FDA Approves Ensitrelvir for Post-Exposure Prophylaxis of COVID-19

The FDA approved ensitrelvir (Xocova) as the first and only oral antiviral for the post-exposure prophylaxis of COVID-19 in adults and adolescents 12 years and older. The indication is for patients who had contact with an infected patient, and the approval arrives prior to the Prescription Drug User Fee Act action date of June 16, 2026.

“Ensitrelvir inhibits viral replication, helping protect people who have been exposed to COVID-19 from developing illness. The PEP strategy has the potential to benefit anyone who does not want to get COVID-19. It could be useful not only in household settings but also in other exposure circumstances, such as outbreaks in nursing homes, chronic or acute care facilities, and following travel-related exposures,” Frederick Hayden, MD, Richardson Professor Emeritus of Clinical Virology and Professor Emeritus of Medicine, University of Virginia School of Medicine, said in a news release. ¹

About the Trial

The FDA's decision is primarily supported by data from the global phase 3 SCORPIO-PEP (NCT05897541) trial, which demonstrated that ensitrelvir significantly reduced the risk of symptomatic COVID-19 by 67% compared to a placebo through day 10. Unlike previous trials of other oral antivirals such as nirmatrelvir–ritonavir and molnupiravir, which failed to show significant protection in household PEP settings, SCORPIO-PEP met its primary efficacy end point.^1,2

For pharmacists, a key clinical takeaway is that this protection was observed regardless of a patient's vaccination status or baseline immunity from prior infections. The trial also indicated that ensitrelvir was associated with a 34% relative risk reduction in general SARS-CoV-2 transmission within households.^1,2

Pharmacists will play a critical role in managing the unique dosing and safety profile of this 5-day oral regimen. The therapy requires a loading dose of 375 mg (3 tablets) on the first day, followed by 125 mg (1 tablet) once daily on days 2 through 5. Clinical data published in the New England Journal of Medicine indicates that the drug is generally well-tolerated, with adverse event rates of 15.1% in the treatment group compared to 15.5% for placebo. The most frequent adverse effects reported include headache, diarrhea, and cough. Notably, clinical trials reported no cases of dysgeusia, a common complaint associated with other COVID-19 antivirals, which may improve patient adherence.^1,2

Considerations for Pharmacists

Clinical considerations for the pharmacy team include a thorough screening for drug-drug interactions, as ensitrelvir acts as a moderately strong cytochrome P450 3A (CYP3A) inhibitor. It is strictly contraindicated for use with several common medications, including simvastatin, rifampin, carbamazepine, and St. John wort, as these interactions can lead to life-threatening adverse effects or reduced efficacy.²

Furthermore, laboratory results from the trials showed a reversible, dose-related decrease in high-density lipoprotein levels that typically returned to baseline within 2 weeks after finishing the course. Pharmacists should also advise that the drug is not recommended during pregnancy or breastfeeding, and females of childbearing potential should use effective contraception during treatment and for two weeks following the final dose.²

The availability of an oral PEP option addresses a persistent public health challenge, as household secondary attack rates remain as high as 32% to 48% during the omicron era. While vaccines have reduced the risk of severe illness, the CDC estimates millions of new cases continue to occur annually, leading to hundreds of thousands of hospitalizations.^1-3

Prophylactic strategies are especially vital for protecting vulnerable populations in close-community settings, such as long-term care facilities, where outbreaks can be devastating. By inhibiting viral replication during the critical window between exposure and symptom onset, ensitrelvir provides a new tool to mitigate the impact of the virus on high-risk individuals and the broader health care system.³

“Xocova is the first and only oral option clinically proven to help prevent symptomatic COVID-19 after exposure among study participants regardless of vaccination status or baseline immunity from prior infection. With Xocova, people who are exposed to COVID-19 can act early to help protect themselves,” Nathan McCutcheon, president and CEO, Shionogi Inc, said in the news release.¹

READ MORE: COVID-19 Resource Center

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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. 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, Luetkemeyer AF, Sax PE, Hanage WP, Gebo KA, Ikematsu H, Izumikawa K, Fukushi A, Kezbor S, Sakaguchi H, Lacey S, Ichihashi G, Ohmagari N, Uehara T; SCORPIO-PEP Study Team. N Engl J Med. 2026 May 14;394(19):1905-1915. doi: 10.1056/NEJMoa2509306.

3. CDC. How to protect yourself and others. March 10, 2025. Accessed June 1, 2026. https://www.cdc.gov/covid/prevention/index.html