Drug Interactions between azithromycin and hydroxychloroquine

GENERALLY AVOID: Coadministration of hydroxychloroquine (HCQ) with azithromycin or other macrolide antibiotics may increase the risk of cardiovascular events, including QT prolongation, torsades de pointes, and cardiovascular mortality. Hydroxychloroquine (HCQ) alone can cause dose-related prolongation of the QT interval; for example, a retrospective study of electronic health records observed a statistically significant QTc interval increase of 18 msec in patients on HCQ monotherapy. The addition of QT-prolonging macrolides, such as azithromycin, may lead to additive effects, further increasing the risk of ventricular arrhythmias including torsade de pointes, and sudden death. A multinational, retrospective study evaluating HCQ use in the treatment of rheumatoid arthritis found that long-term use of HCQ was not associated with excess severe adverse events compared to sulfasalazine, however, when combined with azithromycin, it was linked to increased cardiovascular mortality (HR 2.19), chest pain or angina (HR 1.15) and heart failure (HR 1.22). Cardiovascular death occurred even with short-term HCQ and azithromycin therapy, likely due to their synergistic effects on QT prolongation and the subsequent risk of fatal arrhythmias. Similarly, in a cohort study of 90 hospitalized COVID-19 patients, HCQ in combination with azithromycin was associated with a larger increase in the QTc interval (23 msec vs. 5.5 msec with HCQ alone), with one patient developing torsades de pointes. Most patients also had cardiovascular comorbidities, were on multiple QTc-prolonging medications, and may have been predisposed to cardiac risks due to COVID-19. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such advanced age, congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s). Data are not available for all macrolide antibiotics with HCQ.

MANAGEMENT: Coadministration of hydroxychloroquine (HCQ) with azithromycin or other macrolide antibiotics should generally be avoided, particularly in patients with pre-existing cardiovascular comorbidities, those being treated for COVID-19, and/or patients who are taking multiple agents that can prolong the QT interval. Close monitoring of QTc interval, electrolyte levels, and renal and hepatic function is recommended if concomitant use is required, and benefits are anticipated to outweigh the risks. Electrolyte abnormalities should be corrected prior to initiating treatment with HCQ. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope. Because hydroxychloroquine is eliminated slowly from the body (terminal half-life: 40-50 days), potential drug interactions may persist for several weeks to months after its discontinuation.