rufinamide ( 1-[(2,6-difluorophenyl)methyl]-1hydro-1,2,3-triazole-4 carboxamide ) is a novel antiepileptic drug ( aed ) that is structurally distinct from other aeds available on the market ( levy et al 2002a ) .
an application was filed by eisai ltd in 2005 for european approval of this agent as an adjunctive treatment for seizures associated with lennox - gastaut syndrome ( lgs ) in children and adults ( eisai co ltd 2005 ) .
lennox - gastaut syndrome is a catastrophic epileptic encephalopathy of childhood onset ( typically at age 35 years ) , for which effective treatment options are limited .
this syndrome is associated with multiple types of generalized seizures , especially drop attacks and tonic seizures , delayed psychomotor development , behavioral and personality disorders , and a characteristic electroencephalogram pattern containing both generalized slow spike wave activity and paroxysms of generalized fast rhythmic activity during sleep which reflect excessive neocortical excitability ( markand 2003 ; nabbout and dulac 2003 ; guerrini 2006 ) .
the long - term prognosis is very poor , with persistence of seizures in more than 75% of patients and severe mental retardation in more than 50% of patients ( markand 2003 ; dulac and engel 2003 ; schmidt and bourgeois 2000 ) .
consequently , lgs is viewed as one of the most difficult epilepsies to treat . currently available treatment options for the epileptic encephalopathies in europe center around the use of valproate , with adjunctive benzodiazepines , topiramate , lamotrigine , or felbamate ( guerrini 2006 ) . however
, a cochrane review has concluded that no single aed could be considered highly efficacious for lgs ( hancock and cross 2003 ) .
indeed , the efficacy of valproate as a first - line treatment has been described as  unimpressive  , and its use in young children should be accompanied by great caution due to the risk of life - threatening hepatic toxicity ( schmidt and bourgeois 2000 ) .
other first - generation aeds ( carbamazepine , phenytoin , and phenobarbital ) are not recommended for the treatment of lgs , due to the potential for aggravation of absence and myoclonic seizures by carbamazepine and phenytoin , and exacerbation of the behavioral problems seen in patients with lgs by barbiturates . among the benzodiazepines
, clobazam may be viewed as the best tolerated , although there is no head - to - head comparison to confirm this . however , for this class of drugs , development of tolerance is well documented in the literature ( levy et al 2002b ) .
the only aeds which have been evaluated in a randomized , controlled trial in lgs are lamotrigine , topiramate , and felbamate , the outcomes of which are discussed later in this paper .
although felbamate is licenced for the treatment of lgs in the usa and some other countries ( eg , germany ) , its use has been limited following reports of serious toxicity ( borowicz et al 2004 ) .
this has led to the recommendation that , in lgs , it should be used only in patients aged over 4 years who can not be treated satisfactorily with other aeds ( schmidt and bourgeois 2000 ) .
thus , there is a clear need for new options in the management of this intractable condition .
rufinamide was granted orphan drug status by the european medicines agency ( emea ) and the us food and drug administration ( fda ) in 2005 .
this review will evaluate the relevant pharmacologic and clinical data for rufinamide , and explore its potential role in the future management of this severe form of epilepsy in the context of other products currently available for lgs .
an extensive preclinical evaluation has suggested that the principal mechanism involved in the antiepileptic activity of rufinamide is its ability to modulate the activity of sodium channels , limiting high - frequency firing of neuronal action potentials over a broad range of concentrations , as demonstrated in vitro ( mclean et al 2005 ) . in radioligand
binding studies , rufinamide does not interact with other neurotransmitter systems , including monoamine , adenosine , acetylcholine , histamine , glycine , -amino-3-hydroxy-5-methyl-4-isoxazole propionate ( ampa)/kainite , n - methyl - d - aspartate ( nmda ) , and -amino butyric acid ( gaba ) systems ( bialer et al 1996 ) .
rufinamide has demonstrated broad spectrum anticonvulsant activity in animal models of epilepsy , elevating both electrically and chemically induced seizure thresholds and preventing seizure spread following oral and intraperitoneal administration in mice and rats ( white et al 2005 ) .
