PEDIATRIC PHARMACOTHERAPY A Monthly Newsletter for Health Care Professionals from the University of Virginia Children’s Hospital

Volume 1 5 Number 4 April 20 09

Ruf inamide: Use in Patients with Refractory Epilepsy or Lennox Gastaut Syndrome Marcia L. Buck, Pharm.D., FCCP

enno x-Gastaut syndrome (LGS) is a rare in children and adults. 5 Clinical trials in adults L form of epilepsy consisting of multiple receiving rufinamide have demons trated a slow, seizure types , including tonic -atonic “drop but complete , absorption with a bioavailability attacks,” and cog nitive impairment. Many approaching 85%. Peak plasma concentrations patients with LGS require a multi -drug regimen, occur 3 to 6 hours after an oral dose. Food with antiepileptics such as valproic acid, increases the extent of absorption by lamotrigine, or topiramate, as well as approximately 30 to 4 5% and shortens the time corticosteroids or immune globulin. Additional to maximum concentr ations . Rufinamide is therapies have included a ketogenic diet, vagus distributed evenly between erythrocytes and nerve stimulation, and surgical resection. plasma with minimal protein binding (34%). The Despite an aggressive approach to treatment, apparent volume of distribution in adults many patients continue to have frequent receiving 3,200 mg rufinamide/day was 50 L. seizures. 1,2 Rufinamide is extensively metabolized via carboxyleste rase -mediated hydrolysis to inactive Several new agents have been under compounds . On ly 2% of a dose is excreted from investigation over the past decade which may be the body as unchanged drug. The average useful in patients with LGS .1,2 In 2004, elimination half -life of rufinamide in adults is 6 rufinamide was granted orphan drug status in the to 1 2 hours. 1,3 -6 United States and Europe .1 It was approved as a prescription drug by the Food and Drug The pharmacokinetic profile of rufinamide in Administration (FDA) on November 14, 2008 for children has bee n evaluated by the manufacturer the adjunctive treatment of seizures associated in several trials .2-7 The largest trial enrolled a with LGS in pa tients 4 years of age and older. 3 It total of 216 pediatric patients, 117 children has also been studied in the management of between 4 and 11 years of age and 99 refractory partial seizures. 1,2 T his issue of adolescents between 12 and 17 years of age . Pediatric Pharmacotherapy will provide an While the full results of th is stud y have n ot yet overview of rufinamide and describe the results been published, the data were reported as being of initial clinical trials with this a gent as an add - similar to the values obtained in adults. 4 Making on antiepileptic in children and adults. a c omparison to adult studies is complicated , however, by differences in concomitant Mechanism of Action medications. The p ediatric patients in clinical Rufinamide , 1-[2,6 -difluorophenyl)methyl] -1H - trials are often being treated with v alproic acid , 1,2,3 -triazole -4 carboxamide), is a triazole which increases rufinamide concentrations , while derivative structurally unrelated to any other most adult patients are treated with antiepileptics current antiepileptic drug. While the e xact that decrease rufinamide concentrations .5 mechanism of rufinamide is still unknown, it is thought to act through modulation of sodium Clinical Trials channels resulting in membrane stabilization . A number of studies were conducted with Rufinamide administration slow s recovery after a rufinamide prior to its approval by the FDA. The prolonged p repulse in cortical neurons and limits largest was a multicenter, randomized, double - sustained rep etitive firing of sodium -dependent blind, placebo -controlled add -on trial in patients action potentials. 1-4 with refractory simple or complex partial seizures . A total of 647 patients, ages 15 to 65 Pharmacokinetics years , were enrolled . The primary ai m of the Over a dozen s tudies have been conducted to study was to evaluate efficacy and safety over the define the pharmacokinetic profile of rufinamide proposed dosage range of 200 to 1 ,600 mg/day. After a 3 -month baseline observation phase, mg/kg/day increments every two days to a patients were randomized to one of four maximum of 45 mg/kg/day or 3,200 mg/day. rufinamide dosages (200, 400, 800, or 1,600 mg/day divided into t wo daily doses ) or The median reduction in seizure frequency was placebo .1,2 32.7% in the rufinamide group versus 11.7% (p=0.0015). The frequency of drop attacks Efficacy was assessed by the seizure frequency decreased by 42.5% in the rufinami de group, but ratio ( the difference between the number of increased in the placebo group by 1.4% seizures at baseline and during treatment) . The (p<0.0001). The rufinamide group also had ratio w as +5% in the placebo group, compared to significantly more patients who experienced a 0% in the 200 mg/day group, -7% in the 400 50% or greater reduction in seizure frequency mg/day group (p<0.03), -11% in the 800 mg/day (31.1% versus 10.9%, p=0.0045). There was no group (p<0.02), and -12% in the 1 ,600 mg/day difference in the numb er of patients who group (p<0.02). The percentage of patients with achieved complete seizure control (4.1% in the a 50% or greater reduction in seizure frequency rufinamide group versus 3.3% of controls, at 28 days was 5% in the placebo group, 4.7% in p=0.84). There was also no significant the 200 mg/ day group, 16% in the 400 mg/day difference between the groups in the group , 11.6% in the 800 mg/day group, and parent/guardian global evaluation (median score 14.3% in the 1 ,600 mg/day group. 1,2 The results 2.30 for rufinamide and 1.77 for placebo). The of this study formed the basis of the FDA primary adverse effects reported with rufinamide approval. included somnolence (24.3%) and vomiting (21.6%). Based on their results, the authors In 2001, Palhagen and colleagues published the concluded that rufinamide was an effective and results of a nother multicenter, randomized, relatively well -tolerated adjunctive therapy in double -blind, placebo -controlled add -on trial of patients with LGS. 9 rufinamide in adults with partial or primary generalized tonic -clonic seizures .8 Fifty patients Kluger and colleagues recently published the were randomized to receive either rufinamide, results of an observational study of rufinamide as beginning at 400 mg/day and increased at weekly an add -on therapy in children and adults with inte rvals to 1,600 mg/day, or placebo for 28 refractory epilepsy. 10 The study incorporated days. At the end of the trial, seizure frequency data from institutions througho ut Germany and had decreased by 41% in the rufinamide group, Austria. A total of 60 patients were evaluated, while it had increased by 52% in the placebo including 45 children and 15 adults (mean patient group. A 50% or greater reduction in seizure age 14.5 +11.6 years, range 1 -50 years). Th e frequency from baseline was achieved in indications for treatment were as follows: LGS significantly more of the rufinamide patients (31 patients), idiopathic generalized epilepsy (39%) than controls (16%, p=0.096). The most syndromes (5) , cryptogenic unclassified frequently reported adverse effects in the generalized seizures (7) , and partial epilepsy rufinamide group were fatigue (20%), headache (17) . The average number of antiepileptics used (12%), and tremor (12%). The se results added in the study patients prior to enrollment was further evidence t hat rufinamide is a safe and 11 +4 (range 4 to 20). The most frequent effective adjunct therapy for patients with concomitant therapies during the s tudy were refractory epilepsy. valproic acid, used in 43.3% of the patients, and clobazam, used in 28.3%. Nine patients were on Two additional rufinamide studies were a ketogenic diet, 14 patients had a vagus nerve published last year. 9,10 Glauser and colleagues stimulator, and eight patients had undergone conducted a randomized double -blind, placebo - unsuccessful epilepsy surgery. controlled add -on trial o f rufinamide in 138 patients with LGS. 9 The patients ranged from 4 While the choice of ruf inamide dose was to 30 years of age . All had a minimum of 90 determined by the treating physician, the most seizures per month at the time of enrollment and common initial rufinamide dose used in the study evidence of a slow spike and wave pattern on patients was 10 mg/kg/day. The mean final dose electroencephalogram (EEG). After a 28 -day was 35.5 +17.3 mg/kg/day. Efficacy was basel ine observation period, patients were evaluated by comparing baseline seizure randomized to receive rufinamide or placebo for frequency with r esults after at least 4 weeks of 84 days. Dose titration was conducted over the treatment and again at 12 weeks . A 50% or first two weeks, followed by a 70 -day greater reduction in seizure frequency occurred maintenance phase. Rufinamide was initiated at in 46.7% of the treated patients. Twenty percent a dose of 10 mg/kg/day and titrated by 10 achieved a 75% or greater reduction in seizures and 8.3% achieved complete seizure control. The highest response rate was achieved in the patients developed leu kopenia (WBC < patients with LGS (54.8%). Patients with 3x10 9L). 