When rufinamide received its approval from the U.S. Food and Drug Administration (FDA) in November 2008, it was the first time that a new anticonvulsant medication was approved for use in the United States with an initial pediatric indication. Previously, in 2004, rufinamide had been designated as an orphan drug by the FDA for adjunctive use in the treatment of seizures associated with Lennox–Gastaut syndrome (LGS) in patients 4 years of age and older. After rufinamide was approved for use in Europe in 2007, this was followed by approval from the FDA in November 2008 for the adjunctive treatment of seizures associated with LGS in patients 4 years of age and older. Most recently, in February 2015, the FDA expanded the approval of rufinamide for the adjunctive treatment of seizures associated with LGS to patients 1 year of age and older.

CHEMISTRY, ANIMAL PHARMACOLOGY, AND MECHANISM OF ACTION

Rufinamide [1-(2,6-difluoro-phenyl) methyl-1 hydro-1,2,3-triazole-4 carboxamide] is atriazole derivative anticonvulsant medication which is structurally unrelated to any other currently used anticonvulsant medication. Preclinical animal studies suggest the anticonvulsant mechanism of action to include, at least in part, the prolongation of the recovery of sodium channels from the inactivated state, which results in a decrease in the frequency of sustained repetitive firing in neurons (1). Oral rufinamide has shown anticonvulsant activity in several different animal models to include pentylene-tetrazol–induced and maximal electroshock–induced seizures in mice (2). In addition, intraperitoneal rufinamide suppresses pentylene-tetrazol–induced, bicuculline-induced, and picrotoxin-induced clonic seizures in mice (2). This range of effectiveness in animal studies is supportive of the possibility of broad anticonvulsant properties for rufinamide.

BIOTRANSFORMATION, PHARMACOKINETICS, AND INTERACTIONS

Rufinamide is well absorbed (>85%) with oral administration, and this absorption is enhanced when taken with food (3) (Table 61.1). Although not likely to be clinically significant, absorption may be slightly less with incremental dose increases over 600 mg (3). Peak plasma concentration occurs within 4 to 6 hours, with a plasma half-life of 6 to 10 hours. Plasma protein binding is low (26% to 34%) (3). Metabolism is near complete (<2% is excreted unmetabolized) and occurs via hepatic hydrolysis of the carboxamide group by carboxylesterases, forming a metabolically inactive intermediate which is cleared renally. In younger children (less than 4 years of age), however, pharmacokinetic studies have found parameters such as maximum plasma concentration, average plasma concentration, and half-life to be extremely variable, compared to studies in older children (4).

Owing to its minimal effect upon the cytochrome P450 system, rufinamide has a relatively low potential for drug–drug interactions (3). Rufinamide does not modify the clearance of topiramate or valproic acid. Rufinamide may slightly increase the clearance of carbamazepine and lamotrigine, and may slightly decrease the clearance of phenobarbital and phenytoin, with all predicted changes less than 17.5% (3). In terms of effects upon rufinamide metabolism, lamotrigine and topiramate do not affect the clearance of rufinamide. Valproic acid, however, may decrease the clearance of rufinamide, with the most prominent effects occurring in children. This occurrence, in part, may be due to the fact that children are on higher doses of valproic acid, rather than an age-related effect (3). In clinical practice, rufinamide dosing in children taking concomitant valproic acid may need to be considered for a decreased dosing, on average, by approximately 50% (3). Rufinamide may decrease blood levels of hormonal contraceptives, but the clinical significance of this is not known (5).

TABLE 61.1

CLINICAL EFFICACY

The approval of rufinamide by the FDA was advanced by pivotal trials focusing on refractory seizures in patients with LGS. LGS is a childhood epileptic encephalopathy of heterogeneous etiologies, which is characterized by medication-refractory epilepsy of multiple seizure types (most commonly tonic, atypical absence, and drop attacks), electroencephalogram findings of a slow spike-and-wave pattern, and cognitive impairment (6). Some seizure types in LGS, such as atypical absence, can occur so frequently that they are near impossible for caregivers to count. Thus, many studies involving rufinamide and LGS have focused on more easily countable seizures, such as “drop attack” seizures, in addition to caregiver estimates of total seizures. The term tonic–atonic seizures has been agreed upon by an international panel of child neurologists as an acceptable nomenclature for “drop attacks,” due to the difficulty that caregivers can have in separating tonic and atonic seizures (7). Furthermore, tonic–atonic seizures are a clinically significant outcome due to their relatively higher potential for injury (8). Although the optimal treatment of LGS has yet to be established (9), randomized placebo-controlled trials, open-label studies, and retrospective data support the efficacy and safety of rufinamide in the treatment of seizures associated with LGS, in addition to a broader range of seizure types in children.