furthermore , the protective index for rufinamide ( ratio of the concentration required for 50% anticonvulsant efficacy to that for neurotoxicity ) was superior to that of each of the comparator aeds examined ( phenytoin , phenobarbital , ethosuximide , and valproate ) .
the pharmacokinetic properties of rufinamide have been established both in healthy volunteers and in patients with epilepsy . in a study of 3 healthy volunteers ,
an oral dose of 600 mg rufinamide demonstrated high absorption , and monoexponential elimination with a mean half - life ( t ) of 9 hours ( waldmeier et al 1996 ) .
excretion was largely renal ( 85% ) and complete ( 98% ) within 7 days .
following administration of 400 mg rufinamide as two 200-mg tablets or 400-mg oral suspension after a standard meal , mean maximum plasma concentrations ( cmax ) of 3.03 and 3.32 g / ml were reached after 6.6 and 7.2 hours , respectively , leading to elimination with a terminal t of 8.8 and 9.1 hours , respectively ( cheung et al 1995 ) . in a further study ,
the absorption of a single dose of 400 mg rufinamide was accelerated in fed subjects compared with fasting conditions , resulting in a 43% increase in exposure ( 96-hour exposure ) , without affecting the t ( cardot et al 1998 ) .
however , no effect of food was observed with repeat dosing ( eisai , data on file ) , and no difference in rufinamide pharmacokinetics has been found between older ( aged 6677 years ) and younger ( 1840 years ) healthy subjects in either single- or multiple - dosing conditions ( chang et al 1998 ) .
rufinamide pharmacokinetics in a study of 16 children aged between 2 and 17 years treated with 10 or 30 mg / kg daily rufinamide for 2 weeks were also comparable to those reported elsewhere for adult patients ( sachdeo et al 1998 ) .
overall , evaluation of these data suggests that no age - related dose adjustments are likely to be required for either pediatric or elderly populations ( bialer et al 2001 ) .
the pharmacokinetic parameters of single ascending doses of rufinamide ( 0 , 400 , 800 , 1200 mg ) have also been compared between 3 healthy subjects and 16 patients with epilepsy receiving enzyme - inducing aeds ( brunner et al 1994 ) .
absorption rates were comparable , and both groups showed dose - related increases in cmax and exposure .
rufinamide elimination was accelerated in aed - treated patients compared with healthy subjects , but t was independent of the dose administered in both groups .
the pharmacokinetics of rufinamide have also been evaluated in 129 pediatric and adult patients with lgs ( critchley et al 2005 ) .
rufinamide clearance was not affected by concomitant lamotrigine or topiramate , and was also unaffected by liver or kidney function .
however , rufinamide concentrations were increased by concomitant valproate : 40% in children and 11% in adults .
therefore , the rufinamide dosage may require adjustment during the addition or withdrawal of concomitant valproate therapy .
rufinimade is extensively metabolized ( 2% excreted unchanged in urine and 2% in feces ) , predominantly via hydrolysis of the carboxylamide group to yield an inactive metabolite ( cgp-27292 ) , and is largely excreted in urine ( 84.7% of dose ) ( bialer et al 1999 ) .
thus , rufinamide has a low propensity for drug  drug interactions , based on its low protein binding ( approximately 34% ) and absence of metabolism via hepatic cytochrome p450 or inhibition of the major enzyme subclasses ( bialer et al 1996 ; kapeghian et al 1996 ) .
this is supported by the absence of clinically relevant alterations of concomitant aed levels observed in a population pharmacokinetic drug
this analysis was conducted using data from 5 double - blind studies involving pediatric and adult patients with inadequately controlled seizures despite previous treatment with up to 3 aeds . in total
, 903 patients were receiving carbamazepine , 588 valproate , 200 lamotrigine , 299 phenytoin , 149 phenobarbital , and 69 topiramate .
rufinamide co - administration did not affect the clearance of topiramate or valproate , but increased the clearance of carbamazepine and lamotrigine and decreased clearance of phenobarbital and phenytoin .
