Rufinamide is a triazole derivative identified by screening in animal seizure models. It is effective for atonic seizures in Lennox-Gastaut syndrome, but there is also some evidence of efficacy in the treatment of focal seizures. In the USA and Europe, rufinamide is only approved for treatment of seizures associated with the Lennox-Gastaut syndrome.
Mechanism of Action
In mice and rats, rufinamide is protective in the MES test and, at higher doses, in the PTZ test. Its only known action that is relevant to seizure protection is as a blocker of voltage-gated sodium channels.
In the Lennox-Gastaut syndrome, rufinamide is effective against all seizure types but especially against atonic seizures. Some clinical data suggest it may be effective against focal seizures. Treatment in children is typically started at 10 mg/kg/d in two equally divided doses and gradually increased to 45 mg/kg/d to a maximum of 3200 mg/d. Adults can begin with 400–800 mg/d in two equally divided doses up to a maximum of 3200 mg/d as tolerated. The drug should be given with food. The most common adverse events are somnolence and vomiting.
Rufinamide is well absorbed, and plasma concentrations peak between 4 and 6 hours. The half-life is 6–10 hours, and minimal plasma protein binding is observed. Although cytochrome P450 enzymes are not involved, the drug is extensively metabolized to inactive products. Most of the drug is excreted in the urine; an acid metabolite accounts for about two-thirds of the dose. Most drug-drug interactions are minor except that valproate may decrease the clearance of rufinamide; dosing with valproate, particularly in children, may need to be decreased, typically by 50%.
Dravet’s syndrome (severe myoclonic epilepsy of infancy) is a rare genetic epileptic encephalopathy characterized by diverse generalized and focal seizure types, including myoclonic seizures, tonic-clonic seizures, absence seizures, atonic seizures, and one-sided hemiconvulsive and focal seizures. Mutations of the SCN1A gene encoding Nav1.1 voltage-dependent sodium channels cause 79% of diagnosed cases of Dravet’s syndrome. Although drugs such as clobazam, valproate, and topiramate are used, none of these is very effective. Stiripentol is not approved in the USA but is widely used in Europe. In patients with SCN1A gene mutations, sodium channel-blocking antiseizure drugs are contraindicated because they worsen seizures.