Fatal intoxication with ivabradine: First case report.

Abstract Ivabradine is a bradycardic drug used worldwide in the treatment of chronic stable angina and chronic heart failure. We presented here a case of a 61-year-old woman who was admitted to emergency department for overdose. She presented with drowsiness, bradycardia (45 bpm) and a low blood pressure (116/21 mm Hg). She died ten hours after admission from multiple organ failure. Ivabradine was quantified in different matrices sampled during autopsy using a method on LC-MS/MS (TSQ Vantage Thermo Fisher Scientific®), after a double liquid-liquid extraction with a mixture of hexane/ethyl acetate (1/1; v/v) and then chloroform/isopropanol (80/20; v/v). Chromatographic separation was achieved using a Hypersyl gold PFP column (200 x 2.1 mm, 1.9 µm) and an acetonitrile/formiate 2 mM, 0.1 % formic acid buffer gradient. Method was fully validated on whole blood. The mean overall recovery was 90%. Linearity was validated in the 5-500 ng/mL range, with intra and inter-day precision lower than 14.3%. The ivabradine concentration found in patient post-mortem blood was 1210 ng/mL. Ivabradine was also quantified in different viscera like lung (2910 ng/g), kidney (1510 ng/g), liver (1050 ng/g), heart (900 ng/g), and brain (110 ng/g). The vitreous humor concentration was 760 ng/mL. Pregabalin and zopiclone were also found in blood at 50 µg/mL and 206 ng/mL, respectively. This case seems to be the first report of a fatal intoxication involving ivabradine and the first published concentrations in organs.