Drug Update · Infectious Disease

FDA Approves Ensitrelvir (XOCOVA) for COVID-19 Post‑Exposure Prophylaxis: 67% Reduction in Confirmed Symptomatic COVID-19 in SCORPIO-PEP

August 28, 2026

Drug

ensitrelvir (XOCOVA)

Indication

Post-exposure prophylaxis of COVID-19 in adults and adolescents 12 years and older

Approval date

2026-05-29

Primary efficacy (mITT)

2.9% vs 9.0% confirmed symptomatic COVID-19 through Day 10; 67% reduction (relative risk ratio 0.33; 95% CI 0.22-0.49; p <0.0001)

Randomized (total)

2,387 subjects randomized

mITT population

2,041 subjects (including 118 adolescents)

Approved dosage

375 mg Day 1; 125 mg Days 2-5

Clinical Perspective

This affects infectious disease clinicians, primary care prescribers, pediatric/adolescent care providers, and pharmacists managing household exposures in adults and adolescents aged 12 years and older as described in the label ^[1]^[3]. The SCORPIO-PEP data support using XOCOVA for post-exposure prophylaxis begun as soon as possible and within 72 hours after contact with an individual who has COVID-19, with attention to pregnancy evaluation and potential CYP3A drug interactions ^[1]^[3]. What is the safety, pharmacokinetic, and efficacy profile of XOCOVA in pediatric patients under 12 years of age, given that pediatric studies for younger children were deferred and are required postmarketing?

Dr. Simran Kohli, MBBS, MD (General Medicine), DM (Infectious Diseases) · Infectious Diseases

The FDA approved ensitrelvir (XOCOVA) for post-exposure prophylaxis of coronavirus disease 2019 (COVID-19) in adults and adolescents 12 years of age and older on 2026-05-29 based on the SCORPIO-PEP trial, which showed a 67% reduction in confirmed symptomatic COVID-19 through Day 10 versus placebo (relative risk ratio 0.33; 95% CI 0.22-0.49; p <0.0001) ^[3]^[1]. The approved dosage is 375 mg (three 125-mg tablets) orally on Day 1 and 125 mg (one 125-mg tablet) orally on Days 2 to 5, begun as soon as possible and within 72 hours of contact with an individual who has COVID-19 ^[1]. Clinicians should consult current prescribing information for full dosing guidance.

Clinical Context

Ensitrelvir (XOCOVA) is an oral severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro; also referred to as 3CLpro or nsp5 protease) inhibitor developed by Shionogi Inc. The FDA approval provides a marketed oral post-exposure prophylaxis option for adults and adolescents 12 years and older following contact with an individual who has COVID-19 ^[1]^[3]. The approval was granted under a standard NDA review; the approval letter and labeling outline required postmarketing pediatric studies and resistance surveillance commitments intended to monitor pediatric extrapolation and emergence of Mpro polymorphisms ^[2]. Prescribing information emphasizes pregnancy evaluation, drug–drug interaction assessment, and contraindications with certain CYP3A substrates and inducers ^[1]^[2].

Key Findings

In SCORPIO-PEP, XOCOVA achieved 2.9% confirmed symptomatic SARS-CoV-2 infection through Day 10 versus 9.0% with placebo in the modified intention-to-treat population (mITT), representing a 67% reduction (relative risk ratio 0.33; 95% CI 0.22-0.49; p <0.0001) ^[3]^[1].
In the intention-to-treat (ITT) population through Day 10, XOCOVA demonstrated a 57% risk reduction for confirmed symptomatic COVID-19 (relative risk ratio 0.43; 95% CI 0.32-0.59; p <0.0001) versus placebo ^[3]^[1].
SCORPIO-PEP randomized a total of 2,387 subjects; the mITT analysis population included 2,041 subjects (including 118 adolescents) and demographics showed 70% had a history of COVID-19 vaccination and >99% had seropositive SARS-CoV-2 antibody at screening ^[3]. These results were the efficacy basis in the prescribing information that supported the FDA approval for post-exposure prophylaxis in persons 12 years and older following household contact with an index case of COVID-19 ^[3]^[1].

