title: Exposure to rufinamide and risks of CNS adverse events in drug-resistant epilepsy: a meta-analysis of randomized, placebo-controlled trials.
abstract: OBJECTIVE
  Epilepsy is a complex disease necessitating continuous development of new therapeutic strategies to encounter drug-resistant cases. Among new adjuvant antiepileptic drugs, rufinamide is structurally distinct from other antiepileptic drugs. It is used to treat partial-onset seizures and seizures associated with Lennox-Gastaut syndrome (LGS) in adult and children. To date, there has been no attempt to evaluate systematically the risks of adverse events with rufinamide.
  
  
  METHODS
  We performed a quantitative risk analysis of central nervous system (CNS) adverse events of rufinamide from all randomized, double-blind, add-on, placebo-controlled trials. The meta-analysis was undertaken with fixed effects models.
  
  
  RESULTS
  Of the 886 publications reviewed, 99 papers were retrieved and five articles met the inclusion criteria. One thousand two hundred and fifty-two patients were included. Our study showed that exposure to rufinamide was associated with a significant increase in risk of somnolence [relative ratio (RR) 1.87; 95% confidence interval (CI) 1.33, 2.62; P = 0.0003], dizziness (RR 2.66; 95% CI 2.00, 3.55; P = 0.00001), fatigue (RR 2.14; 95% CI 1.57, 2.91; P = 0.01) and headache (RR 1.28; 95% CI 1.02, 1.59, P = 0.03). In addition, exposure to rufinamide was associated with higher treatment discontinuation rates as compared with placebo (RR 2.65; 95% CI 1.74, 4.03; P = 0.00001).
  
  
  CONCLUSIONS
  The risk of CNS adverse events appears to be increased in patients exposed to rufinamide as well as the treatment discontinuation rates. However, although statistical associations were significant, additional long term safety studies are required to confirm the clinical significance of these findings, as most reports described only mild and moderate adverse events.
authors.affiliation: Motherisk Program, Division of Clinical Pharmacology and Toxicology, Department of Pediatrics, Hospital for Sick Children and University of Toronto, Toronto, ON; Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada; Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, Riyadh, KSA.
authors.forename: Abdulaziz M S
authors.initials: AM
authors.lastname: Alsaad
authors.forename: Gideon
authors.initials: G
authors.lastname: Koren
mesh_terms: D000927:Anticonvulsants / Q000009:adverse effects*; D002493:Central Nervous System Diseases / Q000139:chemically induced*; D006970:Disorders of Excessive Somnolence / Q000139:chemically induced; D004244:Dizziness / Q000139:chemically induced; D004351:Drug Resistance; D004827:Epilepsy / Q000188:drug therapy*; D005221:Fatigue / Q000139:chemically induced; D006261:Headache / Q000139:chemically induced; D006801:Humans; D016032:Randomized Controlled Trials as Topic; D012306:Risk; D014230:Triazoles / Q000009:adverse effects*
chemical_list: D000927:Anticonvulsants; D014230:Triazoles; C079703:rufinamide
keywords: adults; central nervous system; children; epilepsy; rufinamide; safety