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Rufinamide in Lennox-Gastaut syndrome

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Frank MC Besag FRCP FRCPsych FRCPCH
South Essex Partnership University NHS Foundation Trust (SEPT), Bedford, UK
Key words: rufinamide; Lennox-Gastaut syndrome; epilepsy; seizures
Date received: 27 May 2012
Date accepted: 13 June 2012
Rufinamide is an anti-epileptic drug that received marketing authorisation as adjunctive therapy in Lennox-Gastaut syndrome (LGS) from the European commission in January 2007 and the FDA in November 2008. It has a different mode of action from other anti-epileptic drugs: it modulates the frequency of sodium-dependent neuronal action potentials, although the precise mechanism is yet to be determined. The Cmax is approximately six hours and the half-life is six-to-ten hours in healthy volunteers. Sodium valproate may decrease the clearance. It is not strongly protein bound. Although licensed only for the treatment of LGS, efficacy has also been demonstrated in other epilepsy syndromes and seizure types, notably partial seizures.
Although several new anti-epileptic drugs have become available over recent years, a large proportion of people with epilepsy continue to have uncontrolled seizures. Epilepsy should not be considered as a single disorder but as a number of different syndromes with very different prognostic outcomes. The Lennox-Gastaut syndrome (LGS) is a severe form of epilepsy that is often unresponsive to treatment, implying that any new treatments that are effective in this syndrome represent a significant advance. Rufinamide has a specific licence for treating the seizures associated with LGS and emerging evidence suggests that it may be effective and in other seizure types and syndromes.
Pharmacology
Rufinamide is a triazole derivative: 1-(2,6-difluoro-phenyl)methyl-1H-1,2,3-triazole-4-carboxamide. Although it is said to modulate the frequency of sodium-dependent neuronal action potentials, the mechanism has yet to be elucidated fully. The Cmax is approximately six hours and the half-life about six-to-ten hours in healthy volunteers. In vitro studies have indicated that it is approximately 34% protein bound. It is mostly eliminated by metabolism. The main pathway is hydrolysis of the carboxylamide group to the inactive CGP 47292. Renal impairment does not appear to alter the pharmacokinetics significantly.
There appears to be little or no inhibition of P450 isoenzymes but rufinamide induces the cytochrome P450 enzyme CYP3A4, implying that plasma concentrations of drugs metabolised by this may fall. The effect has been described as being ‘modest to moderate’.(1) When administered with the combined oral contraceptive, the ethinyl estradiol and norethindrone concentrations have been shown to decrease. It has consequently been recommended that additional measures should be used in females taking rufinamide who require contraception.
Because there is some decrease in the clearance by sodium valproate, children weighing less than 30kg who also take sodium valproate should be treated with a lower maximum rufinamide dose.(1)
Dosage
Children weighing <30kg
Initial dose (whether taking valproate or not) is 200mg. The dose can be escalated by 200mg/day at minimum intervals of two days. Maximum recommended dose is 600mg/day if taking valproate; maximum recommended dose is 1000mg/day if not taking valproate, although doses of up to 3600mg/day have been used.
Children and adults >30kg
Initial dose is 400mg/day. The dose can be escalated by 400mg/day at minimum intervals of two days. Maximum recommended dose depends on weight: 1800mg/kg/day if weight 30.0–50.0kg, 2400mg/day if weight 50.1–70.0 kg, 3200mg/day if weight >70.1kg. Rufinamide is available in 100mg, 200mg and 400mg film-coated tablets. It is also available in suspension at 40mg/ml.
Efficacy
Palhagen et al(2) established proof of principle of the efficacy of rufinamide in a double-blind, placebo-controlled 28-day trial of rufinamide in a rising dose (400–1600mg/day) in 50 patients with partial or primary generalised tonic–tonic seizures. The responder rate (≥50% seizure reduction relative to baseline) was 39% in the rufinamide-treated group and 16% in the placebo-treated group (p=0.096).
