Adjunctive Rufinamide Research Articles

Safety and efficacy of rufinamide in children and adults with Lennox-Gastaut syndrome: A post hoc analysis from Study 022

BackgroundLennox-Gastaut syndrome (LGS) is a developmental and epileptic encephalopathy with the first symptoms usually appearing during early childhood. Due to the highly variable underlying etiologies, LGS cannot be considered as one disease but as an electro-clinical entity, often challenging to diagnose early and treat accordingly. The anti-seizure medication, rufinamide, is indicated for the adjunctive treatment of patients with LGS aged ≥1 year. This post hoc analysis assessed the safety and efficacy of adjunctive rufinamide for total and tonic-atonic seizures during Study 022 in children (aged <16 years) and adults (aged ≥16 years). MethodsRandomized, placebo-controlled, phase III Study 022 included patients with a diagnosis of LGS and a history of multiple seizure types (including tonic-atonic or astatic seizures and atypical absence seizures; ≥90 seizures in the month prior to baseline). Assessments included monitoring of treatment-emergent adverse events (TEAEs), percent change in tonic-atonic seizure frequency/28 days during the double-blind phase relative to study baseline (a primary endpoint), and percentage of patients with ≥25%, ≥50%, or ≥75% reduction in seizure frequency relative to baseline. ResultsOf 138 enrolled patients, 74 received rufinamide (<16 years, n = 49 [66%]) and 64 received placebo (<16 years, n = 43 [67%]). Incidence of TEAEs was generally similar between age groups. The frequency (per 28 days) of tonic-atonic seizures was reduced with rufinamide (vs. placebo) in both younger and older patients: age <16 years (−41% vs. −6%), age ≥16 years (−55% vs. +16%) (p < 0.025; both age groups). In patients aged <16 years receiving rufinamide, 38% and 17% achieved ≥50% and ≥75% reductions in tonic-atonic seizure frequency vs. 18% and 3% with placebo, respectively. Corresponding responder rates for patients aged ≥16 years were 52% and 32% (rufinamide) vs. 15% and 5% (placebo), respectively. ConclusionsIn this post hoc analysis, adjunctive rufinamide was well tolerated and improved seizure control in patients with LGS, irrespective of age.

Cognitive, adaptive, and behavioral effects of adjunctive rufinamide in Lennox–Gastaut syndrome: A prospective observational clinical study

IntroductionLennox–Gastaut syndrome (LGS) is a severe pediatric epilepsy syndrome characterized by multiple drug-resistant seizure types. Children with LGS usually experience cognitive regression, and LGS is almost always associated with moderate to severe cognitive impairment. Rufinamide (RFM) was approved by the European Medicines Agency in 2007 for the adjunctive treatment of seizures associated with LGS in patients ≥4 years of age. The primary objective of our study was to assess cognitive, adaptive, and behavior functioning of patients with LGS after 12 months of RFM therapy. MethodsThis was an observational, multicenter, prospective study involving 16 patients diagnosed with LGS aged between 7 and 58 years (mean = 22 ± 16.3). Fourteen of 16 patients were already on therapy with 3 antiseizure drugs and 2/16 with 4 antiseizure drugs; RFM has been added with 100 mg/week increments up to a dose of 300–2400 mg/day. The participants and their parents underwent a neuropsychological evaluation for the assessment of intellectual, adaptive, and emotional/behavioral functioning (Leiter International Performance Scale-Revised (LEITER-R), Vineland, and Child Behavior CheckList (CBCL), respectively) before the RFM introduction (baseline) and 12 months after the RFM therapy (T2). Physical and neurological examination, electroencephalography (EEG) recording, seizure type and frequency, and adverse reactions were also considered. ResultsAfter 12 months, the total intelligence quotient (IQ) assessed by LEITER-R did not show statistical significant changes, such as there were no statistically significant changes in adaptive functions, assessed by Vineland. Furthermore, there were no statistically significant changes in internalizing and externalizing problems assessed by CBCL. ConclusionAdjunctive treatment with RFM did not negatively affect cognitive, adaptive function, and emotional profile in patients with LGS after 1 year of follow-up.

