Domperidone safety: a mini-review of the science of QT prolongation and clinical implications of recent global regulatory recommendations

Abstract

Aims: In New Zealand, domperidone is approved for gastrointestinal motility and nausea and vomiting. The European Medicines Agency (EMA) recently concluded that domperidone poses a significant risk of sudden cardiac death (SCD) and has restricted use in Europe. This paper reviews the risk of QT prolongation and cardiac adverse effects with domperidone and provide information to allow prescribers to make informed decisions on usage.

Methods: A search of two bibliographic databases, the European Medicines Agency (EMA) website, Micromedex, Lexicomp and reference texts was undertaken for domperidone related reports of QT prolongation, cardiac arrhythmias and/or SCD. The New Zealand Centre for Adverse Drugs Reaction Monitoring was also contacted for cardiac adverse event reports with domperidone.

Results: Over 30 published papers, EMA documents and other information sources were collated, including two studies that met thorough QT study (TQT) criteria (ICH-E14). The first TQT1 was negative while the second was marginally positive. Reports of QT prolongation, ventricular arrhythmias and SCD were located (predominantly high/very high-dose IV domperidone). With oral domperidone, a Dutch case-controlled study reported an adjusted odds ratio of SCD of 11.4 (95% CI 1.99-65.2), based on only three patients out of 1,366 cases of SCD. A second nested case-controlled study calculated an odds ratio of ventricular arrhythmia or SCD of 1.59 (1.28-1.98) vs. placebo.

Discussion: Based on the results of the two TQT (the regulatory agency gold standard for assessment of QT prolongation) domperidone does not appear to be strongly associated with QT prolongation at oral doses of 20 mg QID in healthy volunteers. Further, there are limited case reports supporting an association with cardiac dysfunction, and the frequently cited case-control studies have significant flaws. While there remains an ill-defined risk at higher systemic concentrations, especially in patients with a higher baseline risk of QT prolongation, our review does not support the view that domperidone presents intolerable risk.