Low safety index of domperidone: mechanism for increased odds ratio for sudden cardiac death.

OBJECTIVE: Domperidone is a dopamine antagonist with anti-nausea and anti-emetic activity. There have been several reports of sudden cardiac death (SCD) associated with the compound. Recently it was estimated to increase SCD nearly fourfold. I therefore tested domperidone for liability of cardiac repolarization disturbances (triangulation, reverse use dependence, instability and dispersion or TRIaD) and induction of arrhythmias. METHODS AND
RESULTS: In Langendorff perfused rabbit hearts, domperidone significantly prolonged the action potential duration starting at 30 nM. It induced proarrhythmic TRIaD from 100 nM on. Since therapeutic free drug concentrations extend to 19 nM, the safety ratio for domperidone equals 100/19 = 5.25, i.e., far below the minimum safety ratio of 30. Hence, widespread use of domperidone cannot be without danger; especially since it is frequently used as an over the counter medication.
CONCLUSION: In light of these new preclinical and of recent clinical warnings, domperidone should best be restricted to patients in whom its benefit is proven to justify the risks. Availability without prescription and advertising as an 'innocent' relief is incorrect and unsafe, and needs to be reconsidered.