Efficacy and Safety of Adjunctive Rufinamide in Lennox-Gastaut Syndrome (LGS): Results from Studies 022, 022E, 303, 304, and 305 (P1.273)

Efficacy and Safety of Adjunctive Rufinamide in Lennox-Gastaut Syndrome (LGS): Results from Studies 022, 022E, 303, 304, and 305 (P1.273)

Rufinamide in children and adults in routine clinical practice.

To explore the long-term effectiveness of rufinamide in managing Lennox-Gastaut Syndrome (LGS), other epileptic encephalopathies, and intractable focal epilepsies in adults and children in routine clinical practice. A multicentre, retrospective chart review of patients prescribed adjunctive rufinamide at seven Spanish epilepsy centres, with assessments at six and 12 months. We evaluated data from 58 patients (40 male, age range 7-57 years), 25 of whom were diagnosed with LGS, 12 with other epileptic encephalopathies and 21 of whom were diagnosed with focal epilepsies, mainly frontal lobe. The mean daily rufinamide dose was 32.0 mg/kg (range 12.5-66.7 mg/kg) in children and 24.7 mg/kg (range 5.0-47.0 mg/kg) in adults, and the most commonly used concomitant antiepileptic drugs were levetiracetam and valproate. Rufinamide was discontinued in 25 patients (43.1%) during the 1-year follow-up, and the most common reason was lack of effectiveness (n = 12, 20.7% of total). The frequency of generalized tonic-clonic seizures was significantly reduced from baseline at 6 and 12 months (P = 0.001), both in patients with generalized epilepsies and in patients with focal epilepsies. Significant seizure frequency reduction from baseline was observed at 12 months (P = 0.01) for tonic/atonic seizures and at 6 months (P = 0.001) for focal seizures. Side effects were reported in 21 patients (36.2%): nausea, vomiting and weight loss were most frequent. Rufinamide was well tolerated and was effective in reducing frequency of generalized tonic-clonic, tonic/atonic and focal seizures in both children and adults with severe refractory epilepsies, primarily LGS.

Treatment of Adults with Lennox-Gastaut Syndrome: Further Analysis of Efficacy and Safety/Tolerability of Rufinamide.

IntroductionManagement of Lennox–Gastaut syndrome (LGS) in adulthood can be particularly challenging. Published reports describing the use of rufinamide specifically in adult patients with LGS are scarce. A post hoc subgroup analysis of data from a phase III trial was conducted to investigate the efficacy and safety/tolerability of rufinamide in adults with LGS.MethodsA randomized, double-blind, placebo-controlled trial was conducted in patients with LGS, aged 4 years and above. During an 84-day, double-blind treatment period, patients received either adjunctive rufinamide therapy or placebo. Efficacy and safety/tolerability were assessed in a post hoc subgroup analysis of adult patients (≥18 years). Efficacy was assessed as change from baseline in 28-day seizure frequency, 50% responder rate, and seizure freedom rate; each calculated for total seizures and drop attacks. Safety/tolerability assessments included the evaluation of adverse events (AEs).ResultsThirty-one adults aged 18–37 years with LGS received treatment with either rufinamide (n = 21) or placebo (n = 10). Three patients in the rufinamide group did not complete the trial. The median change from baseline in seizure frequency was −31.5% for rufinamide versus +22.1% for placebo (P = 0.008) for all seizures and −54.9% versus +21.7% (P = 0.002) for drop attacks. Responder rates were 33.3% for rufinamide versus 0% for placebo (P = 0.066) for all seizures and 57.1% versus 10.0% (P = 0.020) for drop attacks. No patient achieved freedom from all seizures but two rufinamide-treated patients (9.5%) became free of drop attacks. Overall, 71.4% of patients treated with rufinamide and 60.0% of patients treated with placebo experienced AEs; most commonly, somnolence (33.3% vs. 20.0%) and vomiting (19.0% vs. 0%). Most AEs were of mild or moderate intensity.ConclusionRufinamide demonstrated favorable efficacy and was generally well tolerated when used as adjunctive treatment for adults with LGS.FundingEisai.Electronic supplementary materialThe online version of this article (doi:10.1007/s40120-016-0041-9) contains supplementary material, which is available to authorized users.

