Detecting drug-drug interactions that increase the incidence of long QT syndrome using a spontaneous reporting system

Drug-induced long QT syndrome (diLQTS) is a rare but serious adverse drug reaction. Drug-drug interaction (DDI) is one of the risk factors for the development of diLQTS. However, the combinations of drugs that increase the risk of diLQTS have not been extensively investigated. This study was performed to analyse the potential DDIs that elevate the incidence of diLQTS using a spontaneous reporting system.

The Japanese Adverse Drug Event Report database from April 2004 to January 2020 was used to assess adverse event reports. We calculated the reporting odds ratio and 95% confidence interval for signal detection.

Signals for concomitant use risk were detected in 31 drug combinations. Combinations of antipsychotics and antidepressants were the most common (olanzapine & fluvoxamine, olanzapine & trazodone, quetiapine & paroxetine, sulpiride & fluvoxamine, sulpiride & trazodone). Sixteen, 17 and 21 combinations were designated as requiring precaution for concomitant use in at least one of the package inserts in Japan, the United States and the United Kingdom, respectively, although no such precautions were described for the remaining combinations. On the contrary, a combination of bepridil & clarithromycin was categorized as "X (avoid combination)" and two combinations (chlorpromazine & haloperidol, amiodarone & metildigoxin) were classified as "D (modify regimen)" in the Lexicomp^® risk rating.

This study identified 31 combinations of drugs that may elevate the risk of diLQTS. The use of these drug combinations should be monitored more carefully in future.