure9 (Table 2).
Intraperitoneal rufinamide blocked clonic seizures induced by subcutaneous bicuculline and picrotoxin in mice with ED50 values of 50.5 mg/kg and 76.3 mg/kg, respectively.34 Similar to its results in the PTZ test, rufinamide was less potent than phenobarbital but more potent than ethosuximide and valproic acid (phenytoin is inactive in this test).9 For seizures induced by intraperitoneal picrotoxin, rufinamide had lower potency (ED50 of about 300 mg/kg). Rufinamide’s lowest potency was seen in mice in the glycine-related subcutaneous or intraperitoneal strychnine test, where the maximum protection rate of 37.5% occurred at a dose of 125 mg/kg.9,29 Overall, rufinamide’s tolerability (determined by either the chimney test in rats or the Rotorod test [6 rpm] at time of peak neurotoxic effect in mice) was similar to or exceeded that of any established AED except phenytoin administered orally to rats.34
Once-daily threshold electrical stimulation of the amygdala in animals induces epileptic electroencephalogram (EEG) afterdischarges and results in the kindling phenomenon.15,16,20,28 In rats treated daily with oral rufinamide (20 mg/kg and 60 mg/kg) an increase in afterdischarge duration occurred, but no change in convulsive behavior was seen compared with controls.29 Carbamazepine and phenytoin produce similar effects.23,30 In cats, oral rufinamide (100 mg/kg and 300 mg/kg) delayed kindling development and suppressed afterdischarges in fully kindled animals. Carbamazepine (40 mg/kg) and valproic acid (180 mg/kg) produced similar effects.9 Rufinamide antagonized kindling but did not provoke motor disturbances.9
Electrically induced hippocampal and cortical afterdischarges are also used to investigate the effects of AEDs against seizures originating from a focus. In cats, intraperitoneal rufinamide (300 mg/kg) reduced hippocampal and cortical afterdischarge duration by more than 50%.9 Rhesus monkeys with aluminum hydroxide implants in the motor cortex provide an animal model of chronically recurring partial seizures with or without secondary generalization. Subchronic treatment with oral rufinamide (30–50 mg/kg daily for 15 days) reduced seizure frequency by 75% to 100% without a significant change in mean seizure duration.9
FIGURE 1. Chemical structure of rufinamide and its major acid metabolite.
Table 1 Rufinamide and other orally administered AEDs. ED50 for the MES test in rodents (performed at NIH and Novartis pharmaceuticals)9,29
  Mouse: ED50 in mg/kg Rat: ED50 in mg/kg
Compound NIH Novartis NIH Novartis
Rufinamide 23.9 19.2 6.1 8.0
Carbamazepine n.r. 13.7 n.r. 8.0
Phenytoin 9.0 11.0 29.8 26.0
Lamotrigine n.r. 6.1 n.r. 4.7
Topiramate n.r. 35.7 n.r. 17.3
Phenobarbital 20.1 16.5 9.1 5.5
Valproic acid 664 220 489 450
Ethosuximide Ø 2,000 >1,000 Ø 1,200 >600
Pretreatment period: variable (NIH), 1 hour (Novartis); n.r., not reported; Ø, no effect at indicated dose; >, less than 50% protection at indicated dose.
Mechanism of Action
Rufinamide’s full mechanism of action is not yet known in detail. Some of its anticonvulsant effect is thought to result, in part, from blocking Na channels.24 In rat cortical neurons, over a wide range of concentrations, rufinamide caused rest- and use-dependent block of Na currents coupled with slowed recovery from inactivation.24 The rufinamide concentration that limited firing in 50% of neurons was 3.8 μmol /L (range 2–10 μmol/L).24
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Rufinamide does not significantly interact with neurotransmitter systems, including γ-aminobutyric acid (GABA), adenosine, monoaminergic and cholinergic binding sites, N-methyl-D-aspartate (NMDA), and other excitatory amino acid binding sites.17,29
Clinical Pharmacokinetics
Absorption
During Phase I clinical trials, single- and multiple-dose studies were performed in healthy subjects to assess the pharmacokinetic profile of rufinamide. Based on urinary recovery of radioactivity following oral administration of C14–labelled drug (600 mg as capsules) with food, the bioavailability of low doses of rufinamide was estimated to be approximately 85%.9 Peak plasma concentration (Cmax) of rufinamide was reached 5 to 6 hours after dosing.2,3,7 The intersubject variability in the mean area under curve (AUC) and Cmax values of rufinamide were less than 26% for both tablets and suspension. Contribution of the intrasubject variability to the overall variability was small (20%).2,7 The tablet formulation was bioequivalent to the suspension in terms of rate and extent of absorption. Rufinamide exhibited dose-limited absorption; doses higher than 400 mg for both fasted and fed healthy subjects demonstrated less than proportional increase in peak concentrations (Cmax) and plasma AUC.9 Similar to the single-dose healthy volunteer studies, multiple-dose studies found a less than dose proportional increase in steady-state rufinamide plasma levels, due to dose-limited absorption.9