Long-term safety and seizure outcome in Japanese patients with Lennox–Gastaut syndrome receiving adjunctive rufinamide therapy: An open-label study following a randomized clinical trial

PurposeTo evaluate the long-term safety and seizure outcome in Japanese patients with Lennox–Gastaut syndrome (LGS) receiving adjunctive rufinamide therapy. Subjects and methodsWe conducted an open-label extension study following a 12-week multicenter, randomized, double-blind, placebo-controlled study of adjunctive rufinamide therapy in Japanese patients with LGS. Fifty-four patients participated in the extension study. Seizure frequency was evaluated until 52 weeks after the start of the extension study. Adverse events (AEs) were evaluated throughout both studies. Key findingsOf the 54 patients, 41 (75.9%) completed the extension study. The median duration of exposure to rufinamide was 818.0 days in all 54 patients, and 38 patients (70.4%) received rufinamide for 2 years or more. The median percent change in the frequency of tonic–atonic seizures relative to the frequency at the start of the double-blind study was −39.3% (12 weeks), −40.6% (24 weeks), −46.8% (32 weeks), −47.6% (40 weeks), and −36.1% (52 weeks). Reduction of total seizure frequency was also maintained until 52 weeks. Frequent treatment-related AEs were somnolence (20.4%), decreased appetite (16.7%), transient seizure aggravation including status epilepticus (13.0%), vomiting (11.1%), and constipation (11.1%). Adverse events were mild or moderate, except for transient seizure aggravation in three patients. Adverse events resulting in discontinuation of rufinamide were decreased appetite, drug eruption, and worsening of underlying autism. When clinically notable weight loss was defined as a decrease ≥7% relative to baseline, 22 patients (40.7%) experienced weight loss at least once during long-term observation, although weight loss was reported as an AE in only three patients. SignificanceThis study demonstrated a long-term benefit of rufinamide as adjunctive therapy for Japanese patients with LGS. Exacerbation of seizures and decreased appetite/weight loss should be monitored carefully.

Effect of Adjunctive Rufinamide in Pediatric Patients With Inadequately Controlled Lennox-Gastaut Syndrome (LGS): Interim Pharmacokinetic and Safety Results From Study 303 (P1.242)

Effect of Adjunctive Rufinamide in Pediatric Patients With Inadequately Controlled Lennox-Gastaut Syndrome (LGS): Interim Pharmacokinetic and Safety Results From Study 303 (P1.242)

Lennox-Gastaut Syndrome: An Update on Treatment

Lennox-Gastaut syndrome (LGS) is a severe epileptic encephalopathy. Few current treatment options are effective in improving seizure control. This paper reviews the available treatments of LGS and discusses a new option in Canada, rufinamide. It is a wide spectrum anticonvulsant, approved in a number of countries for the treatment of LGS. In a randomized controlled trial in the LGS population, adjunctive rufinamide therapy has been shown to offer significantly greater reduction in total seizure frequency and tonic-atonic seizure frequency in comparison to placebo. Efficacy has been assessed over three years and appears to be sustained. Most adverse events were cognitive (e.g. somnolence) or gastrointestinal in nature and in many cases transient or mild. based on the efficacy and safety data on rufinamide obtained to date, this medication will provide additional benefits to patients with LGS in Canada and is an important consideration for our patients in the adjunctive treatment setting.

