title: Lacosamide tolerability in adult patients with partial-onset seizures: Impact of planned reduction and mechanism of action of concomitant antiepileptic drugs.
abstract: OBJECTIVE
  We evaluated the impact of planned dose reduction and mechanism of action of concomitant AEDs on tolerability in adults with partial-onset seizures undergoing lacosamide (LCM) titration.
  
  
  METHODS
  Data were collected at baseline and 3-6 and 12-24 months post-LCM initiation. Subjects were categorized as having planned reduction of concomitant AEDs or not; AEDs were categorized as traditional sodium channel blockers (TSCB) or non-TSCB (NTSCB). Groups with/without planned reduction were compared on the presence and number of treatment-emergent adverse events (TEAEs) using chi-square tests or logistic regression and on time to LCM discontinuation with time-to-event methods controlling for standardized (STD) AED dose, a measure of concomitant AED load. Similar analyses were performed comparing subjects taking TSCB and NTSCB agents and used to identify relationships with ≥50% decreases in seizure frequency.
  
  
  RESULTS
  One hundred six adults (mean age 41.4 ± 13.4; 50% male) underwent LCM titration from June 2009-2011 with complete data. Reduction of concomitant AEDs was planned at the time of LCM initiation in 59 (55.7%) subjects. Fewer subjects with planned reduction had TEAEs (49.2% vs. 68.1%; p=0.05), and these subjects had a lower risk of TEAEs (OR 0.36; p=0.019) after adjusting for STD AED dose. The hazard ratio (95% CI) for LCM discontinuation was 0.46 (0.23, 0.94) in subjects with planned reduction of concomitant AEDs vs. others (p=0.033) and 3.29 (1.01, 10.70) in subjects taking TSCB vs. NTSCB agents (p=0.048). Among all cases, those who ever had TEAEs had significantly higher STD dose at both follow-up visits (p=0.033 and p=0.023, respectively). Seizure outcomes were not significantly different between groups at the last follow-up assessment.
  
  
  CONCLUSIONS
  Planned reduction of concomitant AEDs during LCM initiation and the use of NTSCB agents only are associated with a reduced risk of TEAEs and LCM discontinuation in adults with partial-onset seizures. This study extends prior observations by considering total AED load in the assessment of tolerability and supports the benefits of early reduction of concomitant AEDs during LCM initiation.
authors.affiliation: Cleveland Clinic Neurological Institute, Cleveland, OH, United States. Electronic address: foldvan@ccf.org.
authors.forename: Nancy
authors.initials: N
authors.lastname: Foldvary-Schaefer
authors.affiliation: University of Pittsburgh Department of Neurology, Pittsburgh, PA, United States.
authors.forename: Joanna S
authors.initials: JS
authors.lastname: Fong
authors.affiliation: Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, United States.
authors.forename: Shannon
authors.initials: S
authors.lastname: Morrison
authors.affiliation: Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, United States.
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.affiliation: Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, United States.
authors.forename: James
authors.initials: J
authors.lastname: Bena
mesh_terms: D000081:Acetamides / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004828:Epilepsies, Partial / Q000188:drug therapy*; D005260:Female; D006801:Humans; D000078334:Lacosamide; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012640:Seizures / Q000188:drug therapy*; D026941:Sodium Channel Blockers / Q000627:therapeutic use*; D013995:Time; D016896:Treatment Outcome
chemical_list: D000081:Acetamides; D000927:Anticonvulsants; D026941:Sodium Channel Blockers; D000078334:Lacosamide
keywords: Lacosamide; Mechanism of action; Standardized dose; Tolerability