The first European study and the follow-up study by Kluger and coworkers(3,4) were open studies and should consequently be interpreted with caution. The initial study was in 60 subjects (45 children and 15 adults), mean age 14.5 years, who had severe, uncontrolled epilepsy. This group included 31 with LGS. The ‘responder rate’ (reduction in countable seizures >50%, comparing the baseline period with the last four-week period of observation) was 46.7% (28/60). A total of 25% of the subjects had >75% seizure reduction and complete control was recorded in 8.3%. The highest responder rate, namely 55% (17/31), was in the patients with LGS. In the follow-up study, 41.7% (25/60) were still taking rufinamide at 18 months and the overall responder rate at that time was 26.7% (16/60), with complete seizure control in only one patient. Again, the highest responder rate at 18 months was in LGS: 35.5%.
Key clinical data
Glauser et al(5) carried out the pivotal double-blind, placebo-controlled trial of rufinamide in LGS.
Eligibility criteria
Eligibility criteria were:
  • Age 14–30 years
  • Weight at least 18kg
  • Fixed-dose regimen of one-to-three concomitant anti-epileptic drugs
  • Computed tomography or magnetic resonance imaging scan showing no progressive lesion
  • History of multiple seizure types, which had to include atypical absence seizures and drop attacks (tonic–atonic or astatic seizures)
  • Minimum of 90 seizures in the month before the 28-day baseline period.
  • EEG within six months of the study demonstrating slow spike-wave complexes <2.5Hz.
Exclusion criteria
Exclusion criteria were:
  • More than three concomitant anti-epileptic drugs
  • Pregnant or female and not using adequate contraception
  • ‘Correctable’ seizure aetiology, such as infection or metabolic disturbance
  • History of generalised tonic–clonic status epilepticus in the 30 days before baseline
  • History of a significant non-neurological medical condition.
Primary efficacy variables
The three primary efficacy variables were:
  • Change in total seizure frequency per 28 days.
  • Change in tonic–atonic seizures (the sum of tonic and atonic seizures) per 28 days.
  • Change in global evaluation of the patient’s condition in the double-blind phase relative to the baseline phase.
After the 28-day baseline period, 139 patients were randomised but one did not receive medication. Of the remaining 138 patients, 74 received rufinamide and 64 received placebo.
The baseline characteristics and concomitant anti-epileptic medication of the treatment and placebo groups were similar. The target dose of 45mg/kg/day was achieved in 88% (65 patients).
Results
The results were:
  • Median total seizure frequency change from baseline to treatment: from 290 to 204 per 28 days, compared with no change in the placebo group from 205 per 28 days
  • Median percentage reduction in total seizure frequency per 28 days in the rufinamide group was 32.7% and in the placebo group was 11.7% (p=0.0015)
  • Mean decrease in tonic–atonic seizures per 28 days relative to baseline was 42.5% in the rufinamide group and –1.4% (that is, a 1.4% increase) in the placebo group (p<0.0001)
  • At least 50% reduction in tonic seizure frequency per 28 days relative to baseline: 31.1% in the rufinamide group and 10.9% in the placebo group (p= 0.0045)
  • Complete control of tonic–atonic seizures in 4.1% of the rufinamide group and 3.3% of the placebo group (p=0.84)
  • Improvement in seizure severity 53.4% (39/73) in the rufinamide group and 30.6% (19/62) in the placebo group (p=0.0041).
Although statistically significant decreases in absence seizures (p<0.03) and atypical absence seizures (<0.02) were also reported, it is difficult to know how to interpret this result because such seizures cannot usually be counted reliably by simple observation.
In a prospective, open-label study in Italy, Coppola et al(6) found a responder rate of 51.1% in 43 patients (26 males, 17 females, aged 4–34 years) with LGS treated with rufinamide in doses up to 3200mg/day.
As already stated, the licensed indication for rufinamide is LGS but reports have demonstrated efficacy in other situations.
Brodie et al(7) showed that rufinamide 1600mg twice daily was effective as adjunctive treatment in a double-blind, placebo-controlled, randomised, parallel-group, multicentre trial. 156 subjects received rufinamide and 157 placebo. The responder rate was 28.2% in the rufinamide-treated group compared with 18.6% in the placebo-treated subjects (p=0.04).