however , all produced effects were small , were considered unlikely to be of clinical significance , and were independent of age . at a rufinamide plasma concentration of 15 g / ml , representing steady - state concentrations following doses of 45 mg / kg daily in children or 3200 mg / day in adults , changes in clearance
conversely , in a similar study involving 471 patients , valproate co - administration decreased rufinamide clearance by approximately 22% , while any combination of phenytoin , phenobarbital , or primidone increased rufinamide clearance by approximately 25% , compared with patients not receiving these aeds ( bialer et al 2001 ) .
rufinamide also resulted in a small increase in clearance of the oral contraceptive ortho - novum ( ortho - mcneil pharmaceutical , inc .
raritan , nj , usa ) 1/35 in healthy female volunteers , though the clinical relevance of this effect is not known ( svendsen et al 1998 ) .
the efficacy of rufinamide as an adjunctive therapy for treatment - resistant lgs has been evaluated in a multicenter , randomized , 12-week , double - blind , placebo - controlled , parallel - group study in 138 patients aged 437 years ( mean age 14.1 years ) , followed by an open - label extension phase ( glauser et al 2005a , 2005b ) .
patients diagnosed with lgs , experiencing 90 seizures in the month prior to study entry , and receiving stable treatment with 13 concomitant aeds , were evaluated .
after a 28-day baseline , patients randomized to twice - daily oral treatment with rufinamide ( n=74 ) or placebo ( n=64 ) entered a 14-day titration period ( rufinamide target dose 45 mg / kg daily ) , followed by 70 days of double - blind maintenance treatment .
the reduction from baseline in the frequency of tonic - atonic seizures ( drop attacks ) per 28 days was significantly greater with rufinamide than placebo ( median change 42.5% vs + 1.4% , respectively , p<0.0001 ) .
similarly , the reduction from baseline in total seizure frequency per 28 days was significantly greater with rufinamide than placebo treatment ( median change 32.7% vs 11.7% , respectively , p=0.0015 ) .
these improvements were associated with significantly greater proportions of responders ( patients achieving 50% reduction in seizures per 28 days ) with rufinamide than placebo treatment , both for tonic - atonic seizures ( 42.5% vs 16.7% ,
p=0.0020 ) ( glauser et al 2005a ) and total seizure frequency ( 31.1% vs 10.9% , p=0.0045 ) ( kluger et al 2006 ) .
following completion of the double - blind study , 123 patients continued to receive open - label treatment in the extension phase , at a median dose of 1800 mg / day ( range 1034865 mg / day ) for a median duration of 432 days ( range 101149 days ) ( glauser et al 2005b ) .
the reduction in median total seizure frequency observed at 12 weeks was maintained , with some further improvement noted with continued treatment for up to 3 years ( see figure 1 ) .
similarly , the responder rate for total seizures was maintained , with 36.9% of patients achieving a reduction in total seizures of at least 50% overall during the extension study .
furthermore , 21.3% of patients achieved a 75% reduction in total seizures overall during the extension study .
during the double - blind study of rufinamide in patients with lgs , the most common adverse events ( reported by 10% patients in either treatment group ) were : 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 ) ( glauser et al 2005a ) .
notably , rufinamide treatment was associated with a lower incidence of cognitive / psychiatric adverse events ( such as psychomotor hyperactivity and lethargy ) than placebo treatment ( 17.6% vs 23.4% , respectively ) .
there was no clinically significant change in clinical laboratory tests , physical examinations or vital signs . during the subsequent open - label extension study ,
the most commonly reported all - causality adverse events were vomiting ( 30.6% ) , pyrexia ( 25.8% ) , upper respiratory tract infection ( 21.8% ) , and somnolence ( 21.0% ) ( glauser et al 2005b ) .
there were two deaths , which were not considered to be related to rufinamide treatment .
thus , long - term treatment of patients with lgs does not appear to be associated with any increase in central nervous system ( cns ) adverse events , with somnolence noted with somewhat lower frequency than during the double - blind phase .
these tolerability and safety data in patients with lgs are further supported by a pooled analysis of rufinamide tolerability and safety in a large population of epilepsy patients , in which the data were evaluated separately for patients receiving short - term or long - term treatment ( krauss et al 2005 ) .