After intake in the fasting state, rufinamide has an oral bioavailability of approximately 60%; however, food increases rufinamide’s extent of absorption and plasma exposure (AUC).3,15 In a 1998 Phase I study using an older formulation, food increased the extent of absorption or plasma exposure AUC by 44% and the Cmax by 100%.6 The time to reach Cmax (tmax) was 8 hours in fasted conditions and 6 hours in those fed after breakfast.6 However, unpublished data using a newer formulation of rufinamide indicates food increases rufinamide’s extent of absorption or plasma exposure AUC by 34% and the Cmax by 56%.9 The increase in rufinamide’s AUC when administered concomitantly with food might be due to a change in gastrointestinal absorption and dissolution of the parent drug. The low water solubility and high lipophilicity (as indicated by its relatively large partition coefficient; logP = 0.88) supports the hypothesis of an increased solubility in the presence of food due to a larger volume of liquid and stimulated biliary secretion.5
Plasma Protein Binding and Distribution
Rufinamide’s protein binding is low (34%).2,17 Binding is predominantly to albumin. Rufinamide is evenly distributed between erythrocytes and plasma, and its apparent volume of distribution (V/F) is similar to the total body water (50–80 L).3,9
Metabolism and Elimination
Rufinamide is extensively metabolized, and the metabolites are mainly excreted in the urine. Only a small fraction of the dose is eliminated unchanged in the urine (2%) and feces (2%).2,17 Rufinamide’s major metabolic pathway is hydrolysis of the carboxamide group to form the acid metabolite previously called CGP 47292.2,17 Minor additional metabolites have been detected and appear to be acyl-glucuronides of the acid metabolite.9 This hydrolytic metabolism does not appear to involve the hepatic microsomal cytochrome P450 isozyme system.9
Rufinamide metabolites are predominantly renally excre-ted.17 A single-dose study in three fed healthy male volunteers using 600 mg of [14C] rufinamide administered as microcrystalline solid in capsules found 80% of the total plasma radioactivity was rufinamide, and 16% its acid derivative.9 Rufinamide oral clearance (CL/F) is dose-dependent and, at
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a median dose level, ranges between 2.7 L/hour (children) and 6.6 L/hour (adults). The half-life of rufinamide ranges from 6 to 10 hours.2,17
Pharmacokinetics in Epilepsy Patients
Rufinamide’s pharmacokinetics in patients with epilepsy was studied in a trial involving 647 adults (ages 15 to 65 years), taking one to three concomitant AEDs, with treatment-resistant partial seizures (with or without secondary generalization). Patients were randomized equally to either rufinamide 200 mg/day, rufinamide 400 mg/day, rufinamide 800 mg/day, rufinamide 1,600 mg/day, or placebo. Rufinamide was given twice daily (b.i.d.) in all trials except the monotherapy trials, where it was given three times a day (t.i.d.). Plasma rufinamide levels increased approximately dose-proportionally with doses of 800 mg/day or less, but when doses were more than 800 mg/day, a less than proportional increase in rufinamide plasma levels was observed.10
Rufinamide did not demonstrate linear pharmacokinetics in a study of ascending doses in 16 pediatric patients with inadequately controlled seizures receiving one to two other concomitant AEDs.1 In this study, rufinamide was administered orally (b.i.d. dosing) over 14 days at a starting dosage of approximately 10 mg/kg per day (days 1–7) and then increased to 30 mg/kg per day (days 8–14). A 12–hour pharmacokinetic profile was obtained on days 7 and 14. A threefold increase in rufinamide dose provided only a 2- to 2.5-fold increase in the AUC0–12h, Cmaxss, and minimum concentrations (Cminss) at steady state.1 There were no differences between any 2 of the 3 pediatric subgroups (under 6 years, 7–12 years, and 13 to under 18 years) for AUC0–12h, Cmaxss, and Cminss.1
In a trial of 65 patients with LGS, rufinamide’s CL/F increased linearly with increased body surface area, independent of patient age, sex, or race.8 Using a patient of median body surface area and taking a median dose level for the relevant age group, the typical values of rufinamide’s CL/F in adults was 6.6 L/hour, adolescents 4.5 L/hour, and children 2.7 L/hour. The median body sizes used for this calculation were 24.0, 40.5, and 66.2 kg, respectively, for the three groups. Clearance was not affected by kidney function.8 Rufinamide’s bioavailability decreased with increasing doses.8
Gender did not appear to have a significant influence on rufinamide pharmacokinetics.9 Age (4–65 years) was tested as a covariate in population pharmacokinetic studies and in two studies (one pediatric, one elderly). Age itself was not a significant covariate after taking into account body size.
Table 2 Rufinamide and other orally administered AEDs. ED50 for the s.c PTZ test in rodents (performed at NIH)9
Compound Mouse: ED50 in
mg/kg		 Rat: ED50 in
mg/kg
Rufinamide 45.8 Ø–1000
Phenytoin Ø–300 Ø–800
Phenobarbital 12.6 11.6
Valproic acid 388 179
Ethosuximide 192 54.0
Pretreatment period: variable; Ø, no effect at indicated dose.