A large (647 adults and adolescents) double-blind, randomised, parallel-group, dose-ranging study of rufinamide for the treatment of partial seizures was carried out by Elger et al.(8) The primary outcome measure was the linear trend of dose response for seizure frequency over 28 days in the double-blind phase. This was statistically significantly in favour of rufinamide (p=0.003).
Coppola et al(9), who had already studied the efficacy of rufinamide in the LGS, treated 38 patients with other types of childhood-onset refractory epilepsy (epileptic encephalopathies). The responder rate for the countable seizures in the 38 patients, aged 4–34 years was 39.5%. They commented that rufinamide was most effective in treating patients with drop attacks and bifrontal spike-wave discharges.
Biton et al,(10) in a randomised, double-blind, placebo-controlled, parallel-group multicentre study of the efficacy of adjunctive rufinamide (3200mg/day) in partial-onset seizures in adolescents and adults found a responder rate of 32.5% in the treated group compared with 14.3% in the placebo group (p<0.001).
Vendrame et al(11) carried out a retrospective post-marketing study on 77 children treated with rufinamide.  One third (26/77) had LGS. The responder rates were highest in children with tonic–atonic and partial seizures. The lowest responder rate was in West syndrome. In another study, this group examined the efficacy of rufinamide in the treatment of epileptic spasms (not classical infantile spasms/West syndrome) in 38 patients (17 months–23 years of age). The mean reduction of spasm frequency was 50% (p<0.05).
Malignant migrating partial epilepsy of infancy is generally very resistant to treatment and has a poor prognosis. Vendrame et al(12) treated five patients with this syndrome, two of whom responded well.
Hausler et al(13) treated three boys who had the syndrome of epilepsy with myoclonic absences with rufinamide. There was complete cessation of all seizures in two of these patients and a 50% reduction of seizure frequency in the remaining child.
Mueller et al(14) recently reported results of a trial in 20 patients with Dravet syndrome, a particularly resistant form of epilepsy. In several cases, there was seizure exacerbation. The study provided no evidence to suggest that rufinamide is effective in this syndrome.
Freedom from tonic–clonic seizures and drop attacks for 14 months was noted in a single case report of a five-year-old child with methylmalonic aciduria who had epilepsy that was unresponsive to other anti-epileptic drugs.(15)
Tolerability and safety
The most reliable data are those from the two large double-blind, placebo-controlled trials by Glauser et al(5) and Elger et al.(8) These, together with results from other published papers, are presented in Table 1. The most frequently reported adverse effects are fatigue/drowsiness/somnolence and vomiting in the younger age group or nausea in the older age group. In the older patients, at higher doses, dizziness, diplopia and nystagmus were also reported. In addition, Kluger and Bauer(16) referred to pooled data reported in abstract, comprising 1240 patients treated with rufinamide (mean age 31.7 years) and 635 treated with placebo (mean age 28.6 years). They stated that the incidence of the most frequently reported adverse effects with rufinamide vs placebo were headache (22.9% vs 18.9%), dizziness (15.5% vs 9.4%) fatigue (13.6% vs 9%) somnolence (11.8% vs 9.1%) and nausea (11.4% vs 7.6%).
Wheless et al(17) examined tolerability of rufinamide in a pooled analysis of seven clinical studies comprising 212 rufinamide-treated patients in double-blind studies and 391 patients treated with rufinamide in double-blind and/or open-label extensions. The most common adverse events in the rufinamide-treated patients in the double-blind studies were somnolence, vomiting and headache.
No serious adverse events attributable to rufinamide were reported in the published studies. However, because the overall number of patients reported in all of the studies is relatively small,it is not possible to make any reliable statements about safety at this stage.
Conclusions
Rufinamide appears to be a valuable addition to the range of anti-epileptic drugs currently available, particularly because it has proven efficacy in one of the most drug-resistant and handicapping forms of epilepsy, namely LGS. It also appears to be effective in other situations, notably in treating partial seizures. Adverse effects are moderately frequent, particularly fatigue and drowsiness in all ages, vomiting in the younger patients and nausea in the older patients. Further experience is required before the full range of epilepsies/seizure types that might respond to rufinamide will become known. More data are also required before definitive statements about safety can be made, although the limited information currently available has raised no major safety issues.
