title: Neurological adverse events of new generation sodium blocker antiepileptic drugs. Meta-analysis of randomized, double-blinded studies with eslicarbazepine acetate, lacosamide and oxcarbazepine.
abstract: OBJECTIVE
  Analysis of overall tolerability and neurological adverse effects (AEs) of eslicarbazepine acetate (ESL), lacosamide (LCM) and oxcarbazepine (OXC) from double-blind, placebo-controlled trials. Indirect comparisons of patients withdrawing because of AEs, and the incidence of some vestibulocerebellar AEs between these three antiepileptic dugs (AEDs).
  
  
  METHODS
  We searched MEDLINE for all randomized, double-blind, placebo-controlled trials investigating therapeutic effects of fixed oral doses of ESL, LCM and OXC in patients with drug resistant epilepsy. Withdrawal rate due to AEs, percentages of patients with serious AEs, and the proportion of patients experiencing any neurological AE, nausea and vomiting were assessed for their association with the experimental drug. Analyses were performed between recommended daily doses of each AED according to the approved summary of product characteristics (SPC). Risk differences were used to evaluate the association of any AE [99% confidence intervals (CIs)] or study withdrawals because of AEs (95% CIs) with the experimental drug. Indirect comparisons between withdrawal rate and AEs dizziness, coordination abnormal/ataxia and diplopia were estimated according to network meta-analysis (Net-MA).
  
  
  RESULTS
  Eight randomized, placebo-controlled, double-blind trials (4 with ESL, 3 with LCM, and 1 with OXC) were included in our analysis. At high doses (OXC 1200mg, ESL 1200mg and LCM 400mg) there was an increased risk of AE-related study withdrawals compared to placebo for all drugs. Several AEs were associated with the experimental drug. Both number and frequency of AEs were dose-related. At high recommended doses, patients treated with OXC withdrew from the experimental treatment significantly more frequently than patients treated with ESL and LCM. Furthermore, the AEs coordination abnormal/ataxia and diplopia were significantly more frequently observed in patients treated with OXC compared to patients treated with LCM and ESL.
  
  
  CONCLUSIONS
  The overall tolerability of AEDs and the incidence of several neurological AEs were clearly dose-dependent. Indirect comparisons between these AEDs, taking into account dose-effect, showed that OXC may be associated with more frequent neurological AEs than LCM and ESL.
authors.affiliation: U.O. Neurologia, Azienda Sanitaria di Firenze, Firenze, Italy. gaetano.zaccara@asf.toscana.it
authors.forename: Gaetano
authors.initials: G
authors.lastname: Zaccara
authors.forename: Fabio
authors.initials: F
authors.lastname: Giovannelli
authors.forename: Dario
authors.initials: D
authors.lastname: Maratea
authors.forename: Valeria
authors.initials: V
authors.lastname: Fadda
authors.forename: Alberto
authors.initials: A
authors.lastname: Verrotti
mesh_terms: D000081:Acetamides / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D000927:Anticonvulsants / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D001259:Ataxia / Q000139:chemically induced / Q000453:epidemiology; D002220:Carbamazepine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D003984:Dibenzazepines / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D004172:Diplopia / Q000139:chemically induced / Q000453:epidemiology; D004244:Dizziness / Q000139:chemically induced / Q000453:epidemiology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006801:Humans; D000078334:Lacosamide; D009422:Nervous System Diseases / Q000139:chemically induced* / Q000453:epidemiology / Q000503:physiopathology; D000078330:Oxcarbazepine; D016032:Randomized Controlled Trials as Topic; D018570:Risk Assessment; D026941:Sodium Channel Blockers / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000081:Acetamides; D000927:Anticonvulsants; D003984:Dibenzazepines; D026941:Sodium Channel Blockers; D002220:Carbamazepine; D000078334:Lacosamide; C416835:eslicarbazepine acetate; D000078330:Oxcarbazepine
keywords: Adverse events; Antiepileptic drugs; Epilepsy; Eslicarbazepine; Lacosamide; Oxcarbazepine