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Paediatric drugs

Rufinamide for pediatric patients with Lennox-Gastaut syndrome: a comprehensive overview.


PMID 21351809

Abstract

Rufinamide is a triazole derivative with broad-spectrum antiepileptic effects that is unrelated to any antiepileptic drug currently on the market. The European Commission and the US FDA approved rufinamide in 2007 and 2008, respectively, for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in children 4 years of age or older and adults. The mechanism of action of rufinamide is not completely understood but it is believed to prolong the inactive state of sodium channels, therefore limiting excessive firing of sodium-dependent action potentials. Rufinamide is well absorbed when taken with food, with an absolute bioavailability between 70% and 85%. The elimination half-life of the drug is around 6-10 hours, with a time to maximum plasma concentration (C(max)) of approximately 4-6 hours. The C(max) at a dosage of 10 mg/kg/day and 30 mg/kg/day is 4.01 μg/mL and 8.68 μg/mL, respectively, and the area under the plasma concentration-time curve from time 0 to 12 hours was 37.8 ± 47 μg · h/mL and 89.3 ± 58 μg · h/mL, respectively. Rufinamide exerts non-linear pharmacokinetics with increasing doses. The volume of distribution in children is similar to that in adults (0.8-1.2 L/kg) and the drug binds rather poorly to plasma protein (26.2-34.8%). Rufinamide is mainly metabolized by carboxylesterases to an inactive metabolite (CGP 47292), and the majority of the metabolites are excreted in the urine (91%). No dosage adjustment is required in patients with renal dysfunction. Rufinamide does not affect the plasma concentration of other antiepileptics, but phenytoin, phenobarbital, valproate, and primidone affect the clearance of rufinamide. In a clinical study of 138 patients averaging 12 years of age, rufinamide used as an adjunctive therapy (with an initial dosage of 10 mg/kg/day up to a target dosage of 45 mg/kg/day) in patients with Lennox-Gastaut syndrome reduced the median total seizure frequency by 32.7% versus 11.7% in the placebo group (p = 0.0015). Similar reduction in total seizure frequency was maintained in the extension phase of this study. In other studies, rufinamide also seemed to provide improvement in both partial seizures and refractory epilepsy, but further studies need to validate this observation and to identify its clinical significance. Rufinamide is usually started orally at 10 mg/kg/day, titrating up by 10 mg/kg/day every 2 days to a target dosage of 45 mg/kg/day divided twice daily (maximum dosage of 3200 mg/day). Dosing of rufinamide has not been established in patients <4 years of age. Rufinamide is available as 100, 200, and 400 mg tablets in Europe, and 200 and 400 mg tablets in the US; a suspension of 40 mg/mL can be prepared extemporaneously. Rufinamide is well tolerated, with the most common adverse effects being dizziness, fatigue, nausea, vomiting, diplopia, and somnolence. From the current data, rufinamide serves as an adjunctive therapy in the management of Lennox-Gastaut syndrome. Further studies need to evaluate its efficacy as a first-line agent in the management of this neurologic disorder.

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R8404
Rufinamide, ≥98% (HPLC), powder
C10H8F2N4O