Active Ingredient: CHLOROQUINE
Hydroxychloroquine exhibits a documented regulatory and literature discordance regarding cardiac repolarization. In a controlled PK/PD study in young and elderly healthy volunteers (2400 mg over 5 days), plasma concentrations up to 200 ng/mL showed no significant concentration-dependent QTcF prolongation (mean ddQTcF below 5 ms, upper 90% CI below 10 ms) and preserved T-wave morphology. However, FDA labelling and product characteristics (SmPC) mandate boxed warnings and precautions for drug-induced QTc prolongation, ventricular arrhythmias, and torsades de pointes, notably when combined with other QT-prolonging agents or in acute infection settings. Hydroxychloroquine cardiotoxicity in acute respiratory infection (SARS-COV2) is uncommon but significantly magnified by co-prescriptions and advanced age. In a meta-analysis of 28 studies (n = 9124), the overall incidence of critical long QT was 6.7%, dropping to 1.7% in studies without concomitant QT-prolonging drugs. Drug discontinuation due to long QT occurred in 3.7%. Reported rates of torsades de pointes, ventricular arrhythmias, and arrhythmogenic death were 0.06%, 1.68%, and 0.69%, respectively. Patients older than 60 years had the highest risk (p < 0.001). ECG monitoring is mandatory when combining therapies or in elderly patients. Hydroxychloroquine safety analysis includes long-term chronic rheumatology real-world data from Heart Rhythm 2020 (819 patients, median duration 1006 days). Mean QTc increased significantly from 424.4 ms to 432.0 ms (p < 0.0001). Overall, 7% reached QTc 470-500 ms and 1.5% exceeded 500 ms. Chronic kidney disease, atrial fibrillation, and heart failure were established as independent risk factors for QTc prolongation. A QTc above 470 ms was associated with increased univariable mortality (HR 1.78). Regular ECG monitoring is recommended in high-risk comorbid patients.
https://doi.org/10.1016/j.hrthm.2020.06.029, https://doi.org/10.1016/j.ijantimicag.2020.106212, https://doi.org/10.1111/bcp.15013, https://doi.org/10.1161/JAHA.120.016887, https://doi.org/10.1016/j.semarthrit.2003.09.012, https://doi.org/10.1016/j.hrthm.2020.05.008, https://www.fda.gov/media/178811/download