the short - term safety population comprised 1240 patients treated with rufinamide ( mean age 31.7 years ; mean rufinamide dose 1373 mg / day ; mean duration of treatment 2.8 months ) and 635 placebo recipients ( mean age 28.6 years , mean duration of treatment 3.0 months ) .
somnolence was reported somewhat less frequently in this population than in the lgs study , with an incidence of 11.8% for rufinamide and 9.1% among placebo recipients .
the timing of events in this pooled analysis indicated a pattern of early onset and rapid resolution , and a tolerability profile not substantially different from placebo ; the incidence of the most frequently reported adverse events with rufinamide vs placebo were headache ( 22.9% vs 18.9% ) , dizziness ( 15.5% vs 9.4% ) , fatigue ( 13.6% vs 9.0% ) , somnolence ( 11.8% vs 9.1% ) , and nausea ( 11.4% vs 7.6% ) .
the pooled tolerability and safety analysis included 1978 patients assessed for long - term tolerability and safety ( mean age 31.3 years , mean rufinamide dose 1700 mg / day , maximum dose 7200 mg / day ) , 47% of whom were treated with rufinamide for at least 12 months ; the most frequently reported adverse events in this population were headache ( 29.5% ) , dizziness ( 22.5% ) , and fatigue ( 17.7% ) ( krauss et al 2005 ) .
few randomized , controlled clinical trials have been conducted in patients with lgs , none of which is a head - to - head comparison .
consequently , the available treatments for lgs can not be compared directly , and only limited conclusions may be drawn from indirect comparisons . the most robust approaches for indirect comparisons include systematic reviews and meta - analyses , such as those conducted by the cochrane group . a systematic ( cochrane ) review of randomized , controlled trials in lgs ( hancock and cross 2003 ) retrieved only 5 evaluable studies : one each conducted with topiramate , lamotrigine , felbamate , cinromide , and a thyrotropin releasing hormone ( trh ) derivative , respectively ( anonymous 1989 , 1993 ; inanaga et al 1989 ; motte et al 1997 ; sachdeo et al 1999 ) .
this review concluded that no single agent was found to be highly efficacious in lgs , and that of those evaluated only lamotrigine , topiramate and felbamate were considered potentially efficacious as add - on therapy ( hancock and cross 2003 ) .
data derived from this cochrane analysis for each of the clinical trials are summarized in table 1 , together with data from the more recently reported rufinamide study ( glauser et al 2005a ) .
although this provides an indirect comparison , it is of interest to note that rufinamide produced a particularly marked effect in the reduction in drop attacks ( tonic - atonic seizures ) , since this is also the parameter viewed as the primary outcome variable for lgs according to guidelines from the american academy of neurology ( french et al 2004 ) .
the median reduction in tonic - atonic seizures was 42.5% with rufinamide , which compares well with rates observed in the separate studies with topiramate ( 14.8% reduction ) or lamotrigine ( 34% reduction ) ; the effect of felbamate on drop attacks was not reported . when corrected for the magnitude of placebo response ,
the median effect size for rufinamide on drop attacks was 41.1% , compared with 19.9% for topiramate and 14.8% for lamotrigine .
similarly , the proportion of patients who could be considered responders to therapy ( achieving at least a 50% decrease in drop attacks ) was 42.5% with rufinamide , 45.6% with topiramate , and 37.3% with lamotrigine , or 25.8% , 25.6% , and 14.8% , respectively , when corrected for placebo response .
as with drop attacks , the effects of these agents on total seizure frequency produced some interesting findings .
the rufinamide , topiramate , and lamotrigine studies demonstrated 32.7% , 20.6% , and 32.0% median reductions in total seizures , and treatment effect sizes ( adjusted for placebo ) of 20.0% , 12.6% , and 17.6% , respectively .
in the felbamate study , outcomes were reported as mean rather than median values , resulting in a 19% mean reduction in total seizures , and a 23% mean effect size .
the number of patients achieving complete cessation of seizures has only been reported with felbamate , and although these results are favorable , can not be compared with the other aeds in the studies available to date . of course , the overall benefit of treatment comprises a balance between reduction in ( or cessation of ) seizures and tolerability / safety .
