Arrhythmias associated with psychiatric drugs : Analysis of data from the German Summaries of Product Characteristics (SmPCs) of psychiatric drugs

Abstract

Most psychiatric drugs, such as antidepressants (AD) and antipsychotics (AP), might induce cardiac adverse events (CAE), which could be potentially life threatening. The risk of psychiatric drugs to induce cardiac arrhythmias attracted more attention. Some psychiatric drugs were previously removed from the market because of inducing arrhythmias. The aim of this work was to use summaries of product characteristics (SmPC) in creating ranking lists and a category assessment for the likelihood of AD and AP to cause cardiac adverse events. A further aim was to create rank lists that assess both approved brand name drugs and generic products of AD and AP in Germany regarding their risk of causing QT-prolongation, TdP, and ventricular arrhythmia. In order to reach this aim, the anatomical-therapeutic-chemical ATC classification of the German Institute of Medical Documentation and Information (DIMDI) was used for the identification of the active substances of AP and AD. Then, the brand name drugs of AP and AD were identified using information from the European medical agency and through contacting the German marketing authorization holder for nationally authorized medicines. After that, a search on all brand name drugs and generic products of antidepressants and antipsychotics approved in Germany was conducted through PharmaNet.Bund, Gelbe liste®, Rote Liste®, Fachinfo-Service®, and via manufacturer contact. The frequencies of reported cardiac adverse events (QT-prolongation, Torsade de Pointes tachycardia, and ventricular arrhythmia) were extracted and a category risk assessment based on those cardiac adverse events was performed. According to the SmPCs, many AP and AD increase the risk of different arrhythmias. Invega® (paliperidone), Serdolect® (sertindole) were associated with the highest risk of QT-prolongation "Common (frequent) (≥1/100 and <1/10), and Fluoxetin-dura® (fluoxetine) (≥1/100 and <1/10); regarding Torsade de Pointes tachycardia were found for Serdolect® (sertindole) (≥ 1/1.000 – < 1/100). Various amisulpride, olanzapine, droperidol, and sulpiride preparations were associated with the following risk of ventricular arrhythmia: (≥ 1/1.0000 – < 1/1000), and among antidepressants, various preparations of venlafaxine and fluoxetine had the following risk of ventricular arrhythmia: (≥ 1/1.0000 – < 1/1000). The risk and frequency of CAE, as reported in the SmPCs, varied significantly among substances 52 and between groups. There are more reports for AP than AD. The AP with the most frequently reported CAE (QT-prolongation and Torsade de Pointes tachycardia) was Serdolect®; for AD, Zoloft® (QT-prolongation, Torsade de Pointes tachycardia), and Trevilor® (Torsade de Pointes tachycardia and ventricular tachycardia) carried the highest cardiac risk. Surprisingly, we found a discrepancy in the frequency of CAE between original medicinal products and commercial preparations of the same active substance. The difference in reported cardiac adverse effects between commercial preparations of the same active substance leads to difficulty in providing a clear risk assessment. It remains unclear how could those discrepancies of CAE would be interpreted and if they could have implications for prescribing physicians or for pharmacists in concern the aut-idem regulation Despite that our results may aid in choosing the most advantageous substance in patients at risk, the interpretation of reported risk assessment has to be done carefully, keeping in mind the limitations of SmPCs. Head to head clinical trials or network meta-analysis studies which compare the cardiac risk of one drug versus another would provide more reliable evidence.