Levetiracetam extended release and levetiracetam immediate release as adjunctive treatment for partial-onset seizures: An indirect comparison of treatment-emergent adverse events using meta-analytic techniques q Florent F. Richy a,b, * , Soutrik Banerjee c,d , Yves Brabant e , Sandra Helmers f a G3P Epidemiology, UCB Pharma S.A., Brussels, Belgium b Epidemiology and Health Economics, Faculty of Medicine, University of Liege, Liege, Belgium c Business & Decision SA, Brussels, Belgium d University Clinic of Geriatric Medicine, Joseph Fourier University, Grenoble, France e UCB Pharma S.A., Brussels, Belgium f Emory University School of Medicine, Atlanta, GA, USA article info Article history: Received 9 May 2009 Revised 26 June 2009 Accepted 5 July 2009 Available online 20 August 2009 Keywords: Epilepsy Partial-onset seizures Levetiracetam extended release Levetiracetam immediate release Safety Adverse events Meta-analysis abstract The safety profiles of once-daily adjunctive levetiracetam (LEV) extended release (XR) (1000 mg/day) and adjunctive LEV immediate release (IR) (500 mg twice daily) were compared using data from three ran- domized, placebo (PBO)-controlled phase III clinical trials in patients with partial-onset seizures. Med- DRA 9.0 treatment-emergent adverse events (TEAEs) were indirectly compared using meta-analytic techniques, including calculation of risk difference (RD) and mixed-effects analysis. Statistical signifi- cance was set at 10% alpha risk, the normative value for these analyses. Data from 555 patients older than 16 (204 LEV IR, 70 LEV XR, 281 PBO) were analyzed. Following adjustment for incidence of placebo TEAEs, LEV XR showed statistically significantly lower rates of TEAEs than LEV IR across nervous system disor- ders (RD = 18%, P = 0.03), psychiatric disorders (RD = 11%, P = 0.08), and metabolism and nutrition dis- orders (RD = 3%, P = 0.08). Among nervous system disorders, the RD for headache favored LEV XR (RD = 11%, P = 0.08). These results suggest that adjunctive LEV XR may be associated with a lower inci- dence of nervous system, psychiatric, and nutritional and metabolic TEAEs as compared with LEV IR. However, this difference was observed at a broad scale and not at a specific TEAE level except for headache. Ó 2009 Elsevier Inc. All rights reserved. 1. Introduction Limiting the dosing frequency of an antiepileptic drug (AED) to once or twice daily is considered an important advantage in the management of patients with epilepsy [1,2]. In several studies, an inverse relationship between number of daily doses and compli- ance has been reported; increase in daily dose frequency (from one to four doses) resulted in worsened compliance and missed doses [2–4]. Claims have been made that the more steady plasma con- centration profiles of extended-release formulations might result in fewer peak concentration-related treatment-emergent adverse events (TEAEs) and potentially improve compliance, efficacy, and safety [5–9]. Previous studies evaluating conventional versus controlled-release formulations of carbamazepine have shown im- proved safety for the controlled-release formulation in terms of number of patients reporting TEAEs [7–12] and a significant reduc- tion in headache, dizziness, and disturbances of vision, speech, and coordination. Persson et al. did make the link between peak phar- macodynamic effects of carbamazepine and the better tolerability profile of its controlled-release formulation on dizziness and blurred vision [11]. McCabe et al. showed that switching from de- layed-release sodium valproate to the extended-release formula- tion resulted in reduced tremor, weight gain, and nausea/ vomiting [12]. Levetiracetam (LEV) (Keppra, UCB) is an AED with linear phar- macokinetics [13] and a specific binding site in the brain, the synaptic vesicle protein 2A (SV2A) [14,15]. Its half-life in adults is around 7 hours [13]. The efficacy and safety of adjunctive LEV immediate release (IR) have been demonstrated in adult patients with refractory partial-onset seizures [16–19], children aged 1525-5050/$ - see front matter Ó 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2009.07.013 q The results from this study were accepted for presentation at the American Epilepsy Society (AES) 2008 Congress, December 5–9, Seattle, Washington, and the American Association of Neurology (AAN) 2009 Congress April 25–May 2, Seattle, Washington. * Corresponding author. Address: UCB Pharma S.A., G3P Epidemiology, Allée de la Recherche, 60, 1070 Brussels, Belgium. Fax: +32 2 559 9370. E-mail address: florent.richy@ucb.com (F.F. Richy). Epilepsy & Behavior 16 (2009) 240–245 Contents lists available at ScienceDirect Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh