Safety Profile of Eslicarbazepine Acetate as Add-On Therapy in Adults with Refractory Focal-Onset Seizures: From Clinical Studies to 6 Years of Post-Marketing Experience

Abstract

IntroductionEslicarbazepine acetate was first approved in the European Union in 2009 as adjunctive therapy in adults with partial-onset seizures with or without secondary generalization.ObjectiveThe objective of this study was to review the safety profile of eslicarbazepine acetate analyzing the data from several clinical studies to 6 years of post-marketing surveillance.MethodsWe used a post-hoc pooled safety analysis of four phase III, double-blind, randomized, placebo-controlled studies (BIA-2093-301, -302, -303, -304) of eslicarbazepine acetate as add-on therapy in adults. Safety data of eslicarbazepine acetate in special populations of patients aged ≥65 years with partial-onset seizures (BIA-2093-401) and subjects with moderate hepatic impairment (BIA-2093-111) and renal impairment (BIA-2093-112) are also considered. The incidences of treatment-emergent adverse events, treatment-emergent adverse events leading to discontinuation, and serious adverse events were analyzed. The global safety database of eslicarbazepine acetate was analyzed for all cases from post-marketing surveillance from 1 October, 2009 to 21 October, 2015.ResultsFrom a pooled analysis of four phase III studies, it was concluded that the incidence of treatment-emergent adverse events, treatment-emergent adverse events leading to discontinuation, and adverse drug reactions were dose dependent. Dizziness, somnolence, headache, and nausea were the most common treatment-emergent adverse events (≥10% of patients) and the majority were of mild-to-moderate intensity. No dose-dependent trend was observed for serious adverse events and individual serious adverse events were reported in less than 1% of patients. Hyponatremia was classified as a possibly related treatment-emergent adverse event in phase III studies (1.2%); however, after 6 years of post-marketing surveillance it represents the most frequently (10.2%) reported adverse drug reaction, with more than half of these cases occurring with eslicarbazepine acetate at daily doses of 1200 mg. Other adverse drug reactions reported in post-marketing surveillance are seizure (5.8%), dizziness (4.1%), rash (2.6%), and fatigue (2.1%). The safety profile of eslicarbazepine acetate in renal and hepatic impairment subjects (phase I studies) and in elderly patients (phase III study) did not raise any specific concern.ConclusionAfter 6 years of post-marketing surveillance, eslicarbazepine acetate maintains a similar safety profile to that observed in pivotal clinical studies.

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

“…These possible explanations for the higher rate of hyponatremia in the monotherapy trials than in the adjunctive trials are similar to those identified during postmarketing surveillance of ESL, where most hyponatremia cases were associated with high ESL doses (>1200 mg), dosing errors (eg, no uptitration and not following the administration guidelines), concomitant medications, and/or comorbidities …”

“…It is of note that the threshold for clinically significant hyponatremia is not clear-cut, and that different thresholds are used in different settings. For example, publications have defined hyponatremia as [Na + ] <125 mEq/L (in line with this analysis), 27,29 ≤132 mEq/L, 30 ≤134 mEq/L (with severe hyponatremia defined as ≤128 mEq/L), 6,31 <135 mEq/L, 32 and <137 mEq/L. 33 Therefore, comparisons of hyponatremia rates across studies should be interpreted with caution.…”

“…These possible explanations for the higher rate of hyponatremia in the monotherapy trials than in the adjunctive trials are similar to those identified during postmarketing surveillance of ESL, where most hyponatremia cases were associated with high ESL doses (>1200 mg), dosing errors (eg, no uptitration and not following the administration guidelines), concomitant medications, and/or comorbidities. 27 Use of SSRIs and thiazides has been associated previously with the development of hyponatremia. 10,11 In these controlled trials of ESL, thiazides did not appear to be associated with the occurrence of low [Na + ] (≤125 mEq/L).…”

Risks and management of antiepileptic drug induced skin reactions in the adult out-patient setting

“…Up to 2.6% of patients report ESL related adverse skin reactions. Less than a third stops the medication as a consequence [54]. The lower incidence of skin reactions may be due to the absent toxic epoxide metabolite when compared to CBZ.…”

Hyponatremia and Psychotropic Drugs

“…This new antiepileptic has potential uses for the treatment of trigeminal neuralgia and bipolar disorder. Cases of hyponatremia were recorded [91,100,101].…”