The warning came only a few hours after the FDA rescinded Emergency Use Authorization (EUA) for hydroxychloroquine and chloroquine for the treatment of COVID-19.
The U.S. Food and Drug Administration (FDA) warned about a newly-discovered potential drug interaction with remdesivir Monday afternoon. The warning came only a few hours after the FDA rescinded Emergency Use Authorization (EUA) for hydroxychloroquine and chloroquine for the treatment of COVID-19.
Remdesivir, by Gilead Sciences, remains available to use alone as an investigational drug under an EUA. It was the first treatment proven to have an effect against the SARS-CoV-2 virus, which causes COVID-19.
Based on a non-clinical laboratory study in which remdesivir was administered with either chloroquine phosphate or hydroxychloroquine sulfate, the FDA revised its fact sheet for health care providers so that co-administration of these drugs is no longer recommended. The change in recommendation is based on the suggestion that co-administration diminishes remdesivir’s antiviral activity. The FDA admits the anti-viral effect was only seen in a non-clinical setting. It has not been observed among patients.
The fact sheet noted that co-administration of these drugs, during an in vitro study, demonstrated a dose-dependent “antagonistic effect of chloroquine on the intracellular metabolic activation and antiviral activity of remdesivir.”
Continuing, it pointed out that when remdesivir and chloroquine phosphate were co-incubated at clinically relevant concentrations in HEp-2 cells that were infected with respiratory syncytial virus (RSV), the antiviral activity of remdesivir was antagonized.
“Increasing concentrations of chloroquine phosphate reduced formation of remdesivir triphosphate in normal human bronchial epithelial cells,” the FDA noted. So, the higher the dose of chloroquine phosphate, the higher the dosage of remdesivir had to be to affect the virus. Quantitative values on that point, however, were not provided in the FDA fact sheet for health care providers.
Gilead had not yet issued a response to the FDA decision by close of business Monday.
When administered alone, remdesivir appears to shorten COVID-19 hospitalizations, according to a May article reporting on a National Institutes of Health (NIH) study in the New England Journal of Medicine. That double-blind, randomized, placebo-controlled study administered remdesivir when patients initially were admitted to the hospital and for up to nine days thereafter. The 538 patients who received remdesivir recovered in an average pf 11 days, versus 15 days for the 521 patients who received a placebo. Fourteen-day mortality results also were better with remdesivir: 7.1% for remdesivir versus 11.9 % for placebo. Adverse reactions included increased liver transaminases. That reaction, however, also is a characteristic of COVID-19 itself so causation was difficult to determine.
Remdesivir works by obscuring viral RNA polymerase and evades proofreading by viral exonuclease, thus decreasing viral RNA production. Both in vivo and in vitro animal studies indicate antiviral activity against SARS, MERS, Marburg, Ebola and SARS-CoV-2 viruses.
The drug was approved by the Japanese Ministry of Health, Labor and Welfare in early May as a treatment for COVID-19 under the name Veklury®. Approval was under Japan’s exceptional approval pathway, referencing the U.S. EUA and multiple studies.
In the U.S., it remains an investigational drug available under an EUA. The safety and efficacy of remdesivir for the treatment of COVID-19 continue to be evaluated in multiple clinical trials.
When the FDA made its recommendation against co-administering remdesivir with the just-banned hydroxychloroquine and chloroquine as treatments for COVID-19, it also revised the fact sheet for health care providers to clarify dosing and administration recommendations and to provide additional safety data and supporting data from clinical trials conducted by both the National Institutes of Health and Gilead. The fact sheet for patients and caregivers was also updated to include additional information about possible allergic reactions and to alert patients to tell their healthcare providers if they are taking chloroquine phosphate or hydroxychloroquine sulfate.
“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,” Patrizia Cavazzoni, M.D., acting director of the FDA’s Center for Drug Evaluation and Research, said in a statement Monday afternoon. “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.
“As we have done throughout the pandemic, the FDA continues to evaluate all of the emergency use authorizations issued and their related materials, and will continue to make changes as appropriate based on emerging science and data,” Cavazzoni added.
A variety of drugs still are being studied for possible repurposing against the SARS-CoV-2 virus. They include the antiviral agents remdesivir, lopinavir, umifenovir, favipiravir and oseltamivir, as well as such supporting agents as ascorbic acid, azithromycin, corticosteroids, nitric oxide and IL-6 antagonists.
As yet, the FDA cautioned, “There are no medicines approved by the FDA as safe and effective to treat people in the hospital who have COVID-19.”
