FDA Rejects Cheap Antidepressant to Treat Early COVID

The FDA rejected an emergency use authorization (EUA) application for the use of the selective serotonin reuptake inhibitor fluvoxamine to treat COVID-19 on Monday.

In a brief summary of their decision, attached to their detailed analysis of the evidence for the rejection, the agency noted that “the data are insufficient to conclude that fluvoxamine may be effective in the treatment of nonhospitalized patients with COVID-19 to prevent progression to severe disease and/or hospitalization.”

When David Boulware, MD, MPH, an infectious disease physician and researcher at the University of Minnesota, submitted the EUA, he reasoned that an authorization would allow more patients to use the low-cost antidepressant to treat early COVID.

In many cases, doctors are able to prescribe the drug off-label to patients if they choose. But Boulware’s colleague Carolyn Bramante, MD, MPH, who led a trial on fluvoxamine, told MedPage Today in December that providers might be more inclined to prescribe it if the FDA authorized it specifically for COVID-19.

According to the FDA, the fluvoxamine trials included in the EUA application had shortcomings. The double-blind randomized controlled TOGETHER trial measured a composite endpoint of more than 6 hours of observation in a COVID emergency setting or transfer to a tertiary hospital due to COVID by day 28, which they deemed less “clinically meaningful” than other outcomes, such as a reduction in deaths.

STOP COVID 2 and COVID-OUT (the trial led by Bramante) were both “terminated early for futility.” The FDA also noted that the trials included in the application were conducted at different times during the pandemic and among different populations.

The agency further stated that the mechanism by which fluvoxamine works “has not yet been well characterized” and the optimal dosing regimen is unclear.

“I think my biggest disappointment is the use by FDA of unequal standards for different medications,” Boulware told MedPage Today in an email. “FDA guidance for outpatient clinical trials worked well for 2020, but [it] is woefully behind the times.”

In a letter to FDA’s Center for Drug Evaluation and Research, Boulware argued that the agency is using an inconsistent definition of “hospitalization” to evaluate brand-name versus generic drugs. For example, he said, while the FDA used COVID-hospitalizations and deaths by day 28 as the “regulatory endpoint” for EUAs, hospitalization was defined as more than 24 hours of acute care for molnupiravir and ritonavir/nirmatrelvir (Paxlovid).

Boulware also noted that molnupiravir had an equally modest effect as fluvoxamine, and was still authorized for emergency use.

Moreover, because so many more people are now vaccinated and boosted, using hospitalizations and deaths as a primary endpoint is “unrealistic,” he said. “A medication is beneficial for many reasons, including shortening duration of illness or preventing progression to severe COVID-19.”

Furthermore, the STOP COVID 2 trial wasn’t necessarily stopped because fluvoxamine wasn’t effective, but because researchers were having trouble recruiting enough participants with the funding available. More funding, Boulware argued, could have offset the effect that vaccines were having on participant enrollment.

While he acknowledged that the need for the fluvoxamine is now less urgent than when he submitted the EUA application, due to the wider availability of antivirals, he concluded that “there remains a clinical need of effective medications and possible options.”