(cid:9) CURRENT REVIEW IN CLINICAL SCIENCE
`
`RUFINAMIDE: A NOVEL
`BROAD-SPECTRUM ANTIEPILEPTIC
`DRUG
`
`James W. Wheless, MD, FAAP1 and Blanca Vazquez, MD2
`
`'Professor and Chief of Pediatric Neurology & LeBonheur
`Chair in Pediatric Neurology, University of Tennessee Health
`Science Center, Tennessee; Director, Neuroscience Institute
`& LeBonheur Comprehensive Epilepsy Program, LeBonheur
`Children's Medical Center, Tennessee; and Clinical Chief &
`Director of Pediatric Neurology, St Jude Children's Research
`Hospital, Tennessee
`'Assistant Professor of Neurology, New York University, New
`York, New York
`
`The last 20 years have witnessed a tremendous explosion in the
`number of antiepileptic drugs (AEDs) as well as the introduction
`ofAEDS developed for specific epilepsy syndromes. The study of the
`efficacy and side effect profile ofAEDs for unique epilepsy syndromes
`has allowed neurologists to utilize evidence-based medicine when
`treating patients. In late 2008, the Food and DrugAdministration
`approved rufinamide for adjunctive use in the treatment of seizures
`associated with Lennox—Gastaut syndrome. This unique chemical
`compound is also the first new AED to reach the market in the
`United States having a pediatric indication prior to approval for
`adults. Rufinamide appears to have a broad spectrum ofefficacy, is
`well tolerated and may be rapidly initiated—properties that will
`likely extend its use outside of Lennox—Gastaut syndrome.
`
`Rufinamide's chemical name is: 1-[(2,6-difluorophenyl)
`methyl]-1H-1,2,3-triazole-4 carboxamide (see Figure 1); it is
`a triazole derivative structurally unrelated to any currently mar-
`keted antiepileptic drug (AED) (1). Rufinamide was granted
`orphan drug status for adjunctive treatment of patients with
`
`Address correspondence to James W. Wheless, MD, FAAP, Professor
`and Chief of Pediatric Neurology & LeBonheur Chair in Pediatric Neu-
`rology, University of Tennessee Health Science Center, Tennessee; Di-
`rector, Neuroscience Institute & LeBonheur Comprehensive Epilepsy
`Program, LeBonheur Children's Medical Center, Tennessee; and Clin-
`ical Chief & Director of Pediatric Neurology, St Jude Children's Re-
`search Hospital, 777 Washington Avenue, Suite 335, Memphis, TN
`38105. E-mail: jwheless@utmem.edu
`Epilepsy Currents, Vol. 10, No. 1 ( January/February) 2010 pp. 1-6
`Wiley Periodicals, Inc.
`American Epilepsy Society
`
`Lennox—Gastaut syndrome in October 2004, received its mar-
`keting authorization in Europe in January 2007, and was ap-
`proved by the FDA in December in 2008 for adjunctive treat-
`ment of seizures associated with Lennox—Gastaut syndrome for
`children 4 years or older and for adults. The purposes of this
`paper are to present the significant parameters for the use of
`rufinamide in clinical practice and to summarize the results of
`phases II and III clinical trials.
`
`Pharmacology
`
`The precise mechanisms by which rufinamide exerts its
`antiepileptic effect are unknown. In vitro studies suggest that
`a principal mechanism of action is the modulation of activity
`in sodium channels, particularly prolongation of the inactive
`state. In cultured cortical neurons from immature rats, rufi-
`namide significantly slowed sodium channel recovery from in-
`activation after a prolonged prepulse and limited the sustained
`repetitive firing of sodium-dependant action potentials (1,2).
`Rufinamide has no effect on benzodiazepine or GABA recep-
`tors or on adenosine uptake; it also has no significant interac-
`tions with glutamate, adrenergic, tryptophan, histamine, and
`muscarinic cholinergic receptors.
`The antiepileptic effect of rufinamide has been assessed
`in several animal models of generalized and partial seizures.
`For instance, oral rufinamide exhibited acute anticonvul-
`sive activity in mice and rat models, suppressing maximal
`electroshock-induced tonic—clonic seizures in both species and
`pentylenetetrazol-induced clonic seizures in mice (2). In the
`maximal electroshock test conducted in mice, the effective dose
`required for a 50% response against induced seizures (i.e., ED50)
`was 23.9 mg/kg for rufinamide compared to values of 9.0, 20.1,
`664.8, and >2,000 mg/kg for the established AEDs pheny-
`toin, phenobarbital, valproate, and ethosuximide, respectively.
