Ensitrelvir (XOCOVA) for Postexposure Prevention of COVID-19

In 2026 the Food and Drug Administration (FDA) approved ensitrelvir (XOCOVA), an oral medication, to prevent coronavirus disease 2019 (COVID-19) in people aged 12 years and older following contact with someone recently diagnosed with the disease.[1] The approval was based on the findings of a single clinical trial.

Public Citizen’s Health Research Group has classified ensitrelvir as Do Not Use for Seven Years to allow time for more data to emerge about the drug’s safety and effectiveness. A single course of ensitrelvir costs approximately $1,400.[2]

COVID-19

In the United States, there were 36 COVID-19 hospitalizations per 100,000 people between October 2025 and mid-July 2026, with the highest rates among people older than 64 years (143 hospitalizations per 100,000) and younger than 4 years (29 hospitalizations per 100,000).[3]

The FDA has approved four COVID-19 vaccines (COMIRNATY, MNEXSPIKE, NUVAXOVID, SPIKEVAX) to prevent hospitalizations and deaths. Approved postexposure treatments include remdesivir (VEKLURY), which is administered intravenously, and oral nirmatrelvir and ritonavir (PAXLOVID); these treatments are indicated only after symptoms appear.[4],[5]

Ensitrelvir

Ensitrelvir is a SARS-CoV-2 protease inhibitor that decreases the activity of proteins the virus relies upon for replication.[6] The drug is supplied in 125-milligram (mg) tablets, which can be taken with or without food. The first dose of 375 mg is taken as soon as possible and within 72 hours after contact with someone who has COVID-19. Additional 125-mg doses are then taken each day for the next four days. Ensitrelvir should not be taken during pregnancy, as it may harm the fetus, or while breastfeeding.

The clinical trial

The FDA approved ensitrelvir based on a single randomized, double-blinded, placebo-controlled trial conducted in the United States, Japan, South Africa, Argentina and Vietnam.[7],[8] Participants were 12 years of age or older, living in a household with a new confirmed “index” case of COVID-19, and had a negative screening test for SARS-CoV-2 prior to enrollment. Almost all the participants had SARS-CoV-2 antibodies in their blood, indicative of prior infection or COVID-19 vaccination — 70% of participants had a history of vaccination.

Participants received a five-day regimen of ensitrelvir or placebo, began treatment within 72 hours of their index case diagnosis, and were followed for 10 days after randomization. The primary outcome was the incidence of COVID-19, defined as the onset of symptoms with a duration of at least 48 hours and laboratory-confirmed SARS-CoV-2 infection within the 10 days of follow-up. Participants who were subsequently found to be infected at baseline with more-sensitive testing were excluded from this analysis.

For the primary endpoint, 30 (2.9%) of 1,030 participants in the treatment group had confirmed symptomatic infection, compared with 91 (9.0%) of 1,011 participants in the placebo group. Results for a secondary endpoint, which included all randomized participants (“intent to treat”), were similar: 552 (4.4%) of 1,194 participants in the treatment group and 122 (10.2%) of 1,193 participants in the placebo group had confirmed symptomatic infection.

Adverse effects were more common in participants who received ensitrelvir than in those who received placebo.[9] The most common adverse effects were headaches (2.9% versus 2.3%, respectively), diarrhea (1.7% versus 1.3%) and cough (1.1% versus 0.6%).

Ensitrelvir as a treatment for mild to moderate COVID-19

In 2023, Japan approved ensitrelvir as a treatment for mild to moderate COVID-19.[10] However, Japanese treatment guidelines identify remdesivir as a better drug for hospitalized patients with COVID-19, and other researchers have noted the limited data demonstrating ensitrelvir’s safety and effectiveness for symptomatic COVID-19.[11]

A meta-analysis published in the journal Infection in 2025 included six randomized placebo-controlled trials of ensitrelivir for mild to moderate COVID-19. Data were available for 1,860 persons treated with ensitrelvir and 933 treated with placebo. Although SARS-CoV-2 viral load was significantly reduced by ensitrelvir compared with placebo, metabolic changes (cholesterol and triglyceride levels), liver abnormalities (increased bilirubin) and headaches were significantly increased.