Rufinamide from clinical trials to clinical practice in the United States and Europe

Rufinamide is a triazole derivative structurally unrelated to other antiepileptic drugs that is indicated for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients aged ≥4 years. Originally granted orphan drug status, marketing authorisation was obtained on the basis of a randomised, double-blind, placebo-controlled trial conducted in 138 LGS patients. An open-label extension study subsequently demonstrated that rufinamide's efficacy and tolerability were maintained over the longer term (median duration of treatment, 432 days). Recently published reports from Europe and the United States have described the use of adjunctive rufinamide to treat LGS in clinical practice. These data complement the clinical trial results, by providing information on the efficacy and tolerability of rufinamide when used on an individualised basis in real-world practice, under less tightly restricted conditions in terms of patient population and dosing strategies. A comparison of the data reveals that a "lower and slower" dosing strategy tends to be adopted in clinical practice, in comparison with the clinical trial, which does not appear to compromise efficacy, but may provide improvements in tolerability. Individual case reports provide additional valuable information on how rufinamide is being used to treat different seizure types associated with LGS. Since clinical experience with rufinamide is currently at an early stage, there are still unanswered questions relating to its use, and it is likely that its place in the adjunctive treatment of LGS will evolve as further data emerge.

Activation of suicidal ideation with adjunctive rufinamide in bipolar disorder

Antiepileptic drugs are effective psychotropics, especially for bipolar disorder, which leads to their use off-label in treatment-refractory cases. A recent publication suggests that rufinamide may be beneficial adjunctively for bipolar disorder with comorbid psychopathology. This report addresses two negative cases with significant psychiatric adverse effects: increased depression, agitation, and activation of suicidal ideation. These findings suggest that adjunctive rufinamide may lead to increased suicidal ideation in patients with treatment-refractory bipolar disorder. Secondary to the course of severe bipolar disorder, rufinamide cannot be specifically implicated; however, clinicians should be aware of this potential significant adverse effect and monitor high-risk patients. Further studies are required to address rufinamide treatment efficacy and severity of adverse effects in patients with bipolar disorder.

A randomized, double‐blind, placebo‐controlled, parallel‐group study of rufinamide as adjunctive therapy for refractory partial‐onset seizures

Efficacy and safety of adjunctive rufinamide (3,200 mg/day) was assessed in adolescents and adults with inadequately controlled partial-onset seizures receiving maintenance therapy with up to three antiepileptic drugs (AEDs). This randomized, double-blind, placebo-controlled, parallel-group, multicenter study comprised a 56-day baseline phase (BP), 12-day titration phase, and 84-day maintenance phase (MP). The primary efficacy variable was percentage change in total partial seizure frequency per 28 days (MP vs. BP). Secondary efficacy outcome measures included ≥50% responder rate and reduction in mean total partial seizure frequency during the MP. Safety and tolerability evaluation included adverse events (AEs), physical and neurologic examinations, and laboratory values. Pharmacokinetic and pharmacodynamic assessments were conducted. Three hundred fifty-seven patients were randomized: 176 to rufinamide and 181 to placebo. Patients had a median of 13.3 seizures per 28 days during BP; 86% were receiving ≥2 AEDs. For the intent-to-treat population, the median percentage reduction in total partial seizure frequency per 28 days was 23.25 for rufinamide versus 9.80 for placebo (p = 0.007). Rufinamide-treated patients were more than twice as likely to have had a ≥50% reduction in partial seizure frequency (32.5% vs. 14.3%; p < 0.001) and had a greater reduction in median total partial seizure rate per 28 days during the MP (13.2 vs. 5.2; p < 0.001). Treatment-emergent AEs occurring at ≥5% higher incidence in the rufinamide group compared with placebo were dizziness, fatigue, nausea, somnolence, and diplopia. Adjunctive treatment with rufinamide reduced total partial seizures in refractory patients. AEs reported were consistent with the known tolerability profile of rufinamide.