1-4 refractory partial seizures were the least likely to respond to rufinamide (23.5%). The most The average rate of discontinuation of therapy in frequently reported adverse effects were fatigue pediatric trials was 8 to 9%, similar to rates in (18.3%), vomiti ng (13.3%), and loss of appetite clinical trials conducted in adults. The most (10%). No serious adverse effects were observed frequent reasons for discontinuation were by the investigators. This preliminary continued seizures, rash, or fatigue ( each observational study co nfirm s the results with reported in 2% of patients), or vomiting (1%). 1-4 rufinamide demonstrated in clinical trials and supports its use as an adjunctive antiepil eptic Drug Interactions therapy. 10 Rufinamide is weak inducer of cytochrome P450 (CYP) 3A4. Conc omitant administration of Warnings and Precautions rufinamide and triazolam or oral contraceptives Rufinamide is contraindicated in patients with may reduce the concentrations of these drugs. known or suspected short QT syndrome. In Triazolam area under the concentration curve clinical trials, rufinamide shortened the QT (AUC) values may be decrease d by up to 30 - interval up to 20 msec or greater. There were no 40%. Ethinyl estradiol and norethindrone AUC cases of QT intervals < 300 msec or reports of values have been reduced by 22% and 14%, drug -induced ventricular arrhythmias or sudden respectively, in clinical studies. While the cardiac death. Patients taking other drugs that impact of this reduction on oral contraceptive might shorten the QT interval should not take efficacy is not known, it is recommended that rufinamide ..3,4 women of child -bearing age use an additional form of contraception during treatment. Rufinamide also carries the black box warning Rufinamide is also a weak inhibitor of CYP2E1, for suicidal ideation common to all antiepileptic but no drug interactions resulting from this effect drugs. Although there are not adequate data to have been identified .1-4 determine if rufinamide use places patients at higher risk for suicide, p atients and their families Conc omitant administration of rufinamide and should be aware of this risk and the need to other antiepil eptic drugs ha s been studied in both discuss c hanges in mood or behavior with t heir children and adults. In general, children, physician .3,4 especially those receiving higher rufinamide doses, appear to have the most significant drug Rufinamide has also been associated with interactions. Rufinamide has no significant antiepileptic multi -organ system hypersensitivity effect on the concentrations of topir amate or reactions. The initial presentation in clinical valproate. It may decrease concentrations of trials with rufinamide has been fever and rash. carbamazepine or lamotrigine by 7 to 13%. In Patients typically progress to development of contrast, rufinamide may increase serum hematuria, lymphadenopathy, and elevated serum concentrations of phenobarbital and phenytoin by transaminases. In the cases reported during 7 to 21%. 1-4 premarketing clinical studies, symptoms resolved after discontinuation of therapy. 3,4 Several antiepileptic drugs alter rufinamide con centrations. Administration of phenobarbital, Adverse Effects primidone, or phenytoin may decrease In premarketing clinical trials in children, rufinamide concentrations by up to 25 to 46%. rufinamide ha s generally been well -tolerated. Carbamazepine may decrease rufinamide The most frequent ly reported adverse effects concentrations by 19 to 26%. Vigabatrin have been central nervous system -related: decreases rufinamide concentrations by somnolence (in 17% of patients based on approxi mately 13%. Concomitant administration combined study results ), headache (16%), fatigue of valpro ic acid derivatives may increase (9 %), dizziness (8%), ataxia (4%), and rufinamide concentrations by 16 to 70% . The psychom otor hyperactivity, aggression, or magnitude of the effect depend s on the serum inattention (3%). Other adverse effects included valproate concentration. Pediatric patients vomiting (17%), nausea (7%), loss of appetite, receiving rufinamide s hould have a slow nasopharyngitis, influenza (5%), rash, diplopia introduction of the va lpro ic acid/valproate (4%), and abdominal pain, pruritus, bronchitis, product with gradual dose titration. sinusitis, and ear infection s (3%). Similar Benzodiazepines, lamotrigine, and topiramate reactions were reported in studies conducted in have no significant effect on rufinamide adults. In combined data from pediatric and concentrations. 