`In mouse pentylenetetrazol tests, the ED50 values were lower for
`rufinamide (45.8 mg/kg) than for ethosuximide (192.7 mg/kg),
`phenytoin (>300 mg/kg), and valproate (388.3 mg/kg). Sim-
`ilarly, the behavioral toxicity of rufinamide was equivalent or
`much better than the four AEDs tested in this study. Intraperi-
`toneal rufinamide suppressed pentylenetetrazol-, bicuculline-
`and picrotoxin-induced clonus in mice. Efficacy in all seizure
`models suggests that rufinamide is likely to be of value in a broad
`spectrum of seizure types, although results in animal models
`may not translate to humans.
`
`Pharmacokinetics
`
`Rufinamide is well absorbed after oral administration. The ex-
`tent of absorption decreases slightly as the dose is increased,
`4$ (cid:9)
`EXHIBIT
`ARGENTUM Exhibit 1064
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`Current Review in Clinical Science
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`removed during dialysis. There is no autoinduction of rufi-
`namide metabolism. The effect of hepatic impairment has not
`been studied.
`Clinical trials have shown no significant differences in the
`pharmacokinetic parameters as a function of age within the
`range tested (i.e., age 4 years to elderly subjects). However, ap-
`plying the parameters derived from the pooled population phar-
`macokinetic analysis, one would predict rufinamide clearance
`at a full dose (45 mg/kg/day) to be 50% higher in a 4-year-old
`child than in an adult. Serum rufinamide levels can help guide
`the clinical decision making for a given patient, as variability
`in the rate and extent of absorption, comedications, and indi-
`vidual differences in drug clearance may impact the serum level
`and clinical efficacy. In addition, the significant relationship
`between therapeutic and adverse effects and plasma rufinamide
`concentrations suggests that measurement of rufinamide levels
`will be of value in clinical practice. Identifying the concen-
`tration at which a patient shows a good response provides a
`reference when evaluating the cause of a subsequent change in
`clinical status (4,5). Population pharmacokinetic studies reveal
`a positive correlation between reduction in seizure numbers and
`plasma rufinamide concentrations. Rufinamide reduced partial
`seizures and seizures associated with Lennox—Gastaut syndrome
`in a concentration-dependant manner. The mean plasma rufi-
`namide concentration to reduce seizure frequency by 25% or
`50% was predicted to be 15 and 30 mcg/mL, respectively (3).
`
`Drug Interactions
`
`Rufinamide does not have significant pharmacokinetic in-
`teractions with benzodiazepines, carbamazepine, lamotrigine,
`phenytoin, phenobarbital, valproate, topiramate, vigabatrin,
`oxcarbazepine, or primidone (3). However, cytochrome P450
`enzyme inducers, such as phenobarbital, primidone, phenytoin,
`and carbamazepine, increase the clearance of rufinamide, which
`likely is secondary to induction of carboxylesterases activity. The
`coadministration of these enzyme-inducing AEDs with rufi-
`namide leads to dramatically decreased rufinamide levels and
`potentially decreased efficacy (6). These patients may require
`a higher rufinamide dose. In contrast, valproate administra-
`tion may lead to elevated levels of rufinamide; the effect was
`most dramatic in children, for whom rufinamide concentra-
`tions can increase by 60 to 70 percent (1,3). The highest serum
`levels of rufinamide are noted in patients with high serum val-
`proate levels and who are concurrently taking high doses of rufi-
`namide. The exact mechanism for this interaction is unclear, but
`valproate is known to inhibit a number of drug-metabolizing
`enzymes.
`Clinical studies have shown that rufinamide can increase
`the clearance of oral contraceptives, specifically ethinyl estra-
`diol and norethindrone. The clinical significance of this mild
`
`N H 2
`
`FIGURE I . Chemical structure of rufinamide.
`
`however the effect is negligible at most clinical doses (3). Rufi-
`namide absorption is enhanced by food, probably by improved
`solubility. This enhancement results in over a 50% increase in
`the peak exposure (Cmax) and approximately a one-third in-
`crease in overall absorption. Patients will need to be advised
`to take rufinamide each time in the same temporal relation to
`their meals to maintain steady concentrations from one dose
`to the next. Rufinamide has low protein binding (about 34%),
`suggesting that competition for protein binding would not be
`a source of drug interaction, and its volume of distribution af-
`ter an oral dose approximates total body water (i.e., 50-80 L)
`(Table 1).