Rufinamide: A New Antiepileptic Medication for the Treatment of Seizures Associated with Lennox-Gastaut Syndrome

To review the pharmacology, pharmacokinetics, efficacy, and safety of rufinamide in the treatment of epileptic seizures and describe its potential place in therapy. MEDLINE (1966-January 2010) and PubMed (1966-January 2010) literature searches were conducted to identify primary literature investigating rufinamide. References from selected publications discussing rufinamide, as well as the package insert, were reviewed. Published controlled trials describing the efficacy and safety of rufinamide were given preference. Available abstracts were also reviewed. Four published trials were identified and included and a retrospective review of the clinical use of rufinamide was also analyzed. The remainder of the information described is from 4 abstracts. Rufinamide is a new antiepileptic agent that differs structurally from other antiepileptic drugs and is approved as adjunctive therapy for Lennox-Gastaut syndrome (LGS). It presumably provides its antiseizure activity by prolonging sodium channel inactivity, stabilizing cell membranes. It is absorbed and metabolized extensively, then excreted renally as an inactive metabolite. Clinical trials show that adjunctive rufinamide is effective at reducing seizure frequency in patients with LGS and refractory partial seizures. Rufinamide showed no effect on cognitive function in patients with refractory partial seizures. Short-term adverse event rates were similar to those of placebo. Safety data from long-term studies show that rufinamide is well tolerated, causing headache, dizziness, and fatigue at rates of >10%. Rufinamide has few clinically relevant drug interactions, although it does increase phenytoin serum concentrations, while valproate increases rufinamide serum concentrations. Data show that rufinamide is safe and effective as an adjunctive agent for LGS and may be used to treat partial seizures. The benefits of rufinamide include its pharmacokinetics, limited drug interactions, and lack of effect on cognitive function, but its use is limited by the rarity of LGS and the lack of comparative data with other antiepileptic agents.

Adjunctive rufinamide in Lennox-Gastaut syndrome: a long-term, open-label extension study

This open-label extension evaluated the long-term efficacy and tolerability of rufinamide in patients with Lennox-Gastaut syndrome (LGS) who had previously completed a 12-week double-blind study. In total, 124 patients (aged 4-37 years), receiving 1-3 concomitant antiepileptic drugs, were treated with rufinamide approximately 25-60 mg/kg/day. Efficacy was assessed by seizure frequency; tolerability by adverse events (AEs) and laboratory tests. Overall, patients were treated with rufinamide for a median (range) of 432 (10-1149) days. Reductions in seizure frequency were observed throughout the study; during the last 12 months of treatment, 41.0% and 47.9% of patients had > or = 50% reduction in total and tonic-atonic seizure frequency, respectively. The most common AEs were vomiting (30.6%) and pyrexia (25.8%). In this open-label extension, rufinamide appeared to be an effective long-term adjunctive therapy for the treatment of LGS-associated seizures in children and young adults.

The Cost Effectiveness of Rufinamide in the Treatment of Lennox-Gastaut Syndrome in the UK

