title: Long-term tolerability and safety of lamotrigine extended-release: pooled analysis of three clinical trials.
abstract: BACKGROUND
  In three randomized double-blind clinical trials, lamotrigine extended-release (lamotrigine XR) was demonstrated to be effective in the adjunctive treatment of intractable partial seizures or primary generalized tonic-clonic seizures and as monotherapy for partial seizures.
  
  
  OBJECTIVE
  A pooled analysis of the data from these three clinical trials was performed to determine whether the tolerability and safety profile of lamotrigine XR was similar to lamotrigine immediate-release (lamotrigine IR).
  
  
  METHODS
  This report describes results of a pooled analysis of the tolerability and safety data from the double-blind and open-label phases of these three trials. The number of patients in the integrated database exposed to one or more doses of lamotrigine XR was 662.
  
  
  RESULTS
  Duration of exposure to lamotrigine XR was ≥26 weeks in 82.5 % of patients and ≥52 weeks in 40.8 % of patients [mean (standard deviation) 39.8 (23.3) weeks]. The number of patients with one or more adverse events during double-blind or open-label treatment was 455 (69 %). The most common treatment-emergent adverse events, regardless of suspected cause, were headache (25 % of patients) and dizziness (16 % of patients). The number of patients with one or more adverse events considered to be reasonably attributed to lamotrigine XR during double-blind or open-label treatment was 202 (31 %). The most common adverse events considered to be reasonably attributed to lamotrigine XR were dizziness (10 % of patients) and headache (6 % of patients). Lamotrigine-attributed rash was reported in 4 % of patients and was the reason for premature withdrawal in 2 %. Adverse events leading to premature withdrawal were reported in 7 % of patients. The incidence of serious lamotrigine-attributed adverse events was 1 %. One case of serious rash was reported. No cases of rash were reported to be Stevens-Johnson syndrome or toxic epidermal necrolysis. Two deaths (acute cardiac failure and acute lamotrigine poisoning) were considered reasonably attributable to lamotrigine XR. No evidence of lamotrigine-attributed changes was observed in clinical laboratory data or vital signs.
  
  
  CONCLUSIONS
  The results show that lamotrigine XR is well tolerated with safety and tolerability profiles similar to those of lamotrigine IR. Given the similar safety, tolerability and efficacy profiles of lamotrigine XR and lamotrigine IR, the extended-release formulation may be preferable for many patients because of its ease of use (with once-daily dosing regardless of concomitant antiepileptic drug), the potential for enhanced compliance with once-daily dosing, and the provision of more stable serum drug concentrations. The benefit of once-daily dosing must be balanced with the potentially greater negative impact of a missed dose.
authors.affiliation: Arkansas Epilepsy Program, Little Rock, AR 72205, USA. vbiton@gmail.com
authors.forename: Victor
authors.initials: V
authors.lastname: Biton
authors.forename: Bassel F
authors.initials: BF
authors.lastname: Shneker
authors.forename: Dean
authors.initials: D
authors.lastname: Naritoku
authors.forename: Anne E
authors.initials: AE
authors.lastname: Hammer
authors.forename: Alain
authors.initials: A
authors.lastname: Vuong
authors.forename: Paul T
authors.initials: PT
authors.lastname: Caldwell
authors.forename: John A
authors.initials: JA
authors.lastname: Messenheimer
mesh_terms: D000927:Anticonvulsants / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002626:Chemistry, Pharmaceutical; D003692:Delayed-Action Preparations; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D006801:Humans; D000077213:Lamotrigine; D016032:Randomized Controlled Trials as Topic; D018570:Risk Assessment; D012307:Risk Factors; D012640:Seizures / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D013997:Time Factors; D016896:Treatment Outcome; D014227:Triazines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D000927:Anticonvulsants; D003692:Delayed-Action Preparations; D014227:Triazines; D000077213:Lamotrigine