Randomized, Placebo-Controlled Trials

Several large randomized placebo-controlled trials have been published evaluating rufinamide as an adjunctive treatment in older adolescents and adults for partial-onset seizures, demonstrating significant differences in favor of rufinamide versus placebo in responder rates (defined as a 50% or greater reduction in seizure frequency) (10–13), and with a significant linear trend of dose response (12). A recent meta-analysis also supports the efficacy of rufinamide as adjunctive therapy in patients with medication-refractory epilepsy (14).

Two randomized placebo-controlled trials evaluating the use of rufinamide in the treatment of seizures associated with LGS in a mostly pediatric study population have been published. In 2008, Glauser et al published their double-blind, randomized, placebo-controlled trial of rufinamide in patients with LGS (7). In this study, there were 74 patients randomized to adjunctive rufinamide, with an age range of 4 to 37 years (median age 12 years), and 64 to placebo. The approximate target dosing was 45 mg/kg/day, achieved by 87.8% of the rufinamide-treated group, up to 3,200 mg/day. After a 12-week parallel-group treatment period, the median percentage decrease in caregiver-reported total countable seizures per 28 days for those treated with rufinamide was 32.7%, compared to 11.7% with placebo (P = .0015). Responder rates for total seizures were higher in the rufinamide group (31.1%) versus placebo (10.9%) (P = .0045). Efficacy for tonic–atonic seizures was especially pronounced, with a median percentage decrease per 28 days with rufinamide of 42.5% compared to an increase of 1.4% with placebo (P < .0001). Although 4.1% treated with rufinamide achieved complete cessation of tonic–atonic seizures, 3.3% treated with placebo did also (P = .8414), with no patients achieving complete seizure freedom. Furthermore, based upon a seven-point Likert scale, caregivers rated a greater decrease in seizure severity with rufinamide versus placebo (P = .0041).

In 2014, Ohtsuka et al published their results of a randomized, double-blind, placebo-controlled trial in Japan of rufinamide as adjunctive therapy for LGS (15). Although the majority of patients enrolled were under 18 years of age, the study population trended slightly older with a mean of 16 years of age in the group randomized to adjunctive rufinamide. This was a smaller study, with 29 patients randomized to the rufinamide group, but statistical significance was still achieved in the primary end points: the percent change of both total seizures and tonic–atonic seizures was significant versus placebo (P < .001 and P = .003, respectively). Compared to the study from Glauser et al, the median percentage change in seizure frequency in this study was similar (32.9% decrease versus Glauser et al 32.7% decrease), but the percent change in tonic–atonic seizures was smaller (24.2% decrease versus Glauser et al 42.5% decrease).

Prospective Open-Label Studies in LGS

In the open-label extension of the original randomized controlled study by Glauser et al converting patients with LGS in the placebo group to treatment with rufinamide, 124 patients, with an age range of 4 to 37 years (mean age 14.2 years), were treated with adjunctive rufinamide for 10 to 1,149 days (median 432 days) (7,16). During the open-label period, dosing adjustments were made at the investigator’s discretion, with a median dosing of 52.9 mg/kg/day. During the last 12 months of treatment, the responder rates were 41% for total seizures and 47.9% for tonic–atonic seizures, demonstrating more sustained efficacy over a longer time period.

Two additional prospective open-label studies have also evaluated adjunctive rufinamide in LGS. In one of these studies, 43 patients with LGS, with an age range of 4 to 34 years (median age 15 years), were treated with adjunctive rufinamide for 3 to 21 months (mean 12.3 months) (17). The final mean dosing was 33.5 mg/kg/day if combined with valproic acid and 54.5 mg/kg/day if not. The response rate for countable seizures was 60.5% and for drop seizures the response rate was 46.5% after a mean 12-month observational period. In another study, 128 patients with LGS, with an age range of 1 to 19 years (mean age 9.4 years), were treated with a mean final dosing of 31.7 mg/kg/day of adjunctive rufinamide over a 12-week maintenance treatment period (18). The response rate for overall seizures was 35.9%, and the response rate for drop seizures was 36.5%.

