Ensitrelvir now available in US for COVID-19 postexposure prophylaxis

Ensitrelvir (Xocova), a once-daily oral SARS-CoV-2 main protease inhibitor, is now available by prescription in the United States for COVID-19 postexposure prophylaxis in adults and adolescents aged 12 years or older. The drug must be started within 72 hours after contact with an individual with COVID-19.¹,²

“Post-exposure prophylaxis, or PEP for short, has been used successfully with influenza as well as HIV and other sexually transmitted infections, and it has the potential to help reduce the burden of COVID-19,” David Wohl, MD, professor of medicine at the University of North Carolina at Chapel Hill School of Medicine, said in the company announcement.¹

The FDA approval was supported by SCORPIO-PEP, a global, double-blind, placebo-controlled phase 3 trial conducted from June 2023 through September 2024. The study enrolled 2387 asymptomatic participants aged 12 years or older who had a negative local SARS-CoV-2 screening test after household exposure to a person with symptomatic COVID-19.¹,³

The primary analysis included 2041 participants with centrally confirmed negative SARS-CoV-2 tests at baseline. Participants were randomly assigned 1:1 to ensitrelvir or placebo, initiated within 72 hours of symptom onset in the infected household member. More than 98% had antibodies against SARS-CoV-2 nucleocapsid or spike proteins, indicating previous infection, vaccination, or both.¹,³

Through day 10, ensitrelvir reduced the risk of symptomatic COVID-19 by 67% relative to placebo, according to the company and the trial report. The analysis included 1030 ensitrelvir recipients and 1011 placebo recipients.¹,³

The approved regimen is 375 mg—three 125-mg tablets taken together—on day 1, followed by 125 mg once daily on days 2 through 5. Ensitrelvir inhibits the SARS-CoV-2 main protease, an enzyme required for viral replication.²

Headache, diarrhea, and cough were the most common adverse events reported more frequently with ensitrelvir than placebo. Allergic reactions, including anaphylaxis, are listed as potentially serious adverse effects. The drug also has substantial interaction potential; concomitant use is contraindicated with multiple medications, including carbamazepine, phenytoin, rifampin, simvastatin, and St John’s wort.²

Ensitrelvir may cause fetal harm. Pregnancy status should be assessed before treatment, effective contraception is recommended during use and for 2 weeks after the final dose, and breastfeeding is not recommended during that interval.²

Ensitrelvir previously received emergency approval in Japan in 2022 and full Japanese approval in 2024 for COVID-19 treatment based on the phase 3 SCORPIO-SR trial.⁴ It is approved for postexposure prophylaxis in both Japan and the United States.

References

1. Shionogi Inc. Shionogi announces U.S. availability of Xocova (ensitrelvir), the first and only oral option to help prevent COVID-19 following exposure. July 28, 2026. Accessed July 28, 2026. https://www.businesswire.com/news/home/20260728842806/en/Shionogi-Announces-U.S.-Availability-of-XOCOVA-ensitrelvir-the-First-and-Only-Oral-Option-to-Help-Prevent-COVID-19-Following-Exposure

2. Shionogi Inc. Xocova (ensitrelvir) prescribing information. 2026. Accessed July 28, 2026. https://www.shionogi.com/content/dam/shionogi/si/products/pdf/xocova.pdf

3. Hayden FG, Shinkai M, Clark TW, et al. Ensitrelvir for Covid-19 Postexposure Prophylaxis in Household Contacts. N Engl J Med. 2026;394(19):1905-1915. doi:10.1056/NEJMoa2509306

4. Yotsuyanagi H, Ohmagari N, Doi Y, et al. Efficacy and Safety of 5-Day Oral Ensitrelvir for Patients With Mild to Moderate COVID-19: The SCORPIO-SR Randomized Clinical Trial. JAMA Netw Open. 2024;7(2):e2354991. Published 2024 Feb 5. doi:10.1001/jamanetworkopen.2023.54991