Efficacy
Overview of Clinical Efficacy Trials in Humans
Following a proof-of-principle study in adults with partial or primary generalized tonic–clonic seizures,25 rufinamide had been studied in randomized controlled trials of adults with treatment-resistant partial onset seizures either as adjunctive therapy5,10 or monotherapy,21,32 children with treatment-resistant partial onset seizures,12 adults with treatment-resistant generalized tonic–clonic seizures,4 and children with LGS.13,14 Adjunctive rufinamide therapy was more efficacious than placebo adjunctive therapy in adults with treatment-resistant partial onset seizures and children with LGS.
Proof-of-Principle Study
A small, double-blind, placebo-controlled, randomized, parallel-group, weekly rising dose (400–1,600 mg/day) study was performed as the first proof-of-principle clinical trial examining the efficacy and tolerability of rufinamide therapy. Fifty patients with therapy-resistant partial or primary generalized tonic–clonic seizures were equally randomized to rufinamide and placebo treatment groups; rufinamide doses were increased weekly (to 400, 800, 1,200, and 1,600 mg/day over the course of the 4-week study). In the evaluable population, the rufinamide group had a larger median percentage change in seizure frequency compared with the placebo group (41% reduction, n = 23 vs. 52% increase, n = 21, p = 0.0397). The 50% responder rate (i.e., patients experiencing ≥50% reduction in seizure frequency per 28 days from Baseline Phase) was higher in the rufinamide group compared with the placebo group (39% vs. 16%, p = 0.096); this trend was seen despite the small sample size. Based on this proof-of-principle study, further studies were conducted to better delineate rufinamide’s anticonvulsant efficacy.25
Adults with Partial Onset Seizures: Adjunctive Therapy
The results of a double-blind, randomized, placebo-controlled, parallel-group study examining the efficacy of rufinamide versus placebo in adults with inadequately controlled partial seizures had been reported in abstract.10 Adults (ages 15–65 years) on one to three concomitant AEDs with nine or more partial seizures (with or without secondary generalization) during a 3-month baseline were eligible for a 3-month double-blind treatment phase. Patients were randomized equally to either rufinamide 200 mg/day, rufinamide 400 mg/day, rufinamide 800 mg/day, rufinamide 1,600 mg/day, or placebo. Among the 737 enrolled patients, 647 were randomized at the end of the baseline period. Rufinamide demonstrated a linear trend for dose response for seizure frequency per 28 days in the double-blind period (p = 0.003) and for treatment responders (p = 0.0035). Compared with the placebo group, the median seizure frequency ratio was significantly reduced in patients treated with rufinamide 400 mg/day (11%, p = 0.0274), rufinamide 800 mg/day (16%, p = 0.0123), and rufinamide 1,600 mg/day (17%, p = 0.0163). The seizure frequency ratio for each patient was the number of seizures that occurred during the double-blind phase divided by the number of seizures that occurred during the baseline phase. This was expressed per 28-day intervals. The authors concluded that rufinamide’s efficacy was demonstrated in a dose-dependent manner.10
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Another multicenter, double-blind, placebo-controlled, randomized, parallel-group study that assessed the efficacy of adjunctive rufinamide therapy in adult patients with inadequately controlled partial seizures was reported in an abstract form.5 Adults (ages 16 and older) on one or two concomitant AEDs with six or more partial seizures during a 56-day baseline were eligible for a 91-day double-blind treatment phase. Eligible patients were then randomized to rufinamide adjunctive therapy (3,200 mg/day) or placebo adjunctive therapy. The titration period was 14 days, and the maintenance period was 77 days. The 313 randomized patients were evenly divided between the two treatment arms (rufinamide, n = 156; placebo, n = 157). The median reduction in partial seizures per 28 days relative to baseline was better in the rufinamide group compared with the placebo group (rufinamide 20.4% reduction; placebo 1.6% median increase, p = 0.0158). The percentage of treatment responders (patients with ≥50% reduction in partial seizure frequency) was higher in the rufinamide group compared with the placebo group (28.2% vs. 18.6%, p = 0.0381). The study concluded that rufinamide adjunctive therapy (3,200 mg/day) was generally effective for adult patients with inadequately controlled partial seizures.5
Children with Partial Onset Seizures: Adjunctive Therapy
Based on the efficacy of rufinamide in adults with partial seizures, a randomized, double-blind, placebo-controlled, adjunctive therapy trial was conducted to assess the efficacy and safety of rufinamide as adjunctive therapy in pediatric patients with inadequately controlled partial seizures taking stable dosages of one or two other AEDs. The results have been reported in abstract form.12 Following a 56-day baseline phase, 268 patients (4–16 years) were randomized to either rufinamide or placebo adjunctive therapy. Study drug dosages were titrated to 45 mg/kg per day over 14 days, followed by a 77-day maintenance period. There was no difference in the mean reduction in partial seizure frequency per 28 days between the adjunctive rufinamide patients and the placebo patients (7.0% vs. 12.8% respectively, p = 0.621). There was no difference in the percentage of treatment responders (defined as patients with ≥50% reduction in partial seizure frequency) between the adjunctive rufinamide group and the placebo group (27.2% vs. 18.3%, respectively, p = 0.060). This study did not demonstrate the efficacy of adjunctive rufinamide therapy for pediatric partial seizures.12
Adults with Partial Onset Seizures: Monotherapy
Two studies investigated the efficacy of rufinamide as monotherapy in patients with treatment-resistant partial seizures.21,32 One study employed a double-blind, placebo-controlled, parallel-group, monotherapy design in adolescent (≥12 years) and adult patients with treatment-resistant partial seizures who had completed an inpatient evaluation for epilepsy surgery.21 Following a 48-hour baseline phase, patients were randomized to double-blind monotherapy of either rufinamide or placebo for 10 days. During the double-blind phase, the rufinamide doses were initiated at 2,400 mg/day on day 1, then increased to 3,200 mg/day on day 2, and maintained at that dose for the remainder of the 10 days. Patients exited in the double-blind phase if they met any of four defined sets of types and numbers of seizures. A total of 104 patients were evenly randomized to rufinamide (n = 52) or placebo (n = 52). During the double-blind phase, the group’s mean daily rufinamide dose was 2,970.7 mg/day. The rufinamide-treated patients had a greater median number of days to meet one or more exit criteria versus placebo-treated patients (4.8 vs. 2.4 respectively, p = 0.0499). The rufinamide group had significantly greater median times to first, second, and third partial seizures than did the placebo group (p < 0.0348). This study demonstrated that rufinamide was more effective than placebo as monotherapy for the short-term treatment of refractory partial seizures.21
A second monotherapy study examined the efficacy of high- versus low-dose rufinamide monotherapy in patients with treatment-resistant partial seizures using a double-blind, randomized, parallel-group study design.32 Eligible patients with treatment-resistant partial seizures on one or two AEDs were randomized to either a low rufinamide dose (300 mg/day, n = 70) or a high rufinamide dose (3,200 mg/day, n = 72) for 112 days. During the first 42 days of the double-blind phase, rufinamide was titrated upward and concomitant AEDs were simultaneously tapered. Patients either exited the study by meeting criteria based on severity and frequency of seizures or completed the entire 112 days of therapy. A total of 142 patients (12 years and older) were randomized: 70 to rufinamide 300 mg/day and 72 to rufinamide 3,200 mg/day. There was no significant difference between the groups for the primary outcome variable: the percentage of patients meeting one exit criterion (high-dose 66.7% vs. low-dose 72.5%, p = 0.4402). The median time to meeting one exit criterion was not different between the two groups (high-dose, 56 days vs. low-dose, 32 days, p = 0.0968). Overall, the efficacy analysis did not show a significant difference between the high- and low-dose groups for the efficacy outcome variables.32
Adults with Primary Generalized Tonic–Clonic Seizures
A multicenter, double-blind, placebo-controlled study examined the efficacy of adjunctive rufinamide therapy (800 mg/day) for patients with treatment-resistant primary generalized tonic–clonic (GTC) seizures.4 A 56–day baseline phase was followed by a 140–day double-blind phase. Eligible patients were 4 years and older, with treatment-resistant primary GTC seizures, taking one or two concomitant AEDs, and they had at least three GTC seizures during the 56–day baseline phase (at least one seizure during each of two consecutive 28-day baseline periods). During baseline, the median number of GTC seizures per 28 days during baseline was 3.5 (range, 1.5–84). Following the baseline period, 153 patients (mean age 29.3 years, range, 4–63 years) were randomized to either rufinamide (n = 78) or placebo (n = 75). There was no difference in the median percent change from baseline in GTC seizure frequency per 28 days between the rufinamide and placebo groups (36.4% vs. 25.6%, respectively; p = 0.633). The responder rate (the percentage of patients who had ≥50% reduction in GTC seizure frequency relative to baseline) was not different between the two groups (p = 0.3162).
Lennox-Gastaut Syndrome
The efficacy of adjunctive rufinamide therapy for treatment-resistant LGS was examined in a multicenter, double-blind, placebo-controlled, randomized, parallel-group study.13,14 The study began with a 28-day baseline phase followed by an 84-day double-blind phase (14-day titration phase followed by a 70-day maintenance phase). Patients were eligible if they were between 4 and 30 years, had 90 seizures in the month prior to the baseline phase, and were taking one to three concomitant AEDs. The rufinamide target dose was 45 mg/kg per day. A total of 138 patients, mean age of 14.1 years (range, 4–37 years),
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was randomized to either rufinamide (n = 74) or placebo (n = 64). The median dose in both groups was 1,800 mg/day (42–45 mg/kg/day). In the rufinamide group, the median percent reduction in total seizure frequency per 28 days relative to the baseline phase was significantly higher than in the placebo group (32.7% vs. 11.7%, p = 0.0015). The median percent reduction in tonic–atonic seizure frequency per 28 days relative to the baseline phase was significantly higher in the rufinamide group compared to the placebo group (42.5% vs. 1.4%, p < 0.0001). The tonic–atonic seizure responder rate was significantly higher in the rufinamide group compared with the placebo group (42.5% vs. 16.7%, p = 0.0020) (Fig. 2). An improvement in seizure severity was observed in 53.4% of the rufinamide group compared with 30.6% of the placebo group (p = 0.0041). The authors concluded that rufinamide was efficacious as an adjunctive therapy for the treatment of resistant seizures in patients with LGS.
FIGURE 2. Percentage of Lennox-Gastaut patients with ≥50% reduction in tonic–atonic and total seizure frequency (per 28 days during the double-blind phase relative to baseline).
Adverse Events
Dose-Related, Nonidiosyncratic Adverse Effects
In animal studies, rufinamide’s safety ratio (defined as the toxic dose in 3% of animals/effective dose in 97% of animals, the TD3/ED97) was 3 to 900 times greater than for other AEDs.2
In humans, the short- and long-term safety of rufinamide in patients with epilepsy was evaluated in a pooled analysis of the adverse event reports from clinical studies.19 Safety data from all patients with epilepsy who received one or more doses of study drug in any of 12 double-blind, placebo-controlled studies or 12 controlled or open-label studies of rufinamide for short- and long-term therapy were included. The analysis of adverse events used the Medical Dictionary for Regulatory Activities, and results were presented by system organ class. The results were reported in abstract form and only common adverse events that occurred in 10% or more of patients were identified. In addition, the analysis examined the time to onset of the common adverse events in only the double-blind, placebo-controlled studies.19
Table 3 Adverse events in placebo controlled rufinamide trials
  Rufinamide (n = 1,240) Placebo (n = 635)
Headache 22.9 18.9
Dizziness 15.5 9.4
Fatigue 13.6 9.0
Somnolence 11.8 9.1
Nausea 11.4 7.6
Short-term safety data from 1,240 rufinamide-treated patients and 635 placebo patients (mean ages, 31.7 and 28.6 years, respectively) were analyzed. The median duration of exposure of rufinamide (2.8 months) and placebo (3.0 months) was similar. The group’s mean rufinamide dose was 1,373 mg/day. The most frequently reported short-term adverse events are shown in Table 3.19 The time to onset of these short-term adverse events was comparable between the groups. The most commonly reported serious adverse events were epilepsy-related, such as convulsions. Overall, serious adverse events were noted in 6.3% of rufinamide-treated patients compared with 3.9% of placebo-treated patients. Treatment discontinuations due to adverse events were higher among rufinamide-treated patients compared with placebo-treated patients (8.1% vs. 4.3%).19
The long-term safety of rufinamide was assessed in 1,978 patients (mean age, 31.3 years) who took rufinamide in controlled or open studies of less than 1 month to more than 4 years in duration. Almost half the patients (47%) had taken rufinamide for 12 months or longer. In this long-term exposure group, the mean rufinamide dose was 1,700 mg/day, with a maximum dose of 7,200 mg/day. The most common organ systems involved were the nervous (64.7%) and gastrointestinal systems (42.3%).19 The most frequently reported adverse events seen in patients receiving long-term rufinamide therapy were headache (29.5%), dizziness (22.5%), and fatigue (17.7%). Adverse events led to rufinamide discontinuation in 13.1% of the patients.19 The most common serious adverse events were convulsion, status epilepticus (SE), and pneumonia; overall, 13.2% of patients reported serious adverse events. As the median rufinamide dose increased, the rates of adverse events generally increased. The authors concluded that overall, rufinamide was well tolerated, the commonly occurring short-term adverse events had an early onset with rapid resolution, and long-term rufinamide use was safe and well tolerated.19
In the placebo-controlled adjunctive rufinamide pediatric partial seizure trial, the most commonly reported adverse events were headache (rufinamide, 19.1% vs. placebo, 9.8%), somnolence (14.7% vs. 8.3%), vomiting (13.2% vs. 6.1%),
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and upper respiratory tract infection (6.6% vs. 11.4%). All adverse events classified were mild to moderate in severity. Ten rufinamide-treated patients (7.4%) and four placebo-treated patients (3.0%) prematurely discontinued the study due to adverse events. Ten rufinamide-treated (7.4%) and nine placebo-treated (6.8%) patients had nonfatal serious adverse events.12
In the controlled trial involving LGS patients, the most common adverse events experienced included somnolence (24.3% rufinamide, 12.5% placebo), vomiting (21.6% rufinamide, 6.3% placebo), pyrexia (13.5% rufinamide, 17.2% placebo), and diarrhea (5.4% rufinamide, 10.9% placebo). Cognitive/psychiatric adverse events of interest, such as psychomotor hyperactivity and lethargy, occurred in a lower percentage of patients in the rufinamide group (17.6%) than the placebo group (23.4%).13,14
To date, rufinamide is not associated with consistent clinically significant changes in vital signs, physical examinations, electrocardiogram (ECG) recordings, or laboratory tests.1,4,5,12,13,14,21,32,33 No deaths have been reported in the volunteer-treated population.9 Twenty-eight deaths have been reported in patients who received either rufinamide or placebo to date.9 All deaths occurred in patients with epilepsy. For all treated patients with epilepsy, the rate of deaths was 0.71 per 100 patient-years of exposure to rufinamide. The rates were 0.69 per 100 patient-years of exposure to rufinamide and 2.67 per 100 patient-years of exposure to placebo for all patients with epilepsy who received study drug in double-blind studies. None of the deaths was considered to be causally related to rufinamide therapy by either the investigator or the Novartis Medical Monitor.9 The rate of sudden death was 0 per 100 patient-years for rufinamide and 2.67 per 100 patient-years for placebo.
