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Clinical Trial
. 2019 Jul;60(7):1341-1352.
doi: 10.1111/epi.16069. Epub 2019 Jul 1.

Serum sodium levels and related treatment-emergent adverse events during eslicarbazepine acetate use in adults with epilepsy

Robert T Wechsler  1 , Rodney A Radtke  2 , Michael Smith  3 , David G Vossler  4 , Laura Strom  5 , Eugen Trinka  6 , Hailong Cheng  7 , Todd Grinnell  7 , David Blum  7 , Mariana Vieira  8 , Joana Moreira  8 , Francisco Rocha  8
Affiliations
Clinical Trial

Serum sodium levels and related treatment-emergent adverse events during eslicarbazepine acetate use in adults with epilepsy

Robert T Wechsler et al. Epilepsia. 2019 Jul.

Abstract

Objective: To examine the frequency of hyponatremia and potentially related symptoms in clinical trials of eslicarbazepine acetate (ESL) in adults with focal- (partial-) onset seizures.

Methods: This post hoc, exploratory analysis included data from three controlled phase 3 trials of adjunctive ESL (400-1200 mg once daily), two phase 3 trials of ESL monotherapy (1200-1600 mg once daily), and their open-label extension studies. Exploratory endpoints included clinical laboratory measurements of serum sodium concentrations ([Na+ ]), incidences of hyponatremia-related treatment-emergent adverse events (TEAEs), and incidences of TEAEs that are potential symptoms of hyponatremia.

Results: The controlled trials of adjunctive ESL and ESL monotherapy included 1447 (placebo, n = 426; ESL, n = 1021) and 365 (ESL, n = 365) patients, respectively; 639 and 274 patients continued onto uncontrolled, open-label extensions. In the controlled and uncontrolled trials ≤3.3% of patients taking ESL had a minimum postdose [Na+ ] measurement ≤125 mEq/L, <9% had a >10 mEq/L decrease in [Na+ ] from baseline, <6% had a hyponatremia-related TEAE, and <2% discontinued the controlled trials due to a hyponatremia-related TEAE. Hyponatremia appeared to be more frequent in the monotherapy (vs adjunctive therapy) trials; in the controlled trials of adjunctive ESL and ESL monotherapy, incidence generally increased with increasing ESL dose. The majority of patients with an investigator-reported TEAE of "hyponatremia" or "blood sodium decreased" did not have a corresponding laboratory [Na+ ] measurement ≤125 mEq/L. Some symptoms potentially related to hyponatremia (including nausea and vomiting) were more frequent in patients with a minimum postdose [Na+ ] measurement ≤125 mEq/L.

Significance: Reductions in serum sodium concentrations and hyponatremia-related TEAEs occurred in a small number of patients taking ESL. Suspected hyponatremia should be confirmed and monitored via [Na+ ] measurements.

Keywords: dibenzazepine carboxamides; focal seizures; hyponatremia; safety.

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Conflict of interest statement

R.W. has been a clinical trial investigator for Eisai, Sunovion Pharmaceuticals Inc., Biogen, Pfizer, Lundbeck, UCB, SK Life Science, Aquestive, Engage, Upsher‐Smith, and Greenwich; received advisory board and/or consultancy honoraria to Consultants in Epilepsy & Neurology, Professional Limited Liability Company (PLLC) from UCB Pharma, Eisai, Upsher‐Smith, Engage, Sunovion Pharmaceuticals Inc., Lundbeck, Greenwich, and Brain Sentinel; received speakers bureau honoraria to Consultants in Epilepsy & Neurology, PLLC from LivaNova, Sunovion Pharmaceuticals Inc., UCB Pharma, Greenwich, and Eisai; serves as Medical Director of the Epilepsy Center at St. Luke's Health System in Boise, Idaho; has pay‐for‐call arrangements with St. Luke's Health System in Boise, Idaho; is a member of the Epilepsy Studies Consortium, a Board Member of the National Association of Epilepsy Centers, a member of the Executive Committee of the Consortium of Private Epilepsy Centers, and Board President of the Epilepsy Foundation of Idaho. R.A.R. has received consultancy fees from UCB, Sunovion Pharmaceuticals Inc., and Supernus. M.S. has received consultancy fees from SK Life Science and CW Pharmaceuticals. D.G.V. has received Advisory Board or Committee honoraria from SK Life Science, and received honoraria from Sunovion Pharmaceuticals Inc., UCB Pharma, and Greenwich Pharmaceuticals. L.S. has no conflicts of interest to declare. E.T. has received honoraria from UCB, Eisai, GW Pharmaceuticals, LivaNova, Novartis, Ever Pharma, Newbridge, Biogen, and Sunovion Pharmaceuticals Inc.; received consultancy fees from Eisai, GW Pharmaceuticals, Liva Nova, Biogen, and Ever Pharma; and received grants or funds from Biogen, Novartis, UCB, and Bayer. H.C., T.G., and D.B. are employees of Sunovion Pharmaceuticals Inc. M.V., J.M., and F.R. are employees of Bial ‐ Portela & Cª, S.A. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

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