`The elimination of rufinamide occurs via hepatic
`metabolism with the primary metabolite, resulting from
`carboxylesterase-mediated enzymatic hydrolysis of the carboxy-
`lamide moiety, to form an inactive carboxylic acid derivative
`(CGP 47,292) (1,3). The metabolite has no known pharmaco-
`logic activity, is excreted in the urine, and the metabolic route is
`not cytochrome P450 dependant. Rufinamide is a weak inducer
`of CYP3A4 enzymes and is susceptible to induction by other
`AEDs, with the resulting effect of a decrease in rufinamide
`serum levels in their presence. Rufinamide pharmacokinetics
`are not affected by impaired renal function. The renal excre-
`tion of unchanged rufinamide is less than 2% of the total dose.
`The half-life of rufinamide is approximately 6 to 10 hours and
`does not change with renal impairment. Dose adjustment is
`likely necessary for patients undergoing hemodialysis, as the
`drug's low protein binding would result in the free drug being
`
`TABLE 1. Pharmacokinetics of Rufinamide
`Bioavailability (cid:9)
`Tmax (cid:9)
`Tye
`Protein binding (cid:9)
`Volume of distribution ( VdIF)
`Serum levels (cid:9)
`
`Fed-85%
`4 to 6 hours
`6 to 10 hours
`26 to 34%
`50 to 80 L (0.8-1.2 L/kg)
`5 to 55 mcg/mL
`
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`Current Review in Clinical Science
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`3
`
`interaction is not known. The extent of the decreased plasma
`concentrations caused by rufinamide is much less than that
`caused by phenytoin, carbamazepine, and phenobarbital. The
`finding is consistent with the weak induction of the P450 3A4
`enzyme by rufinamide.
`
`Efficacy Demonstrated in Clinical Studies
`
`Placebo-controlled studies for rufinamide that have efficacy data
`include studies involving: 1) patients with Lennox—Gastaut syn-
`drome (see Table 2), 2) adult partial onset seizures (for both
`monotherapy and adjunctive therapy), 3) pediatric partial on-
`set seizures as adjunctive therapy, and 4) patients with refractory
`generalized tonic—clonic seizures (7).
`
`Seizures Associated with Lennox—Gastaut Syndrome
`
`An international, multicentered, double-blind, placebo-
`controlled, randomized, parallel-group study, performed be-
`tween early 1998 and fall of2000, enrolled 138 patients (ages 4-
`30 years) with a diagnosis of inadequately controlled seizures as-
`sociated with Lennox—Gastaut syndrome (including both drop
`attacks and atypical absence seizures) and who were being
`treated with one to three AEDs (felbamate therapy was not
`allowed in this study) (8). Each patient was required to have
`had at least 90 seizures in the month prior to study entry. After
`a 4-week baseline phase, patients were randomized to receive
`either rufinamide or placebo during a 12-week double-blind
`phase. The double-blind phase consisted of a titration period
`(over 1-2 weeks) and a maintenance period (10 weeks). During
`the titration period, the dose was increased to approximately
`45 mg/kg/day (maximum dose 3,200 mg/day); 77% of pa-
`tients achieved their final dose level by the end of the first week,
`which was kept stable during the maintenance period. Doses
`were given on a twice-daily schedule.
`
`The primary end points evaluated were the percent of
`change in drop attacks (tonic—atonic seizures), total seizure fre-
`quency, and the seizure severity rating taken from a global eval-
`uation of the patient's condition. Rufinamide-treated patients
`had a 42.5% median reduction in drop attacks per 28 days rel-
`ative to the baseline compared to placebo-treated patients, who
`had a 1.4% median increase (p < 0.0001). The rufinamide-
`treated patients also had a significant decrease in the total seizure
`frequency per 28 days relative to the baseline (p = 0.0015: me-
`dian reduction for rufinamide was 32.7% vs 11.7% for placebo).
`These results are comparable to the findings in other clini-
`cal trials involving topiramate, lamotrigine, and felbamate (see
`Figure 2). In addition, there was significant improvement on
`the seizure severity global evaluation for the rufinamide group
`compared with the placebo group (p < 0.005). Population
`pharmacokinetic modeling revealed that the reduction in atonic
`seizures, total seizures, and seizure severity was correlated with
`rufinamide serum concentrations. Patients who received rufi-
`namide were approximately four times more likely to experience
`at least a 50% reduction in drop attacks, compared with those
`receiving placebo. The response to rufinamide could be seen
`as early as week 2. In the open label extension phase, patients
`who switched from double-blind rufinamide to open-label rufi-
`namide continued responding to treatment (9). Figures 2 and 3
`compare the clinical response to other trials involving patients
`with Lennox—Gastaut syndrome (10-14).