Idiosyncratic Reactions
The incidence of skin rash is not higher in rufinamide-treated patients compared with placebo (3.1% vs. 3.3%). None of the 1,978 patients included in the clinical database experienced erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis. However, a total of five patients in the clinical database might have suffered an AED hypersensitivity syndrome (fever, rash, and any evidence of internal organ involvement). In all cases, the reaction appeared during the first 4 weeks of treatment. All patients were children. None of them had mucosal involvement or blistering of the skin. All patients quickly recovered after discontinuation of rufinamide.
Status Epilepticus
Estimates of the incidence of treatment-emergent SE among patients treated with rufinamide are difficult because standard definitions were not employed. In controlled trials, 11 of 1,240 (0.9%) patients had episodes that could be described as SE in the rufinamide-treated patients compared with none in the placebo-treated patients.
Teratogenicity
To date, no reports of newborn malformations have been associated with maternal rufinamide use. Thirteen pregnancies occurred during the clinical studies (database includes 979 females treated with rufinamide). Six of the 13 pregnancies were known to have resulted in the birth of six healthy babies. One pregnancy was ended by a spontaneous abortion, and three by elective abortions. No information was provided to the sponsor about the outcome of the remaining three pregnancies. However, the overall patient exposure is too low to make any definitive conclusions. Rufinamide is likely to be excreted in breast milk.
Drug Interactions
In vitro testing using human liver microsomes demonstrated that rufinamide did not act as a competitive or mechanism-based inhibitor of the following human P450 enzymes: CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2El, CYP3A4/5, or CYP4A9/11.17,18 These results indicate that rufinamide should not be expected to inhibit the pharmacokinetics or biotransformation of coadministered drugs metabolized primarily by CYP isozymes.17
In patients taking AED polytherapy, rufinamide does not cause clinically significant effects on the pharmacokinetics of concomitant AEDs.11 A pooled analysis of rufinamide effect on the pharmacokinetics of carbamazepine, lamotrigine, phenobarbital, phenytoin, topiramate, and valproate was performed using five rufinamide multicenter, double-blind, placebo-controlled, randomized, parallel-group studies. The results have been reported in abstract form.11 These studies involved pediatric and adult epilepsy patients treated with one to three AEDs.11 The population pharmacokinetic analysis used nonlinear mixed-effect modeling (NONMEM). Six separate populations were analyzed based on the concomitant AEDs: carbamazepine (n = 903, median age 32.3 years, range 3.9–68.8 years); lamotrigine (n = 200, median age 22.7 years, range 4.7–68.5 years); phenobarbital (n = 149, median age 34.5 years, range 4.3–62.6 years); phenytoin (n = 299, median age 34.4 years, range 4.5–72.3 years); topiramate (n = 69, median age 15.6 years, range 4.1–53.7 years), and valproic acid (n = 488, median age 27.2 years, range 4.3–68.6 years). Rufinamide did not change the CL/F of topiramate and valproic acid but did increase to a minor extent the CL/F of carbamazepine and lamotrigine, while decreasing to a minor extent the oral clearance of phenobarbital and phenytoin (as a function of rufinamide plasma concentration). Rufinamide-induced changes in AED oral clearance were similar among age groups; rufinamide adjunctive therapy is predicted from the modeling to lead to a less than 18% change in the pre-rufinamide AED CL/F at a rufinamide concentration of 15 ug/mL (i.e., a typical steady-state rufinamide concentration in a patient taking either 45 mg/kg per day in children or 3,200 mg/day in adults). The changes in concurrent AEDs’ oral clearance would result in changes of steady-state AED concentrations of less than 21%.11
Rufinamide’s pharmacokinetics does not appear to be affected by carbamazepine, clobazam, oxcarbazepine, or vigabatrin.17 Valproic acid decreases rufinamide’s CL/F by approximately 22%; phenytoin and barbiturates increase rufinamide’s CL/F by approximately 25%.9,17
The effect of rufinamide on low-dose oral contraceptives was examined in a single-center, open-label, multiple-dose 56-day study.31 Overall, 18 healthy female volunteers took Ortho-Novum 1/35 for at least two cycles prior to randomization and throughout the entire study. Rufinamide 1,600 mg/day was given on days 22 through 35. Coadministration of rufinamide and Ortho-Novum 1/35 resulted in a mean decrease in the ethinyl estradiol AUCO-24 of 22% and norethindrone AUCO-24 by 14% on day 34, as compared with baseline levels taken on day 7. The clinical significance of this decrease is unknown since this study did not measure any markers of ovulation.17,31
