Rufinamide is a tri-azole derivative drug that is structurally unrelated to any other anti-seizure drugs (ASD).[1] It was developed first in 2004 and later was granted an orphan drug status in October 2004 and was first marketed in Europe in January 2007. It was approved by the US FDA on November 14, 2008, for the adjunctive treatment of seizures associated with Lennox Gastaut syndrome (LGS).[2] Interestingly, it was the first anti-seizure medication to reach the US market, having a pediatric indication prior to approval for adults.

FDA Indication: Adjunctive treatment of seizures associated with Lennox-Gastaut Syndrome in pediatric patients one year of age and older and in adults.

Rufinamide (1-[(2,6-difluorophenyl] methyl))-1hydro-1,2,3-triazole-4 carboxamide) has a tri-azole group within its structure, which has a structural resemblance to anti-fungal and fungicidal drugs; however, rufinamide has no structural similarity to any of the anti-seizure medications.

The exact mechanism of action of rufinamide is unknown. In vitro, it stabilizes the inactive state of the sodium channel, thus limits the sustained bursts of high-frequency action potentials and prevents sodium channels from returning to an activated state, therefore, decreases the neuronal hyperexcitability and action potential propagation.[3] Rufinamide has no effect on benzodiazepine, gamma-aminobutyric acid (GABA) receptors, or adenosine uptake and has no interactions with glutamate, adrenergic, tryptophan, histamine, and muscarinic cholinergic receptors.[2]

Rufinamide administration iv via twice-daily dosing. In children, it is started at 10 mg/kg/day and is gradually increased by 10mg/kg every other day to 45 mg/kg/day or 3200 mg/ day (whichever is less). In adults, the dosing regimen begins with 400 to 800 mg/day, gradually increased by 400 to 800 mg every other day, up to a maximum of 3200 mg/day. Rufinamide is administered orally and is available in two formulations: Film-coated tablets (200 mg, 400 mg) and oral suspension (40 mg/ml). The US labeling recommends, if on valproic acid, the initial rufinamide dose should be 400mg daily (<10 mg/kg/day) due to enzyme inhibition effects of valproic acid.[4]

Rufinamide has a slow absorption (T-max 4 to 6 hours) and has bioavailability up to 85%.[1] The bioavailability is better when taken with food. The half-life of rufinamide is 6 to 10 hours and has relatively low protein binding, 26 to 34%, and binds primarily to albumin, thus has little displacement drug-drug interactions. It is metabolized via a non-CYP450 pathway by carboxylase mediated hydrolysis in the liver into its inactive metabolite. It is primarily excreted, up to 85% from kidneys, and 2% is excreted unchanged in the urine. No dose adjustment is necessary for renal impairment.[2]

The common adverse effect of rufinamide includes somnolence, vomiting, headache, fatigue, dizziness, nausea, and rarely flu-like symptoms, nasopharyngitis, rash, ataxia, and diplopia.

Four less common, but potentially significant adverse effects related to rufinamide are shortening QT interval, multi-organ hypersensitivity/drug reaction with eosinophilia and systemic symptoms (DRESS), leukopenia, and Stevens-Johnson syndrome.

The QT interval shortening below 300 was not observed in the studies with doses up to 7200 mg per day. There was no sign for drug-induced sudden death or ventricular arrhythmias with rufinamide. However, in patients with a history of familial short QT syndrome, rufinamide was associated with an increased risk of sudden death, ventricular arrhythmia/fibrillation. Such events tend to occur when the QT interval falls below 300 msec. Therefore, caution is also necessary with concomitant use of rufinamide with other potential drugs that shorten the QT interval.[5]

In the clinical trials, DRESS is most commonly seen in children less than 12 years of age, occurred within four weeks of rufinamide initiation, and resolved or improved with its discontinuation. Therefore, if there is an index of suspicion of DRESS, the patient should be evaluated, and rufinamide should be discontinued, and alternative treatment initiated.

The only major contraindication to use of rufinamide is familial short QT syndrome. As discussed above, rufinamide was associated with significant ventricular arrhythmia, including cardiac death in patients with a history of short QT syndrome.

Minor contraindications include concomitant use of rufinamide with other potential drugs that shorten QT interval and the presence or history of the short QT interval; therefore, the recommendation is to check the QT interval in these patient populations routinely. Other contraindications include hypersensitivity to rufinamide and/or triazole derivative.

Warnings /precautions include central nervous system (CNS) effects, including cognitive and coordination dysfunction. Therefore, caution is necessary regarding participating in tasks that require mental alertness. Other warnings/precautions include multi-organ hypersensitivity reactions (like DRESS as discussed above), dermatological reactions such as Steven Johnson syndrome (SJS), leukopenia, and suicidal ideation.

Hepatic impairment: Rufinamide is not recommended for use in severe hepatic impairment; however, caution is advised in mild to moderate hepatic impairment.

Rufinamide is a Pregnancy Category C drug and is likely to be excreted in human milk. However, there is no contraindication to breastfeeding with rufinamide use.[6]