Remdesivir
Maria G. Tanzi, PharmD
New data suggest that the investigational antiviral drug remdesivir may interact with chloroquine phosphate or hydroxychloroquine sulfate and concurrent use of these agents is not recommended for the management of patients with COVID-19.
FDA approved the use of remdesivir under an emergency use authorization (EUA) in May for the treatment of COVID-19 in adult and pediatric patients with severe disease.
“Over the course of this unprecedented pandemic, the FDA has issued emergency use authorizations for a variety of medical products after evaluating the available scientific evidence and carefully balancing any known or potential risks against the benefits of making these products available during the current public health emergency,” said Patrizia Cavazzoni, MD, acting director of FDA’s Center for Drug Evaluation and Research, in a press release.
“We understand that, as we learn more about these products, changes may be necessary based on new data—such as today’s updates for health care providers about a potential drug interaction and other important information about using remdesivir to treat COVID-19 patients.”
The new alert, which was released by FDA in mid-June, is based on a nonclinical laboratory study demonstrating an antagonistic effect of chloroquine on the antiviral activity of remdesivir. FDA noted that they are not aware of instances of this reduced activity occurring in the clinical setting, but the agency is continuing to evaluate all of the data.
In vitro data
The in vitro data supporting the potential drug–drug interaction comes from laboratory data which showed the antiviral activity of remdesivir was antagonized by chloroquine phosphate in a dose-dependent manner when the two drugs were co-incubated at clinically relevant concentrations in human epithelial type 2 (HEp-2) cells infected with respiratory syncytial virus.
Higher remdesivir EC50 values (i.e., the concentration of a drug that gives half-maximal response) were observed with increasing concentrations of chloroquine phosphate.
In addition, increasing concentrations of chloroquine phosphate reduced formation of remdesivir triphosphate in normal human bronchial epithelial cells.
Antivirals for COVID-19
Currently, there are no FDA-approved drugs for the treatment of COVID-19, although numerous agents have been assessed. Some of these medications have included remdesivir, chloroquine or hydroxychloroquine, and lopinavir/ritonavir or other HIV protease inhibitors.
The National Institutes of Health released guidance on the use of treatments for the management of COVID-19, which includes a section on antivirals. Because remdesivir supplies are limited, the guidance recommends that remdesivir be prioritized for use in hospitalized patients with COVID-19 who require supplemental oxygen but who are not on high-flow oxygen, noninvasive ventilation, mechanical ventilation, or extracorporeal membrane oxygenation.
As for the other agents discussed in this section, the guidance recommends against the use of chloroquine or hydroxychloroquine for the treatment of COVID-19, except in a clinical trial, and against the use of high-dose chloroquine (600 mg twice daily for 10 days). Use of hydroxychloroquine plus azithromycin or lopinavir/ritonavir or other HIV protease inhibitors is also not recommended outside of a clinical trial.
Clinical considerations
Understanding the role of antivirals in managing patients with COVID-19 is necessary when optimizing treatment for patients during this pandemic. Clinicians using remdesivir should read the most up-to-date fact sheet, which can be accessed on FDA’s website (www.fda.gov/media/137566/download).
Given the current in vitro data, which suggests a potential drug–drug interaction with remdesivir and chloroquine phosphate or hydroxychloroquine sulfate, pharmacists managing hospitalized patients with COVID-19 can screen for this interaction and educate clinicians about avoiding this combination. Also, drug interaction alerts added to the electronic medical record may be useful in stopping this combination from being prescribed.
As noted above, chloroquine or hydroxychloroquine is not recommended for use outside the context of a clinical trial for management of COVID-19. In fact, FDA revoked the EUA for use of chloroquine or hydroxychloroquine outside of a clinical trial in mid-June, citing that these treatments are unlikely to be effective and may be associated with serious cardiac adverse events and other potential serious side effects.