Ensitrelvir for Post-Exposure Prophylaxis of COVID-19

Key Takeaways

• FDA cleared ensitrelvir for postexposure prophylaxis in exposed patients 12 years and older, with lower rates of laboratory-confirmed COVID-19 than placebo observed in household contacts within 10 days.
• The reported prophylaxis regimen is 375 mg on day 1, then 125 mg on days 2-5, with day 1 started within 72 hours of exposure.
• Headache, diarrhea, cough, and decreased hemoglobin were common; interactions involving CYP3A, P-gp, and BCRP remain part of the labeling; and use is avoided in pregnancy and breastfeeding.

FDA has approved ensitrelvir (Xocova) for postexposure prophylaxis of COVID-19 in patients 12 years and older after contact with an infected individual, with trial results showing a relative risk of 0.33 versus placebo. The oral SARS-CoV-2 main protease inhibitor is labeled for prevention after exposure rather than treatment of established illness. The approval makes ensitrelvir the first oral antiviral cleared in the United States for this prophylactic setting. Practical prescribing details on dosing, administration, interactions, safety, and cost are included in the current clinical summary for clinicians.

FDA clearance was based on SCORPIO-PEP, a double-blind trial involving 2,041 household contacts aged 12 years and older. Participants had documented exposure to SARS-CoV-2, tested negative at baseline, and were randomly assigned to ensitrelvir or placebo once daily. The study was limited to household contacts of an infected individual and enrolled participants before laboratory-confirmed infection was present, keeping the comparison focused on postexposure prophylaxis rather than active disease.

In SCORPIO-PEP, a 5-day course started within 72 hours of symptom onset in the index patient lowered laboratory-confirmed COVID-19 within 10 days compared with placebo after household contact. Event rates were 2.9% with ensitrelvir and 9.0% with placebo, for a relative risk of 0.33. The number needed to treat was 16.4 across the trial's 10-day assessment window.

The most common adverse effects in clinical trials were headache, diarrhea, cough, and decreased hemoglobin levels, and transient decreases in HDL-C have also been reported. Rare anaphylaxis, angioedema, and urticaria have occurred in other countries. Ensitrelvir can increase serum concentrations of CYP3A substrates and drugs transported by P-gp or BCRP, and certain CYP3A combinations remain contraindicated. Use during pregnancy or breastfeeding is avoided, and effective contraception and breastfeeding avoidance continue during treatment and for two weeks afterward. Postexposure prophylaxis uses a 5-day oral course begun within 72 hours of exposure; the reported cost is $1400, and earlier antibody options are no longer authorized in the US.