Lennox-Gastaut syndrome (LGS) is a catastrophic childhood form of epilepsy. The syndrome is characterized by mental impairment, frequent seizures of multiple types that are particularly resistant to treatment, and high rates of seizure-related injury. With the introduction of newer, but more costly, antiepileptic drugs (AEDs), it is important that decision makers are able to assess their value in the management of this rare and difficult-to-treat condition. To evaluate the cost effectiveness, from the UK NHS perspective, of rufinamide in patients with LGS. An individual patient-simulation model was developed to estimate the total treatment-related costs and clinical benefits of rufinamide compared with topiramate and lamotrigine over a 3-year time horizon. The model examines the treatment scenarios of adding rufinamide, lamotrigine or topiramate to older AEDs (standard therapy), or standard therapy alone within a primary-care or community setting. Three placebo-controlled clinical trials of adjunctive AED treatment for children with LGS were analysed. There are no head-to-head comparator studies. Between 98 and 139 patients were randomized in each study and the mean age in each study was 10, 11 and 14 years. A mixed-treatment comparison using a random-effects model was carried out on the number of patients in each response category, using the placebo arms of the respective trials. The primary outcome measure was the percentage of successfully treated patients, defined as >50% reduction in the frequency of total seizures and drop attacks. The hypothesis being tested was formulated after data collection. Costs ( pound, year 2006/07 values) of patient monitoring, switching treatments, hospitalization due to seizure, treatment of adverse effects, and personal and social services were included in the analysis. Results of 10,000 Monte Carlo simulations were bootstrapped to conduct probabilistic sensitivity analysis. Over 3 years, adjunctive rufinamide resulted in higher total costs than topiramate and lamotrigine; however, with more patients being treated successfully, this leads to acceptable incremental cost-effectiveness ratios. If society is prepared to pay at least 250 pounds for a 1% increase in the number of successfully treated LGS patients, in terms of a 50% reduction in the frequency of drop attacks, the probability of the treatment with rufinamide being cost effective is >80%. This cost-effectiveness analysis suggests that rufinamide results in more LGS patients being treated successfully at a reasonable cost from a UK NHS perspective.

A 24-week multicenter, randomized, double-blind, parallel-group, dose-ranging study of rufinamide in adults and adolescents with inadequately controlled partial seizures

To assess the efficacy, safety, tolerability, and pharmacokinetics of adjunctive rufinamide in adults and adolescents with inadequately controlled partial seizures receiving treatment with one to three concomitant antiepileptic drugs (AEDs). A 24-week multicenter Phase II clinical study was conducted (n=647), comprising a 12-week prospective baseline phase and a 12-week randomized double-blind, parallel-group, five-arm (placebo and rufinamide 200, 400, 800, and 1600mg/day) treatment phase. The linear trend of dose response for seizure frequency per 28 days in the double-blind treatment phase - the primary efficacy outcome measure - was statistically significant in favor of rufinamide (estimated slope=-0.049, P=0.003; minimally efficacious dose, 400mg/day). Response rates, defined as a >or=50% reduction in seizure frequency per 28 days, also revealed a significant linear trend of dose response (P=0.0019, logistic regression analysis). Adverse events were comparable between placebo and all rufinamide groups except the 1600mg/day group; no safety signals were observed. These results suggest that in the dose range of 400-1600mg/day, add-on rufinamide therapy may benefit patients with inadequately controlled partial seizures and is generally well tolerated. These data also suggest that higher doses may confer additional efficacy without adversely affecting safety and tolerability.

Adjunctive therapy of rufinamide in patients with Lennox-Gastaut syndrome

Question: Efficacy and safety of adjunctive rufinamide therapy in patients with Lennox-Gastaut syndrome (LGS).

Rufinamide

Rufinamide, a triazole derivative, reduces the recovery capacity of neuronal sodium channels after inactivation, limiting neuronal sodium-dependent action potential firing and mediating anticonvulsant effects. In children, adolescents and adults, adjunctive oral rufinamide was more effective than placebo in treating seizures associated with treatment-resistant Lennox-Gastaut syndrome in a well designed 16-week trial. Rufinamide recipients experienced significantly greater reductions from baseline than placebo recipients in the median frequency of total seizures and tonic-atonic seizures per 28 days and demonstrated improvements in seizure severity. Furthermore, these beneficial effects of rufinamide on seizure frequency were maintained throughout a subsequent 3-year, open-label extension study. Relative to placebo, adjunctive rufinamide significantly reduced the frequency of partial seizures per 28 days in adult patients with inadequately controlled partial seizures in two well designed trials of approximate, equals3 months duration, with a higher proportion of rufinamide recipients achieving a reduction of >or=50% in partial seizure frequency per 28 days. Rufinamide was generally well tolerated in patients with Lennox-Gastaut syndrome and in those with partial seizures, with adverse events being mostly mild or moderate in severity.