`
`Partial Onset Seizures
`
`Two double-blind, placebo-controlled, randomized, parallel-
`group studies (n = 313 and 647) have been performed using
`rufinamide as adjunctive therapy for partial onset seizures. One
`was a fixed-dose study of adolescents and adults, 16 years or
`older, and the other was a dose-ranging study of adolescents
`
`TABLE 2. Summary of Clinical Studies with Rufinamide
`
`STUDY
`TYPE
`
`Adjunct
`
`Adjunct
`
`SEIZURE TYPE
`
`DAILY DOSE
`
`Lennox—Gastaut
`syndrome
`Partial onset
`
`45 mg/kg (maximum
`3,200 mg) or placebo
`200, 400, 800, 1,600
`or placebo
`3,200 mg or placebo
`3,200 mg or placebo
`
`Partial onset
`Adjunct
`Monotherapy Partial onset
`
`AGE
`(YEARS)
`
`4 to 30
`
`>15
`
`>16
`>12
`
`OUTCOME*
`
`REFERENCE
`
`,,Drop attacks 4, Total seizures
`4.Seizure severity
`4.Total seizures (+) Responder rate
`
`4. Total seizures (+) Responder rate
`Fewer seizures and longer time
`to first, second, and third seizure
`for rufinamide
`No difference vs. placebo
`
`8
`
`1
`
`1
`
`7
`
`Adjunctt
`
`Primary GTC
`
`800 mg or placebo
`
`>4
`
`Abbreviations: GTC, generalized tonic—clonic.
`*All were significant ( p < 0.05) except study Ref. 7.
`The doses used did not provide patients with plasma rufinamide concentrations that are therapeutic for other seizure types, which could explain the lack of
`efficacy seen in this study.
`
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`Current Review in Clinical Science
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`FIGURE 2. Short-term, double-blind stud-
`ies on Lennox-Gastaut syndrome. Abbrevi-
`ations: FLB, felbamate; TPM, topiramate;
`LTG, lamotrigine; RFM, rufinamide; CLB,
`clobazam. References: 1, #10; 2, #11;
`3, #12; 4, #8; 5, #15. Felbamate: ap-
`proved for all ages. Lamotrigine and topi-
`ramate: approved for ages 2 years and older
`in Lennox-Gastaut syndrome. Clobazam:
`high dose is 1 mg/kg/day, max 40 mg/day,
`given BID; low dose is 0.25 mg/kg/day, max
`10 mg/day. There was a significant 14% de-
`crease over 4 weeks.
`
`85%
`
`44%
`
`34%
`
`42.5%
`
`14.8%
`
`Placebo
`n = 50
`
`Placebo
`(n = 60)
`
`FLB' Placebo
`(n = 28) (n = 22)
`
`TPM2
`(n = 48)
`
`LTG3 Placebo
`(n .75)(n= 89)
`
`RFM4
`(n = 73) 1.4%
`
`CLEP
`(n = 36)
`
`5.1%
`
`-85
`
`—45
`
`—25
`
`0
`
`+10
`
`% Decrease in Drop Attacks
`
`and adults, ages 16 to 65 years (1). In both studies, patients had
`inadequately treated partial seizures and were on AED therapy.
`In the first study, the patients were required to have had at least
`one partial seizure in each 4-week period of a baseline phase
`and were then randomized to rufinamide or placebo during a
`13-week double-blind phase (1). Titration of rufinamide oc-
`curred over 1 to 2 weeks. The initial dose of 800 mg/day was
`increased to a target dose of 3,200 mg/day, given as a twice-daily
`dose for an 11-week maintenance period. Rufinamide-treated
`patients experienced a significant, although modest, reduction
`(p = 0.0158) in partial seizure frequency per 28 days com-
`pared with placebo-treated patients (a 20.4% median decrease
`vs a 1.6% median increase). In addition, the responder rate (at
`least a 50% reduction in partial seizure frequency per 28 days)
`during the double-blind phase relative to the baseline phase was
`28.2% for rufinamide compared with 18.6% for placebo (p =
`0.0381).
