Rufinamide

Pharmaceuticals

Pharmaceuticals -> Antiepileptics

Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals -> Nervous system -> Antiepileptics

Breast Feeding; Lactation; Anticonvulsants;

FDA approved drugs -> Active ingredient

EMA approved medicines: Human medicine

FDA approved drugs -> Active ingredient

Warning

H336 (100%): May cause drowsiness or dizziness [Warning Specific target organ toxicity, single exposure; Narcotic effects]

P203, P261, P271, P280, P304+P340, P318, P319, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 5 reports by companies from 5 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

In prelicensure clinical trials, addition of rufinamide to standard anticonvulsant therapy was reported to be associated with only rare elevations in ALT above 3 times the upper limit of normal (ULN). Rufinamide was not linked to instances of clinically apparent liver injury, but a pooled analysis of more than 200 children mentioned that two patients needed to discontinue therapy early because of liver related adverse events, one of which was described as “toxic hepatitis”. Since approval, there have been no reports of clinically apparent liver injury associated with rufinamide use, but it has had limited use in epilepsy. Rufinamide has been linked to instances of severe cutaneous reactions, including Stevens Johnson syndrome which often has some degree of associated liver injury. Thus, rufinamide may cause liver injury, but it is rare.

There is no specific antidote for treating rufinamide toxicity. Hemodialysis can limit rufinamide clearance; therefore, no specific evidence is available for a rufinamide toxicity antidote, except for general maneuvers to remove unabsorbed medication (emesis, gastric lavage, airway protection, etc.).

Drug Induced Liver Injury Rank (DILIrank 2.0)

Rufinamide

Ambiguous-DILI-concern

3

Warnings & precautions

DOI:10.1016/j.drudis.2016.02.015

N03AF03

N - Nervous system

QN - Nervous system

Rufinamide is extensively metabolized but has no active metabolites. Metabolism by carboxyesterases into inactive metabolite CGP 47292, a carboxylic acid derivative, via hydrolysis is the primary biotransformation pathway. A few minor additional metabolites were detected in urine, which appeared to be acyl-glucuronides of CGP 47292. The cytochrome P450 enzyme system or glutathiones are not involved with the metabolism of rufinamide. Rufinamide is a weak inhibitor of CYP 2E1. Rufinamide is a weak inducer of CYP 3A4 enzymes.

Drugs used to prevent SEIZURES or reduce their severity.

A class of drugs that inhibit the activation of VOLTAGE-GATED SODIUM CHANNELS.

The oral suspension and tablet are bioequivalent on a mg per mg basis. Rufinamide is well absorbed but the rate is slow and the extent of absorption decreases as dose is increases. Based on urinary excretion, the extent of absorption was at least 85% following oral administration of a single dose of 600 mg rufinamide tablet under fed conditions. Bioavailability= 70%-85% (decreases with increasing doses); Tmax, fed and fasted states= 4-6 hours; Cmax, 10 mg/kg/day= 4.01 µL/mL; Cmax, 30mg/kg/day= 8.68 µL/mL; AUC (0h-12h), 10mg/kg/day= 37.8±47 µg·h/mL; AUC (0h-12h), 30mg/kg/day= 89.3±59 µg·h/mL.

Renally (91%; 66% as CGP 47292, 2% as unchanged drug) and fecally (9%) eliminated.

Rufinamide was evenly distributed between erythrocytes and plasma. The apparent volume of distribution is dependent upon dose and varies with body surface area. The apparent volume of distribution was about 50 L at 3200 mg/day. Volume of distribution is similar between adults and children and is non-linear.