Abstracts

Rationale: Eslicarbazepine acetate (ESL) is a once-daily (QD) oral antiepileptic drug that is believed to function by preferentially stabilizing the inactivated state of voltage-gated sodium channels (Benes et al, J Med Chem 1999;42:2583-7). ESL is reported to be well-tolerated, with low rates of hyponatremia (0.5-2.2%) (Rogin et al, Epilepsy Curr 2014;14[Suppl.1]). We analyzed data from trials of patients with epilepsy and other conditions, including effects on liver function tests (LFTs), to characterize the hepatic safety of ESL. Methods: Data were included from three phase III trials of adjunctive ESL and 5 phase II ESL trials. Patients with treatment-emergent adverse events (TEAEs) of interest (related to drug-induced liver injury) were identified for the safety population, and categorized using the Medical Dictionary for Regulatory Activities, v13.1. The following LFT abnormalities (see Table 1) were identified from the database: alanine aminotransferase (ALT); aspartate aminotransferase (AST); alkaline phosphatase (ALP); total bilirubin; international normalized ratio (INR). LFT abnormalities with TEAEs that were serious or led to discontinuation were noted, as were increases in ALT or AST with any of the following TEAEs: abdominal pain; abdominal tenderness; anorexia; fatigue; nausea; vomiting; or fever. Results: The epilepsy trial analysis population comprised 1447 patients, 426 for placebo (PBO) and 1021 for ESL (median daily dose: 752mg; median exposure: 98 days). The ‘non-epilepsy' population comprised 1705 patients, 411 for PBO and 1294 for ESL (median daily dose: 755mg; median exposure: 64 days). In the epilepsy trials, the incidence of hepatic events was 9.7% for ESL 400mg, 4.8% for ESL 800mg, 7.1% for ESL 1200mg and 5.6% for PBO. Abnormal LFTs and hepatic TEAEs are shown in Table 1. Most TEAEs were abnormal laboratory values (investigator-reported), except one report of liver disorder with ESL 400mg. Elevated INR was the most frequently reported LFT abnormality. One patient discontinued ESL due to increased gamma-glutamyl transferase (GGT) (ESL 1200mg), and one due to increased ALT (ESL 800mg). In the non-epilepsy trials, hepatic events occurred in 8.4% of the ESL group and 6.6% of the PBO group; most TEAEs were abnormal laboratory values. Increased GGT was the most common hepatic TEAE, while elevated bilirubin levels were the most common LFT abnormality. Three of the ESL group discontinued due to liver disorder, increased ALT, GGT and/or AST. One patient had an LFT abnormality with fatigue, one with vomiting, and one patient discontinued due to increased ALT and AST plus vomiting. Conclusions: In the epilepsy trials, rates of abnormal LFTs and hepatic TEAEs were similar with ESL and PBO. In non-epilepsy trials, a modest increase in incidence of hepatic TEAEs occurred with ESL; reports of elevated AST, ALT and bilirubin were low (<4.0% of patients). Most hepatic TEAEs were abnormal laboratory values. Baseline LFTs are recommended, and ESL should be discontinued in patients with significant liver injury.