FDA Approves Ensitrelvir as First Oral COVID-19 Postexposure Prophylaxis Option

The US Food and Drug Administration has approved ensitrelvir (Xocova; Shionogi), an oral antiviral, for postexposure prophylaxis of COVID-19 in adults and adolescents aged 12 years and older following contact with an individual with COVID-19, according to a company announcement.¹

The approval introduces the first oral option to help prevent COVID-19 after exposure, Shionogi stated. Ensitrelvir is administered as a 5-day oral regimen, with 3 tablets taken on day 1 and 1 tablet taken on days 2 through 5. The approval occurred ahead of the June 16, 2026, Prescription Drug User Fee Act action date.¹

The approval was based on results from SCORPIO-PEP, a global, double-blind, randomized, placebo-controlled phase 3 trial that evaluated ensitrelvir as postexposure prophylaxis after household exposure to COVID-19. In the primary analysis, ensitrelvir reduced the risk of symptomatic COVID-19 by 67% through day 10 compared with placebo among uninfected individuals exposed to an infected household contact.²

The primary analysis included 2041 household contacts with a central laboratory-confirmed negative SARS-CoV-2 test at baseline. Symptomatic COVID-19 through day 10 was assessed among participants randomly assigned to ensitrelvir (n=1030) or placebo (n=1011). Participants began treatment within 72 hours of symptom onset in the household member with COVID-19 and continued therapy once daily for 5 days.²

“Ensitrelvir inhibits viral replication, helping protect people who have been exposed to COVID-19 from developing illness,” Frederick Hayden, MD, Richardson Professor Emeritus of Clinical Virology and Professor Emeritus of Medicine at the University of Virginia School of Medicine, said in the announcement.¹ “The PEP strategy has the potential to benefit anyone who does not want to get COVID-19.”

SCORPIO-PEP enrolled 2387 participants aged 12 years and older who had a negative local screening test for SARS-CoV-2 infection, had no symptoms at enrollment, and had household exposure to a person with symptomatic COVID-19. The trial was conducted from June 2023 through September 2024. More than 99% of household contacts tested positive for antibodies against SARS-CoV-2 nucleocapsid or spike proteins, indicating evidence of previous infection, vaccination, or both.²

Ensitrelvir was generally well tolerated, with adverse events reported in 15.1% of participants in the ensitrelvir group and 15.5% of those in the placebo group. The most common adverse events, regardless of causality, occurring in at least 1% of the ensitrelvir group and more frequently than with placebo were headache, diarrhea, and cough. No cases of altered taste, or dysgeusia, were attributed to ensitrelvir in the trial.²

Ensitrelvir is a SARS-CoV-2 main protease inhibitor developed through joint research between Hokkaido University and Shionogi. The agent suppresses SARS-CoV-2 replication by selectively inhibiting the main protease, an enzyme required for viral replication.¹

COVID-19 remains highly transmissible, and Shionogi noted that up to 47% of people living with an infected individual may develop COVID-19. The company also cited CDC estimates that from October 1, 2025, to May 23, 2026, there were 3.8 million to 12.4 million new COVID-19 cases in the United States, resulting in 800 000 to 2.3 million outpatient visits, 120 000 to 240 000 hospitalizations, and 13 000 to 42 000 deaths.

Ensitrelvir is approved in the US and Japan for postexposure prophylaxis of COVID-19 in adults and adolescents aged 12 years and older following contact with an individual with COVID-19. It is not approved for the treatment of COVID-19 in the US.¹

Reference

1. Shionogi & Co., Ltd. Shionogi announces FDA approval of Xocova (ensitrelvir), the first and only oral option to help prevent COVID-19 following exposure. June 1, 2026. Accessed June 1, 2026. https://www.businesswire.com/news/home/20260531335709/en/Shionogi-Announces-FDA-Approval-of-XOCOVA-ensitrelvir-the-First-and-Only-Oral-Option-to-Help-Prevent-COVID-19-Following-Exposure
2. Hayden FG, Shinkai M, Clark TW, et al. Ensitrelvir for COVID-19 postexposure prophylaxis in household contacts. N Engl J Med. Published online May 13, 2026. doi:10.1056/NEJMoa2509306