Safety & Tolerability

The most common adverse events (occurring in ≥1% of the XOCOVA group and at greater frequency than placebo) were headache, diarrhea, and cough ^[1]^[3].
Hypersensitivity reactions, including anaphylaxis, anaphylactic shock, and angioedema, have been reported with XOCOVA ^[1].
Embryofetal toxicity was observed in animal reproduction studies; XOCOVA may cause fetal harm and females of reproductive potential should use effective contraception during treatment and for 2 weeks after the final dose ^[1].
Co-administration may alter plasma concentrations of concomitant drugs and XOCOVA is a strong CYP3A inhibitor; use with certain CYP3A substrates or strong CYP3A inducers is contraindicated ^[1].

Study Design

SCORPIO-PEP was a randomized, double-blind, placebo-controlled, multinational post-exposure prophylaxis trial in 5 countries evaluating XOCOVA in asymptomatic standard- or high-risk adult and adolescent subjects not infected at baseline; subjects were enrolled within 72 hours of symptom onset in an index household case and randomized 1:1 to XOCOVA (375 mg Day 1; 125 mg Days 2-5) or matching placebo ^[3]. Clinicians should consult current prescribing information for full dosing guidance. A total of 2,387 subjects were randomized; the mITT population analyzed for the primary endpoint included 2,041 subjects (including 118 adolescents) ^[3]. The primary endpoint was the incidence of COVID-19 (onset of symptoms lasting ≥48 hours plus RT-PCR-confirmed SARS-CoV-2 infection) within 10 days of randomization in the mITT population; key secondary analyses included the ITT population through Day 10 ^[3].

FAQ

Q1 What is ensitrelvir (XOCOVA) approved for?

XOCOVA (ensitrelvir) is approved for post-exposure prophylaxis of COVID-19 in adults and adolescents 12 years of age and older following contact with an individual who has COVID-19. The indication and patient population are specified in the prescribing information and approved labeling. The approval was based on SCORPIO-PEP trial results showing reductions in confirmed symptomatic COVID-19 through Day 10.

Q2 How does ensitrelvir work?

Ensitrelvir is a SARS-CoV-2 main protease (Mpro; also referred to as 3CLpro or nsp5 protease) inhibitor. The prescribing information describes ensitrelvir’s mechanism of action as inhibition of the viral main protease, which is essential for viral replication. Further mechanistic and clinical pharmacology details are included in the full prescribing information.

Q3 What is the recommended dose of ensitrelvir (XOCOVA)?

The recommended dosage for adults and adolescents 12 years and older is 375 mg (three 125-mg tablets taken together) orally on Day 1 and 125 mg (one 125-mg tablet) orally on Days 2 to 5, taken with or without food, and to be started as soon as possible and within 72 hours following contact with an individual who has COVID-19. Clinicians should consult current prescribing information for complete dosing guidance.

Q4 What are the side effects of ensitrelvir (XOCOVA)?

The most common adverse events occurring in ≥1% of XOCOVA recipients and at a greater frequency than placebo were headache, diarrhea, and cough. Hypersensitivity reactions, including anaphylaxis, anaphylactic shock, and angioedema, have been reported. The labeling also includes warnings about embryofetal toxicity based on animal studies and extensive information on drug–drug interactions, contraindications, and use in specific populations.

Clinicians should consult current prescribing information for complete dosing guidance.

FDA Approves Ensitrelvir (XOCOVA) for COVID-19 Post‑Exposure Prophylaxis: 67% Reduction in Confirmed Symptomatic COVID-19 in SCORPIO-PEP

Direct Clinical Takeaway & Evidence Summary

FDA Approves Ensitrelvir (XOCOVA) for COVID-19 Post‑Exposure Prophylaxis: 67% Reduction in Confirmed Symptomatic COVID-19 in SCORPIO-PEP

Clinical Perspective

Clinical Context

Key Findings

Safety & Tolerability

Study Design

FAQ

References

Get weekly clinical updates for Infectious Disease in your inbox.

Related Clinical Updates

AREXVY Expanded for Adults 18–59 at Increased RSV Risk

FDA Expands AREXVY to Adults 18–59 at Increased RSV Risk

FDA Approves zoliflodacin for Uncomplicated Urogenital Gonorrhea: 90.9% Microbiologic Cure

Verified HCP Portal