FDA Approves Ensitrelvir as First Oral Postexposure Prevention Option for COVID-19

The US Food and Drug Administration (FDA) approved ensitrelvir (Xocova) for postexposure prophylaxis (PEP) in adults and children 12 years or older following contact with an individual infected with COVID-19.¹

Developed by Shionogi, ensitrelvir becomes the first and only oral antiviral approved in the United States to help prevent symptomatic COVID-19 after exposure. The approval came ahead of the FDA's Prescription Drug User Fee Act target date of June 16, 2026.¹

“The FDA approval of Xocova provides an important new approach to preventing COVID-19, which continues to impact lives,” Frederick Hayden, MD, who is Stuart S. Richardson Professor Emeritus of Clinical Virology and Professor Emeritus of Medicine at the University of Virginia School of Medicine, said in a statement. “COVID-19 can become severe, and even when mild or moderate, it can worsen or exacerbate chronic conditions or trigger new ones, including long COVID.”¹

Hayden noted that preventing infection after exposure may have applications beyond household settings.

“Ensitrelvir PEP could play an important role in helping protect against COVID-19 in persons exposed to SARS-CoV-2, particularly in those at higher risk for complications. Thus, oral ensitrelvir PEP could prove useful not only in household settings but also in other exposure circumstances, such as outbreaks in nursing homes, chronic or acute care facilities, or in travel groups. Preventing COVID-19 in these settings is important because outbreaks can potentially lead to very poor clinical and economic outcomes,” Hayden told Contagion.

About SCORPIO-PEP

The FDA's decision was supported by results from SCORPIO-PEP, a global phase 3, randomized, double-blind, placebo-controlled study evaluating ensitrelvir for postexposure prevention of COVID-19. The findings were published in the New England Journal of Medicine in May 2026.

The trial enrolled 2387 participants 12 years or older who had negative test results for SARS-CoV-2 and had no symptoms at enrollment despite exposure to a household member with symptomatic COVID-19. The primary analysis included 2041 participants with laboratory-confirmed negative baseline test results.²

“To date, SCORPIO-PEP is the first phase 3 study of an oral antiviral to meet the primary end point of preventing COVID-19 after exposure. When started within 72 hours after exposure to a household member with COVID-19, a 5-day course of ensitrelvir significantly reduced the risk of COVID-19 by 67% in uninfected household contacts (mITT [modified intention-to-treat] population) through day 10 compared with placebo (2.9% vs 9.0%),” Hayden told Contagion. “In a prespecified subgroup analysis of participants with 1 or more risk factors for severe disease, a 76% risk reduction for COVID-19 was observed with ensitrelvir through day 10 vs placebo.”

Participants began treatment within 72 hours of symptom onset in the infected household member and received either ensitrelvir or placebo once daily for 5 days.²

Results showed that ensitrelvir reduced the risk of symptomatic COVID-19 by 67% through day 10 compared with placebo. The treatment was generally well tolerated, with adverse event rates similar between the ensitrelvir and placebo groups. The most commonly reported adverse events were headache, diarrhea, and cough. Notably, no cases of altered taste attributed to ensitrelvir were reported during the study.²

About Ensitrelvir

Ensitrelvir is an oral SARS-CoV-2 main protease inhibitor developed through a collaboration between Hokkaido University and Shionogi.¹

The antiviral works by selectively inhibiting the SARS-CoV-2 main protease, an enzyme required for viral replication. By blocking this enzyme, ensitrelvir prevents the virus from reproducing within the body.¹

The drug is approved in both the United States and Japan for PEP of COVID-19 in individuals 12 years or older. Although ensitrelvir previously received approval in Japan for COVID-19 treatment, it is not currently approved in the United States for treating active COVID-19 infection.¹

Public health experts note that despite declining pandemic-era emergency measures, COVID-19 continues to cause substantial illness, hospitalizations, and deaths each year, underscoring the need for additional prevention strategies, particularly among vulnerable populations and in congregate living settings.

Indications and Safety Information

Ensitrelvir is indicated to help prevent COVID-19 in adults and children 12 years or older following contact with a person who has COVID-19 (PEP). It is not known if ensitrelvir is safe and effective in children younger than 12 years.¹

According to the company, ensitrelvir is not indicated for people who are:

• allergic to ensitrelvir or any of its ingredients.
• taking any of the following medicines, as these may interact with ensitrelvir and may cause severe or life-threatening adverse effects or death: apalutamide, carbamazepine, colchicine, dihydroergotamine, enzalutamide, eplerenone, ergotamine, finerenone, ivabradine, lomitapide, lumacaftor/ivacaftor, lurasidone, methylergonovine, phenytoin, pimozide, quinidine, rifampin, simvastatin, St John’s wort, triazolam, or voclosporin.¹

Availability

It has not yet been officially announced when ensitrelvir will be available in the US, but Hayden explains the significance of it for clinicians and the public.

“The availability of oral ensitrelvir PEP would add an important new strategy to protect against COVID-19 and its complications. It would also help shift management from our primarily reactive approach at present—ie, testing and treating after symptoms develop—toward earlier intervention that reduces the risk of COVID-19 development in the first place,” he said. “This is increasingly relevant as SARS-CoV-2 vaccine uptake, even in high-risk persons, continues to wane and new SARS-CoV variants emerge with the potential to cause surges in disease incidence.”

References
1. Shionogi announces FDA approval of XOCOVA (ensitrelvir), the first and only oral option to help prevent COVID-19 following exposure. News release. Shionogi & Co Ltd. 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; SCORPIO-PEP Study Team. Ensitrelvir for COVID-19 postexposure prophylaxis in household contacts. N Engl J Med. 2026;394(19):1905-1915. doi:10.1056/NEJMoa2509306