The researchers concluded that although ensitrelvir shows promise as a treatment for mild to moderate COVID-19, “its safety profile raises concerns…and further research is needed…”

Safety information

The most common adverse events with ensitrelvir are headache, diarrhea and cough. In rare instances, the drug may trigger serious allergic reactions such as anaphylaxis or angioedema (life-threatening reactions that may emerge as swelling and labored breathing).

For patients taking other medications, drug interactions are a concern. Ensitrelvir may change the plasma concentrations of other drugs, and other drugs may change the plasma concentration of ensitrelvir.[12] For example, ensitrelvir increases the effective concentration of various antiarrhythmics (quinidine [generics only]), immunosuppressants (voclosporin [LUPKYNIS]), anti-gout agents (colchicine [GLOPERBA, LODOCO, MITIGARE and generics]), antipsychotics (pimozide [generics only]), cardiovascular agents (eplerenone [INSPRA and generics]) and statins (simvastatin [FLOLIPID, ZOCOR and generics]). Ensitrelvir concentrations are reduced by anticancer drugs (apalutamide [ERLEADA and generic]), anticonvulsants (phenytoin [DILANTIN, PHENYTEK and generics]), antibacterials (rifampin [RIMACTANE and generics]) and drugs for cystic fibrosis (lumacaftor/ivacaftor [ORKAMBI]).

Before prescribing ensitrelvir, physicians should review all of a patient’s medications to determine whether the drug is contraindicated and should not be used, the dose should be adjusted, another medicine stopped, or additional monitoring used.

What You Can Do

Although a double-blind clinical trial has found that ensitrelvir reduces the risk of acquiring COVID-19 for household contacts of an infected individual, the drug is expensive, may interact with many other drugs, and should not be taken during pregnancy or while breastfeeding. Until more data are available about its safety and effectiveness, we have classified ensitrelvir as Do Not Use for Seven Years.

Public Citizen’s Health Research Group also recommends that all eligible children and adults receive and stay up to date on COVID-19 vaccination, including people who are pregnant or breastfeeding.
 

References

[1] Shionogi, Inc. Label: ensitrelvir (XOCOVA). May 2026. https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/220442Orig1s000lbl.pdf. Accessed July 31, 2026. 

[2] Griffis MW. FDA approves COVID-19 antiviral Xocova as PEP. But will it be accessible? The Sick Times. June 23, 2026. https://thesicktimes.org/2026/06/23/fda-approves-covid-19-antiviral-xocova-as-pep-but-will-it-be-accessible/. Accessed July 31 2026. 

[3] Centers for Disease Control and Prevention. Coronavirus Disease 2019 (COVID-19) Hospitalization Surveillance Network (COVID-NET). https://www.cdc.gov/covid/php/covid-net/index.html. Accessed August 5, 2026. 

[4] Pfizer. Label: nirmatrelvir; ritonavir (PAXLOVID). February 2026. https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/217188s017lbl.pdf. Accessed July 31, 2026. 

[5] Gilead Sciences. Label: remdesivir (VEKLURY). https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/214787s032lbl.pdf. October 2025. Accessed July 31, 2026. 

[6] Shionogi, Inc. Label: ensitrelvir (XOCOVA). May 2026. https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/220442Orig1s000lbl.pdf. Accessed July 31, 2026. 

[7] Ibid.

[8] 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. 

[9] Shionogi, Inc. Label: ensitrelvir (XOCOVA). May 2026. https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/220442Orig1s000lbl.pdf. Accessed July 31, 2026. 

[10] Mutoh Y, Yamaguchi T, Sakurai K, et al. Matching-adjusted comparison of the effectiveness and safety of Ensitrelvir versus Remdesivir for high-risk, hospitalized patients with non-severe COVID-19 in Japan. J Infect Chemother. 2026 Aug;32(8):103009. 

[11] Ul Haq MZ, Ashraf S, Shah MSU, et al. Efficacy and safety of ensitrelvir in asymptomatic or mild to moderate COVID-19: a systematic review and meta-analysis of randomized controlled trials. Infection. 2025;53(5):1645-1661. 

[12] Ibid.