the reported tolerability of treatment was broadly comparable among the studies described in table 1 , with relatively small differences in rates of discontinuations due to adverse events .
few randomized , controlled clinical trials have been conducted in patients with lgs , none of which is a head - to - head comparison .
consequently , the available treatments for lgs can not be compared directly , and only limited conclusions may be drawn from indirect comparisons . the most robust approaches for indirect comparisons include systematic reviews and meta - analyses , such as those conducted by the cochrane group . a systematic ( cochrane ) review of randomized , controlled trials in lgs ( hancock and cross 2003 ) retrieved only 5 evaluable studies : one each conducted with topiramate , lamotrigine , felbamate , cinromide , and a thyrotropin releasing hormone ( trh ) derivative , respectively ( anonymous 1989 , 1993 ; inanaga et al 1989 ; motte et al 1997 ; sachdeo et al 1999 ) .
this review concluded that no single agent was found to be highly efficacious in lgs , and that of those evaluated only lamotrigine , topiramate and felbamate were considered potentially efficacious as add - on therapy ( hancock and cross 2003 ) .
data derived from this cochrane analysis for each of the clinical trials are summarized in table 1 , together with data from the more recently reported rufinamide study ( glauser et al 2005a ) .
although this provides an indirect comparison , it is of interest to note that rufinamide produced a particularly marked effect in the reduction in drop attacks ( tonic - atonic seizures ) , since this is also the parameter viewed as the primary outcome variable for lgs according to guidelines from the american academy of neurology ( french et al 2004 ) .
the median reduction in tonic - atonic seizures was 42.5% with rufinamide , which compares well with rates observed in the separate studies with topiramate ( 14.8% reduction ) or lamotrigine ( 34% reduction ) ; the effect of felbamate on drop attacks was not reported . when corrected for the magnitude of placebo response ,
the median effect size for rufinamide on drop attacks was 41.1% , compared with 19.9% for topiramate and 14.8% for lamotrigine .
similarly , the proportion of patients who could be considered responders to therapy ( achieving at least a 50% decrease in drop attacks ) was 42.5% with rufinamide , 45.6% with topiramate , and 37.3% with lamotrigine , or 25.8% , 25.6% , and 14.8% , respectively , when corrected for placebo response .
as with drop attacks , the effects of these agents on total seizure frequency produced some interesting findings .
the rufinamide , topiramate , and lamotrigine studies demonstrated 32.7% , 20.6% , and 32.0% median reductions in total seizures , and treatment effect sizes ( adjusted for placebo ) of 20.0% , 12.6% , and 17.6% , respectively .
in the felbamate study , outcomes were reported as mean rather than median values , resulting in a 19% mean reduction in total seizures , and a 23% mean effect size .
the number of patients achieving complete cessation of seizures has only been reported with felbamate , and although these results are favorable , can not be compared with the other aeds in the studies available to date . of course , the overall benefit of treatment comprises a balance between reduction in ( or cessation of ) seizures and tolerability / safety .
the reported tolerability of treatment was broadly comparable among the studies described in table 1 , with relatively small differences in rates of discontinuations due to adverse events .
each of these currently available agents has been associated with warnings relating to severe adverse events .
the use of felbamate has been restricted in many countries following reports of idiosyncratic aplastic anemia and hepatic failure , which led to its initial withdrawal in the usa , although limited use was granted subsequently ( fda 1994 ) .
similarly , the efficacy of lamotrigine must be balanced against the risk of serious skin reactions in susceptible individuals , for which boxed warnings or safety alerts have been issued ( committee on safety of medicines 1996 ; fda 1997 ) , while the use of topiramate is associated with warnings relating to oligohydrosis and hyperthermia in children , and also metabolic acidosis and glaucoma ( fda 2003 ; janssen - cilag 2006 ) .
in addition , factors such as cognitive slowing and weight loss may be issues with the use of topiramate ( levy et al 2002c ) .