`
`In the second adjunctive trial for partial onset seizures, pa-
`tients were required to have experienced nine or more seizures
`during the 12-week baseline phase (1). They were then random-
`ized to one of five treatment groups (placebo or rufinamide at
`200, 400, 800, or 1,600 mg/day); treatments were administered
`on a twice-daily schedule for the 3-month double-blind phase.
`Significant dose response was observed and pairwise compar-
`isons between placebo and each rufinamide treatment group
`showed that the seizure frequency ratio was statistically signifi-
`cantly lower for the 400-, 800-, and 1,600-mg groups. In addi-
`tion, a significant dose response was observed for the responder
`rate (p < 0.04).
`A single monotherapy study has been performed—a
`double-blind, placebo controlled, randomized, parallel-group
`study (n = 104) involving inpatients, ages 12 years and older,
`with uncontrolled partial seizures, who had just completed an
`inpatient presurgical evaluation. The patients had a 48-hour
`
`70%
`
`a)
`al 60%
`fi2
`0 so%
`V CI
`
`Cl,
`
`C. (cid:9)
`to N
`w (cid:9)
`CC
`
`40%
`
`30%
`
`° e,) 20%
`0
`A 10%
`
`0
`
`Drop Attacks
`
`Total Seizure Count
`
`66%
`
`55%
`
`51%
`
`47.9%
`
`45%
`
`41%
`
`FLB1
`(n = 50;
`12 mo)
`
`TPM2
`(n = 82;
`6 mo)
`
`RFM3
`(n = 56;
`12 mo)
`
`FLB
`(n = 71;
`12 mo)
`
`TPM
`(n = 84;
`6 mo)
`
`RFM
`(n = 50;
`12 mo)
`
`FIGURE 3. Long-term, open-label stud-
`ies of AED efficacy for Lennox-Gastaut
`syndrome. Abbreviations: FLB, felbamate;
`TPM, topiramate; RFM, rufinamide. Ref-
`erences: 1, #13; 2, #I4; 3, #9. Lamotrig-
`ine: no long-term data reported.
`
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`Current Review in Clinical Science (cid:9)
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`5
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`baseline prospective phase and then were randomized to either
`to rufinamide, 2,400 mg/day on day 1 and 3,200 mg/day on
`days 2 to 10 (given three times per day), or to placebo. The pri-
`mary efficacy variable was the mean time to meet the exit crite-
`ria. Outcome data favored rufinamide (p < 0.05) over placebo,
`with a median time to exit of 4.8 days compared with 2.4 days.
`Statistically significantly differences between treatments were
`observed for the time to first, second, and third partial seizures
`(p < 0.04), however the time to the fourth partial seizure failed
`to reach significance (p = 0.0509).
`
`Long-Term Follow-Up
`Both the Lennox—Gastaut study and the studies on par-
`tial seizures were followed by long-term, open-label extension
`studies. The patients who switched from double-blind placebo
`to open-label rufinamide quickly responded to treatment, with
`a marked decrease in seizure frequency. There was no evidence
`of tolerance to the anticonvulsant effect of rufinamide, during
`up to 3 years of follow-up (1).
`
`Dosing, Tolerability, and Safety
`
`Table 3 provides the authors suggestions for dosing in children
`and adults. The clinical trials were performed with administra-
`tion of the drug with food (resulting in enhanced absorption),
`which is the recommended protocol.
`Based on the clinical trials, rufinamide appears to be well
`tolerated. A small number of rufinamide-treated patients (9%
`vs 4% for placebo) discontinued treatment because of adverse
`effects (15). The adverse experiences most commonly associ-
`ated with discontinuation of rufinamide (>1%) were similar
`in adults and children: dizziness (1.8%), fatigue (1.6%), and
`headache (1.1%). The majority of adverse events in the clinical
`trials were judged to be mild to moderate and often transient in
`nature, largely occurring during the titration phase. The most
`commonly observed adverse events (i.e., occurring in >10%
`and at a higher frequency than placebo-treated patients), pooled
`from all of the studies of patients with epilepsy, were headache,
`dizziness, fatigue, somnolence, and nausea. Adverse events were
`
`reported more often in adults than in children and with plasma
`rufinamide concentrations in the higher ranges. Only somno-
`lence and vomiting were significantly more common in the ru-
`finamide group of the Lennox—Gastaut syndrome trial. At the
`fixed titration dose of 45 mg/kg/day in all pediatric trials, only
`somnolence, vomiting, and headache were significantly more
`common with rufinamide than placebo (i.e., observed >5%
`more often). In doses up to 3,200 mg/day in all adult clini-
`cal trials, only dizziness, fatigue, and diplopia were significantly
`more common with rufinamide than placebo. Neuropsychiatric
`side effects were rare (all <5%) and were no more common in
`rufinamide than in placebo groups. The rufinamide side effect
`profile is similar to other drugs that have an effect on the sodium
`channel.