1-5 adult rufinamide trials, approximately 4% of Dosing Recommendations and Availability 6. Cardot JM, Lecaillon JB, Czendlik C, et al. The influence The recommended starting dose for rufinamide in of food on the disposition of the antiepileptic rufinamide in healthy volunteers. Biopharm Drug Dispos 1998; 19:259 -62. children is 10 mg/kg/day divided into two doses 7. Arroyo S, Sac hdeo R, Rosenfeld W, et al. per day. The dose may be increased by 10 mg/kg Pharmacokinetics and safety of ascending doses of increments every 2 days up to a dose of 45 adjunctive rufinamide in pediatric patients with inadequately mg/kg/day or 3,200 mg/day. For adults, the controlled seizures [abstract]. Epilepsia 2005;46(Suppl 8):193. recommended starting dose is 400 to 800 mg/day 8. Palhagen S, Canger R, Henriksen O, et al. Rufinam ide: a di vided into two doses per day. The dose may be double -blind, placebo -controlled proof of principle trial in increased by 400 to 800 mg/day increments patients with epilepsy. Epilepsy Res 2001;43:115 -24. every 2 days until a maximum dose of 3,200 9. Glauser T, Kluger G, Sachdeo R, et al. Rufinamide for generalized seizures associated with Lennox -Gastaut mg/day is reached. No dosage adjustment is syndrome. Neurology 2008;7 0:1950 -8. needed in patients with renal dysfunction. 10 . Kluger G, Kurlemann G, Haberlandt E, et al. Hemodialysis may reduce serum concen trations Effectiveness and tolerability of rufinamide in children and by approximately 30% . D osage adjustment may adults with refractory epilepsy: first European experience. Epilepsy Behav 2009 ;14:491 -5. be necessary based on clinical response. Use of 11. Drug Topics Red Book. Montvale, NJ: Thomps on rufinamide is not recommended in patients with Healthcare (on -line via McKesson). hepatic impairment .1-4 Formulary Update Rufinamide (Banzel ®; Eisai Co., Ltd.) is The following actions were taken by the available as 200 mg and 400 mg scored t ablets. Pharmacy and Therapeutics Committee at their The tablets may be crushed, if necessary, for meeting on 3/2 7/09: patients unable to swallow them whole. 1. Clevidipine butyrate (Cleviprex ®), and IV Rufinamide should be taken with food to calcium channel blocker, was added to the improve absorption. If therapy is going to be Inpatien t Formulary with restriction to use in discontinued, the dose should be gradually perioperative blood pressure management in reduced to minimize the risk of precipitating patients undergoing cardiac or vascular surgery. seizures. In clinical trials, the dose was reduced 2. Fosfomycin (Monurol ®), a broad -spectrum by 25% every two days .3,4 antibiotic, was added to the Inpatient Formulary for the treatment of uncomplicate d urinary tract Cost infections in women. It is a Category A The average wholesale price (AWP) for a bottle antimicrobial. of 30 200 mg rufinamide tablets is $ 46.88. The 3. Oral d oxercalciferol (Hectorol ®), a synthetic AWP for a bottle of 120 400 mg tablets is vitamin D analog, was added to the Inpatient and $375.00 , resulting in an approximate daily cost Outpatient Formularies for the treatment of of therapy of $3.00 to $6.00 .11 secondary hyperparathyroidism associated w ith chronic kidney disease. Summary 4. A second oral live rotavirus vaccine (Rotarix ®) Rufinamide is a useful new option for the was added to the Formulary. Unlike RotaTeq ®, adjunctive treatment of patients with LGS or this vaccine requires only two doses for full refractory partial seizures . While initial clinical immunization. RotaTeq ® will be removed after trials have demonstrated benefi t and an the patients who have already started acce ptable safety profile, further studies are immunization with it have completed the series. needed to define further the place of rufinamide 5. The restriction on caspofungin was amended in therapy and to identify rare or serious adverse to require approval by a Pediatric ID attending effects. physician. The approving physician’s name will be added to the medical order by the prescriber . References 1. Hakimian S, Cheng -Hakimian A, Anderson GD, et al. Contributing Edit or:Marcia L. Buck, Pharm.D. Rufinamide: a new anti -epileptic med ication. Expert Opin Editorial Board: Kristi N. Hofer, Pharm.D. Pharmacother 2007;8:1931 -40. 2. A rr oyo S. Rufinamide. Neurotherapeutics 2007;41:155 - Michelle W. McCarthy, Pharm.D. 62. Susan B. Cogut, Pharm.D. 3. Rufinamide. Drug Facts and Comparisons . Efacts Website: Terry Bennett [online]. 2009. Available from Wolters Kluwer Health, Inc. If you have comments or suggestions for future (accessed 3/16/09). 4. Banzel ® prescr ibing information. Eisai Co., Ltd., issues, please con tact us at Box 800674, UVA November 2008. Available at www.banzel.com (accessed Health System, Charlottesville, VA 22908 or 3/15/09). by e -mail to [email protected] . This 5. Perucca E, Cloyd J, Critchley D, et al. Rufinamide: newsletter is also available a t clinical pharmacokinetics and concentration -response relations hips in patients with epilepsy. Epilespia http://www.healthsystem.virginia.edu/internet/p 2008;49:1123 -41. ediatrics/education/pharmnews.cfm