title: Long-term safety of perampanel and seizure outcomes in refractory partial-onset seizures and secondarily generalized seizures: results from phase III extension study 307.
abstract: OBJECTIVE
  To evaluate safety, tolerability, seizure frequency, and regional variations in treatment responses with the AMPA antagonist, perampanel, in a large extension study during up to 3 years of treatment.
  
  
  METHODS
  Patients ≥ 12 years old with partial-onset seizures despite treatment with 1-3 antiepileptic drugs at baseline completed a perampanel phase III trial and entered extension study 307 (NCT00735397). Patients were titrated to 12 mg/day (or their individual maximum tolerated dose) during the blinded conversion period, followed by open-label maintenance. Exposure, safety (adverse events [AEs], vital signs, weight, electrocardiography [ECG], laboratory values) and seizure outcomes were analyzed; key measures were assessed by geographic regions.
  
  
  RESULTS
  Among 1,216 patients, median exposure was 1.5 years (range 1 week to 3.3 years), with >300 patients treated for >2 years. Treatment retention was 58.5% at cutoff. AEs reported in ≥ 10% of patients were dizziness, somnolence, headache, fatigue, irritability, and weight increase. Only dizziness and irritability caused discontinuation in >1% of patients (3.9% and 1.3%, respectively). The only serious AEs reported in >1% of patients were epilepsy-related (convulsion, 3.0%; status epilepticus, 1.1%). No clinically relevant changes in vital signs, ECG or laboratory parameters were seen. After titration/conversion, responder rate and median percentage change from baseline in seizure frequency were stable: 46% for both measures at 9 months (in 980 patients with ≥ 9 months' exposure) and 58% and 60%, respectively, at 2 years (in the 337 patients with 2 years' exposure). Median percentage reduction in frequency of secondarily generalized (SG) seizures ranged from 77% at 9 months (N = 422) to 90% at 2 years (N = 141). Among the 694 patients with maintenance data ≥ 1 year, 5.3% were seizure-free for the entire year.
  
  
  CONCLUSIONS
  No new safety signals emerged during up to 3 years of perampanel exposure in 39 countries. Seizure responses remained stable, with marked reductions, particularly in SG seizures.
authors.affiliation: Johns Hopkins University, Baltimore, Maryland, U.S.A.
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Krauss
authors.forename: Emilio
authors.initials: E
authors.lastname: Perucca
authors.forename: Elinor
authors.initials: E
authors.lastname: Ben-Menachem
authors.forename: Patrick
authors.initials: P
authors.lastname: Kwan
authors.forename: Jerry J
authors.initials: JJ
authors.lastname: Shih
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Clément
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Wang
authors.forename: Makarand
authors.initials: M
authors.lastname: Bagul
authors.forename: Michelle
authors.initials: M
authors.lastname: Gee
authors.forename: Jin
authors.initials: J
authors.lastname: Zhu
authors.forename: David
authors.initials: D
authors.lastname: Squillacote
mesh_terms: D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000009:adverse effects / Q000627:therapeutic use*; D002648:Child; D004311:Double-Blind Method; D004828:Epilepsies, Partial / Q000175:diagnosis* / Q000188:drug therapy* / Q000503:physiopathology; D004829:Epilepsy, Generalized / Q000175:diagnosis* / Q000188:drug therapy* / Q000503:physiopathology; D005260:Female; D006801:Humans; D008297:Male; D001523:Mental Disorders / Q000139:chemically induced / Q000175:diagnosis; D008875:Middle Aged; D009570:Nitriles; D011728:Pyridones / Q000009:adverse effects / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D009570:Nitriles; D011728:Pyridones; C551441:perampanel
keywords: AMPA receptor; Antagonist; Antiepilepsy drugs; Epilepsy; Seizure freedom