`The overall tolerability of rufinamide is good. During the
`clinical trials, there were no cases of Stevens—Johnson syndrome,
`hepatic failure, agranulocytosis, or pancytopenia. The incidence
`of cognitive disorders in rufinamide-treated patients was higher
`than placebo-treated patients only because of the increased oc-
`currence of somnolence. Psychiatric adverse events were similar
`between rufinamide and placebo patients.
`AED hypersensitivity syndrome has occurred in association
`with rufinamide therapy. While the clinical symptoms varied,
`patients generally presented with fever and rash associated with
`other organ system involvement. In the clinical trials, this syn-
`drome occurred in close temporal association (within the first
`4 weeks) to the initiation of rufinamide therapy and was more
`likely in the pediatric population. If a serious rash related to ru-
`finamide is suspected, rufinamide should be discontinued and
`alternative treatment started.
`In the randomized trial, cognitive assessments were per-
`formed at baseline (before rufinamide treatment) and after
`3 months of adjunctive therapy at doses of 200, 400, 800, and
`1,600 mg/day for adolescents and adults (ages 15-64 years) with
`partial seizures (16). None of the cognitive tests for psychomo-
`tor speed and attention or for working memory demonstrated
`a significant worsening at any of the doses of rufinamide. In a
`placebo-controlled study of the QT interval, a higher percentage
`
`(cid:9) (cid:9)
`
`TABLE 3. Rufinamide Dosing
`
`LABEL (FDA)
`
`AUTHORS' RECOMMENDATIONS
`
`Children Given BID: Begin 10 mg/kg/day, Increase by 10 mg/kg,
`every other day to 45 mg/kg/day or 3,200 mg/day
`(whichever is less)
`Given BID: Begin with 400 to 800 mg/day Increase by
`400 to 800 mg every 2 days, up to a maximum of
`3,200 mg/day
`
`Adults
`
`Given BID or TID: Begin 15 mg/kg/day Increase by
`15 mg/kg/day, every week to 45 mg/kg/day or
`3,600 mg/day (whichever is less)
`Given BID or TID: Begin with 1,200 mg/day Increase
`by 1,200 mg/day every week up to 3,600 mg/day
`
`Abbreviations: BID, twice daily dosing; TID, three times daily dosing.
`Take with food. Supplied in 200- and 400-mg scored tablets (and 100 mg in Europe), which can be administered whole, in half tablets, or crushed.
`
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`of subjects taking 2,400-4,800 mg of rufinamide per day had a
`QT shortening of greater than 20 milliseconds compared with
`placebo, but none had a reduction below 300 milliseconds. Pa-
`tients with potassium channelopathy associated with familial
`short QT syndrome cannot be treated with rufinamide. Cau-
`tion is advised when administering rufinamide with other drugs
`or disease states that shorten the QT interval (e.g., digoxin tox-
`icity, hypercalcemia, hyperkalemia, and acidosis). There is no
`known clinical risk associated with the degree of QT shortening
`induced by rufinamide. No meaningful changes in laboratory
`data were observed, and rufinamide is designated pregnancy
`Category C. When assessing the risk of rufinamide or any new
`drug, it is important to remember that not all potential risks
`may have been identified, which is because only a relatively
`small number of patients have been exposed to the drug for a
`long period of time.
`
`Conclusions
`
`Rufinamide is a new broad-spectrum AED that is structurally
`unique. It offers various advantages: 1) the ability to rapidly
`escalate dosing and obtain a clinical response, 2) few drug in-
`teractions, and 3) a good cognitive and psychiatric adverse event
`profile. The CNS-related adverse events (primarily somnolence)
`largely occurred during the first 2 weeks of therapy, which may
`be related to the rapid fixed titration schedule used in the clinical
`trials. Slower titration helps minimize side effects. No labora-
`tory monitoring is required, and plasma levels correlate with
`clinical efficacy. All of these characteristics will make it a com-
`monly used drug in Lennox-Gastaut syndrome. Further tri-
`als are ongoing. Continuing clinical experience may elucidate
`whether rufinamide eventually will prove beneficial for a wider
`spectrum of patients.
`
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