Key points
  • Rufinamide is an anti-epileptic drug that is marketed as an adjunctive therapy in Lennox-Gastaut syndrome (LGS), a severe form of epilepsy that is often unresponsive to treatment.
  • Rufinamide has a novel mode of action, in that it modulates the frequency of sodium-dependent neuronal action potentials, although its precise mechanism is yet to be determined.
  • Although licensed only for LGS, its efficacy has been demonstrated in other epilepsy syndromes and seizure types, notably partial seizures.
  • Adverse events are moderately frequent, particularly fatigue and drowsiness in all ages, vomiting in younger patients and nausea in the older patients.
References
  1. Summary of Product Characteristics. Rufinamide SPC.  2-4-0012. 27-5-0012.www.medicines.org.uk/emc/medicine/20165/SPC (accessed 31 August 2012).
  2. Palhagen S et al. Rufinamide: a double-blind, placebo-controlled proof of principle trial in patients with epilepsy. Epilepsy Res 2001; 43(2):115–24.
  3. Kluger G et al. Effectiveness and tolerability of rufinamide in children and adults with refractory epilepsy: first European experience. Epilepsy  Behav 2009;14(3):491–5.
  4. Kluger G et al. Adjunctive rufinamide in Lennox-Gastaut syndrome: a long-term, open-label extension study. Acta Neurologica Scandinavica 2010;122(3):202–8.
  5. Glauser T et al. Rufinamide for generalized seizures associated with Lennox-Gastaut syndrome. Neurology 2008;70(21):1950–8.
  6. Coppola G et al. Rufinamide in children and adults with Lennox-Gastaut syndrome: first Italian multicenter experience. Seizure 2010;19(9):587–91.
  7. Brodie MJ et al. Rufinamide for the adjunctive treatment of partial seizures in adults and adolescents: a randomized placebo-controlled trial. Epilepsia 2009;50(8):1899–909.
  8. Elger CE et al. A 24-week multicenter, randomized, double-blind, parallel-group, dose-ranging study of rufinamide in adults and adolescents with inadequately controlled partial seizures. Epilepsy Res 2010;88(2–3):255–63.
  9. Coppola G et al. Rufinamide in refractory childhood epileptic encephalopathies other than Lennox-Gastaut syndrome. Eur J Neurol 2011;18(2):246–51.
  10. Biton V et al. A randomized, double-blind, placebo-controlled, parallel-group study of rufinamide as adjunctive therapy for refractory partial-onset seizures. Epilepsia 2011;52(2):234–42.
  11. Vendrame M et al. Experience with rufinamide in a pediatric population: a single center’s experience. Pediatr Neurol 2010; 43(3):155–8.
  12. Vendrame M et al. Treatment of malignant migrating partial epilepsy of infancy with rufinamide: report of five cases. Epileptic Dis 2011; 13(1):18–21.
  13. Hausler M, Kluger G, Nikanorova M. Epilepsy with myoclonic absences – favourable response to add-on rufinamide treatment in 3 cases. Neuropediatrics 2011;42(1):28–9.
  14. Mueller A et al. Low long-term efficacy and tolerability of add-on rufinamide in patients with Dravet syndrome. Epilepsy Behav 2011;21(3):282–4.
  15. von Stülpnagel C et al. Refractory focal epilepsy in a patient with methylmalonic aciduria: case report on positive and long-lasting effect of rufinamide. Neuropediatrics 2011;42(2):71–3.
  16. Kluger G, Bauer B. Role of rufinamide in the management of Lennox-Gastaut syndrome (childhood epileptic encephalopathy). Neuropsychiatric Dis Treat 2007;3(1):3–11.
  17. Wheless JW et al. Safety and tolerability of rufinamide in children with epilepsy: a pooled analysis of 7 clinical studies. J Child Neurol 2009;24(12):1520–5.





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