the timing of these warnings , some time after the initial marketing of these aeds , illustrates the difficulties in identifying such events during clinical trials , and that further evaluation is required to confirm the long - term safety of rufinamide in comparison with the marketed drugs .
indeed , increased qt interval dispersion has been demonstrated in children with epilepsy , potentially predisposing them to serious cardiac events ( akalin et al 2003 ) .
rufinamide has demonstrated excellent cardiovascular tolerability , with no increase in qt intervals in a cardiac safety study conducted in 15 healthy volunteers treated with placebo or ascending doses of rufinamide ( from 800 to 7200 mg / day ) over 18 days ( marchand et al 2005 ) . on the contrary ,
lgs is a catastrophic and debilitating age - specific epileptic disorder , for which a substantial unmet need exists for highly effective treatment options .
the data reviewed here indicate that adjunctive therapy with rufinamide , a new aed that is structurally unrelated to other currently available aeds , significantly reduces seizure frequency in patients with lgs , accompanied by good tolerability , both of which are maintained during long - term use .
in particular , the reduction in drop attacks adds substantially to patient quality of life .
the efficacy of rufinamide is most likely derived from its ability to block sodium channels , thereby limiting high - frequency action potential firing , a mechanism shared by some other aeds including phenytoin , carbamazepine , lamotrigine , and oxcarbazepine ( mclean et al 2005 ) .
however , it is commonplace for patients with lgs to remain symptomatic despite optimal therapy , and it is notable that , in the studies reviewed , adjunctive rufinamide treatment was able to exert significant improvement in a treatment - resistant population receiving 13 other aeds at baseline . in an indirect comparison with randomized controlled trials examining other aeds , the results with rufinamide appear impressive : a median reduction in drop attacks of 42.5% with rufinamide , compared with 14.8% with topiramate and 34% for lamotrigine , representing treatment effect sizes , after adjustment for placebo response , of 41.1% , 19.9% , and 14.8% , respectively .
this was associated with a median reduction in total seizures of 32.7% with rufinamide , compared with 20.6% in the topiramate study and 32% in the lamotrigine study .
although the full safety data for the rufinamide study in lgs have yet to be reported , data from a pooled safety database suggest a good tolerability profile for both short- and long - term use of rufinamide , with a pattern of early onset and early resolution of events .
cardiac safety profile , based on a dose - ranging study in healthy volunteers which included qt analysis .
however , the full spectrum of efficacy as well as the safety profile of rufinamide will become clear with accumulation of long - term clinical experience and usage .
overall , these findings suggest that rufinamide may be a valuable option for the adjunctive treatment of lgs .
 rufinamide , a triazole derivative that is structurally distinct from currently marketed antiepileptic drugs ( aeds ) , is in development for the adjunctive treatment of lennox - gastaut syndrome ( lgs ) in children and adults . 
 rufinamide is well absorbed after oral administration , demonstrates low protein binding , and is metabolized by enzymatic hydrolysis without involvement of cytochrome p450 enzymes , conferring a low drug interaction potential . in a randomized , double - blind trial involving 138 adult and pediatric patients with lgs , compared with placebo , rufinamide 45 mg / kg / day resulted in significantly superior reductions in drop attacks ( median change 42.5% vs + 1.4% with placebo ) and total seizures ( 32.1% vs 11.7% with placebo ) , accompanied by significantly higher responder rates . 
 these results are comparable with findings reported for other aeds in randomized , controlled clinical trials in patients with lgs . 
 rufinamide produced statistically significant seizure reduction which was maintained during long - term therapy and accompanied by good tolerability . the most frequently reported adverse events from a pooled safety database evaluating short- and long - term therapy were headache ( 22.9% and 29.5% ) , dizziness ( 15.5% and 22.5% ) and fatigue ( 13.6% and 17.7% ) . 
 rufinamide therefore presents a favorable efficacy and tolerability profile and is a promising candidate for the adjunctive therapy of lgs . 
Introduction
Pharmacology and pharmacokinetics of rufinamide
Rufinamide in Lennox-Gastaut syndrome
Tolerability and safety of rufinamide
Rufinamide in context
Other randomized controlled trials in LGS
Additional tolerability and safety considerations
Conclusions