Prospective Open-Label Studies in Broader Patient Populations

In a prospective open-label study, 38 patients, with an age range of 4 to 34 years (median age 12.5 years), with different types of childhood-onset refractory epileptic encephalopathies, were treated with adjunctive rufinamide for 3 to 26 months (mean 11.4 months) (19). The final mean dosing was 37.9 mg/kg/day if combined with valproic acid and 36.4 mg/kg/day if not. This population of epileptic encephalopathies included 22 patients with a multifocal encephalopathy with spasms/tonic seizures, 11 patients with a multifocal encephalopathy with bifrontal spike-wave discharges, 4 patients with Dravet syndrome, and 1 patient with Doose syndrome. The overall response rate for countable seizures was 39.5%.

Further prospective open-label studies have provided evidence of efficacy of rufinamide for focal onset seizures. In one study, 70 patients, with an age range of 3 to 21 years (mean age 10.7 years), with refractory partial-onset seizures were treated with adjunctive rufinamide and followed for 12 months (20). The final mean dosing was 31.8 mg/kg/day if combined with valproic acid and 42.6 mg/kg/day if not. At 12 months the overall seizure response rate was 38.5%. In another study, 32.3% of 68 patients with refractory cryptogenic or symptomatic focal seizures treated with adjunctive rufinamide had a 50% to 99% seizure reduction (21). Rufinamide may be especially effective in patients with refractory epilepsy due to neuronal migration disorders. In an open-label, adjunctive treatment study of 69 patients with neuronal migration disorders, with a mean age of 15 years, 62% of patients treated with rufinamide had a 50% to 99% seizure reduction (22).

Retrospective Studies in Broader Patient Populations

In an open-label retrospective study, 60 patients, with an age range of 1 to 50 years (median age 11 years), with various epilepsy syndromes, were treated with adjunctive rufinamide with results reported at 12 weeks (23), and with further results for 52 out of 60 of the same patient cohort reported at 18 months (24). The median maintenance dose was 35.5 mg/kg/day. At 12 weeks, the overall seizure response rate for seizure reduction was 46.7%, with the highest rate in patients with LGS (54.8%), and the lowest in patients with partial epilepsy (23.5%) (23). At 18 months, the overall seizure response rate was 26.7%, with the highest subgroup still for LGS (35.5%) (24). Although still showing long-term efficacy, there was a slight decrease in this patient cohort from 12 weeks to 18 months. It was noted by the investigators that this could be explained by the fact that the efficacy of rufinamide may be more sustained in LGS than in partial epilepsy, as patients with LGS had the highest retention rates at 18 months (51.6%), with only a 17.6% retention rate for patients with partial epilepsies.

Several other retrospective studies examining the broad clinical use of rufinamide in pediatric epilepsy have also been published. These retrospective studies have reported variable efficacy with responder rates ranging from 21% to 55% (25–31). In the largest retrospective study published of adjunctive rufinamide in 300 patients of heterogenous etiologies (median age of 9.1 years and a median follow-up of 9 months), the responder rate was 54.7%, with a median seizure frequency reduction of 59.2%, and 14% achieving seizure freedom (32).

Retrospective Studies in Focused Patient Populations

In a retrospective study focused on epileptic spasms, Olson et al examined the response to rufinamide in patients with epileptic spasms of varying etiologies (33). Thirty-eight patients, with an age range of 17 months to 23 years (median age 7 years), were treated with adjunctive rufinamide for 10 to 408 days (median 171 days), with a median maintenance dose of 39 mg/kg/day. The responder rate for epileptic spasms was 53%. In addition, several small (3–8 patients) focused retrospective studies have been published on the successful use of adjunctive rufinamide for other epilepsy syndromes, to include epilepsy with myoclonic absences (34), malignant migrating partial epilepsy of infancy (35), myoclonic–astatic epilepsy (Doose syndrome) (36), and a single case report with methylmalonic aciduria (37).

However, a retrospective case series examining the use of adjunctive rufinamide for 20 patients with Dravet syndrome reported low long-term efficacy, with a responder rate at 6 months of 20% and at 34 months of 5% (38). Furthermore, seizure aggravation was reported by 30%. Patients with Dravet syndrome have also been included in other studies with heterogeneous patient populations: Kluger et al reported one out of two Dravet syndrome patients responding to rufinamide (23), Grosso et al reported no responders out of six (39), and Coppola et al reported no patient responders out of four, although one patient was reported to have a 25% to 49% decrease in seizures (19). However, two of the patients with Dravet syndrome in this series had resultant seizure aggravation with rufinamide treatment.

ADVERSE EFFECTS

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