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Role in Epilepsy Treatment
Indications
Rufinamide is not yet approved for prescription use. In controlled clinical trials, it has demonstrated efficacy against partial seizures in adults and in patients with LGS.5,10,14
Dosing Recommendations
In clinical trials, the best rufinamide efficacy results have been seen with doses of 3,200 mg/day in adults and 45 mg/kg per day in children. In adults, treatment should be initiated with a daily dose of 400 to 800 mg/day, as twice-daily dosing. Additional dosing increments may be given (400–800 mg/day every 2 days in two equally divided doses) to a maximum recommended daily dose of 3,200 mg. Doses greater than 3,200 mg/day have been used in open-label studies for periods of 48 months and longer. In general, no clinical trial evidence indicates that doses greater than 3,200 mg/day confer additional benefit. Dose titration should be guided by clinical outcome. In children, treatment should be initiated at a daily dose of approximately 10 mg/kg per day administered in two equally divided doses. The dose should be increased by approximately 10 mg/kg increments every other day to a maximum of 45 mg/kg per day or 3,200 mg/day, whichever is less, administered in two equally divided doses. Some patients have responded at lower doses, whereas others have needed higher dosages (up to 4,800 mg/day in adults). A more complete understanding of the optimal dosing for rufinamide must wait for a larger patient experience (e.g., through large-scale postmarketing clinical trials).
Precautions
In addition to hypersensitivity reactions and the incidence of SE mentioned earlier, rufinamide should be withdrawn gradually to minimize the risk of precipitating seizures, seizure exacerbation, or SE. If abrupt discontinuation of the drug is medically necessary, the transition to another AED should be made under close medical supervision. In clinical trials, rufinamide discontinuation was achieved by reducing the dose by approximately 25% every 2 days.
Contraindications
Rufinamide is contraindicated in patients with a known hypersensitivity to rufinamide, triazole derivatives, or to any excipients used in the formulation.
Summary and Conclusions
Both in animal models and in human clinical trials, rufinamide appears to have efficacy against a broad spectrum of seizure types. Efficacy is well documented as adjunctive therapy against partial-onset seizures in adults and generalized seizures in patients with LGS. Although overall patient exposure is still relatively low, its dose-dependent adverse event profile is encouraging, and there appears to be a low risk of idiosyncratic reactions. Rufinamide undergoes dose-dependent absorption, is eliminated with a half-life of 6 to 10 hours, and it shows a limited potential for drug interactions. It is not yet approved for prescription use.
Based on its characteristics and clinical trial results, rufinamide shows promise as a valuable addition to the currently approved assortment of AEDs.
References
1. Arroyo S, Sachdeo RC, Rosenfeld W, et al. Pharmacokinetics and safety of ascending doses of adjunctive rufinamide in pediatric patients with inadequately controlled seizures. Epilepsia. 2005;46(Suppl 8):193.
2. Bialer M, Johannessen SI, Kupferberg HJ, et al. Progress report on new antiepileptic drugs: a summary of the Fifth Eilat Conference (EILAT V). Epilepsy Res. 2001;43 (1):11–58.
3. Bialer M, Johannessen SI, Kupferberg HJ, et al. Progress report on new antiepileptic drugs: a summary of the Eighth Eilat Conference (EILAT VIII). Epilepsy Res. 2007; 73:1–52.
4. Biton V, Sachdeo RC, Rosenfeld W, et al. Efficacy and safety of adjunctive rufinamide in patients with inadequately controlled primary generalized tonic-clonic seizures. Epilepsia. 2005;46(Suppl 8):206.
5. Brodie MJ, Rosenfeld W, Vasquez B, et al. Efficacy and safety of rufinamide as adjunctive therapy in adult patients with inadequately controlled partial seizures. Epilepsia. 2005;46(Suppl 8):171.
6. Cardot JM, Lecaillon JB, Czendlik C, et al. The influence of food on the disposition of the antiepileptic rufinamide in healthy volunteers. Biopharm Drug Dispos. 1998;19(4):259–262.
7. Cheung WK, Kianifard F, Wong A, et al. Intra- and inter-subject variabilities of CGP 33101 after replicate single oral doses of two 200-mg tablets and 400-mg suspension. Pharm Res. 1995;12(12):1878–1882.
8. Critchley D, Fuseau E, Perdomo CA, et al. Pharmacokinetic and pharmacodynamic parameters of adjunctive rufinamide in patients with Lennox-Gastaut Syndrome. Epilepsia. 2005;46 (Suppl 8):209.
9. Eisai Company, Ltd. Data on file; 2004.
10. Elger C, Stefan H, Perdomo CA, et al. Dose-range relationships of rufinamide in patients with inadequately controlled partial seizures. Epilepsia. 2005;46(Suppl 8):83–84.
11. Fuseau E, Critchley D, Perdomo CA, et al. Population pharmacokinetic drug-drug interaction analyses of rufinamide studies in patients with epilepsy. Epilepsia. 2005;46 (Suppl 8):210–211.
12. Glauser T, Arzimanoglou A, Litzinger M, et al. Efficacy and safety of Rufinamide as adjunctive therapy for inadequately controlled partial seizures in pediatric patients. Epilepsia. 2005;46(Suppl 8):194–195.
13. Glauser T, Kluger G, Krauss GL, et al. Short term and long term efficacy and safety of rufinamide as adjunctive therapy in patients with inadequately controlled Lennox-Gastaut Syndrome. Neurology. 2006;66(Suppl 2):36.
14. Glauser T, Kluger G, Sachdeo RC, et al. Efficacy and safety of rufinamide adjunctive therapy in patients with Lennox–Gastaut Syndrome (LGS): a multicenter, randomized, double-blind, placebo-controlled, parallel trial. Neurology. 2005;64:1826.
15. Goddard GV. Development of epileptic seizures through brain stimulation at low intensity. Nature. 1967;214(92):1020–1021.
16. Goddard GV, McIntyre DC, Leech CK. A permanent change in brain function resulting from daily electrical stimulation. Exp Neurol. 1969;25(3):295-330.
17. Jain KK. An assessment of rufinamide as an anti-epileptic in comparison with other drugs in clinical development. Expert Opin Investig Drugs. 2000;9(4):829–840.
18. Kapeghian JC, Madan A, Parkinson A, et al. Evaluation of rufinamide, a novel anticonvulsant, for potential drug interactions in vitro. Epilepsia. 1996;37 (Suppl 5):26.
19. Krauss GL, Perdomo CA, Arroyo S. Short and long-term safety of rufinamide in patients with epilepsy. Epilepsia. 2005;46(Suppl 8):213.
20. Kupferberg H. Animal models used in the screening of antiepileptic drugs. Epilepsia. 2001;42(Suppl 4):7–12.
21. Lesser RP, Biton V, Sackellares JC, et al. Efficacy and safety of rufinamide monotherapy for the treatment of patients with refractory partial seizures. Epilepsia. 2005;46(Suppl 8):177–178.
22. Loscher W. Animal models of drug-resistant epilepsy. Novartis foundation symposium. 2002;243:149–159;discussion 59–66, 80–85.
23. Loscher W, Wauquier A. Use of animal models in developing guiding principles for polypharmacy in epilepsy. Epilepsy Res Suppl. 1996;11:61–65.
24. McLean MJ, Schmutz M, Pozza M, et al. The influence of rufinamide on sodium currents and action potential firing in rodent neurons. Epilepsia. 2005;46(Suppl 8):296.
25. Palhagen S, Canger R, Henriksen O, et al. Rufinamide: a double-blind, placebo-controlled proof of principle trial in patients with epilepsy. Epilepsy Res. 2001;43(2):115–124.
26. Rogawski M, Porter R. Antiepileptic drugs: pharmacological mechanisms and clinical efficacy with consideration of promising developmental state compounds. Pharmacol Rev. 1990;42:223–286.
27. Rouan MC, Souppart C, Alif L, et al. Automated analysis of a novel anti-epileptic compound, CGP 33,101, and its metabolite, CGP 47,292, in body fluids by high-performance liquid chromatography and liquid-solid extraction. J Chromatogr B Biomed Appl. 1995;667(2):307–313.
28. Schmutz M. Relevance of kindling and related processes to human epileptogenesis. Prog Neuropsychopharmacol Biol Psychiatry. 1987;11(4):505–525.
29. Schmutz M, Allgeier H, Jeker A, et al. Anticonvulsant profile of CGP33 101 in animals. Epilepsia. 1993;34(Suppl 2):122.
30. Schmutz M, Klebs K, Baltzer V. Inhibition or enhancement of kindling evolution by antiepileptics. J Neural Transm. 1988;72(3):245–257.
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31. Svendsen KD, Choi L, Chen BL. Single-center open-label, multiple dose, pharmacokinetic trial investigating the effect of rufinamide administration on Ortho-Novum 1/35 in healthy women. Epilepsia. 1998;39(Suppl 6):59.
32. Todorov A, Biton V, Krauss GL, et al. Efficacy and safety of high- versus low-dose rufinamide monotherapy in patients with inadequately controlled partial seizures. Epilepsia. 2005;46(Suppl 8):218–219.
33. Vazquez B, Sachdeo RC, Maxoutova AL, et al. Efficacy and safety of rufinamide as adjunctive therapy in adult patients with therapy-resistant partial-onset seizures. Epilepsia. 2000;41(Suppl 7):255.
34. White HS, Schmutz M, Pozza M, et al. The anticonvulsant profile and tolerability of rufinamide in mice and rats. Epilepsia. 2005;46(Suppl 8):305–306.
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