Comparative Short-Term Clinical Events Associated with Molnupiravir and Ensitrelvir for COVID-19: A Retrospective Cohort Study Using Community Pharmacy Records in Japan

Molnupiravir and ensitrelvir are widely used for outpatient coronavirus disease 2019 treatment; however, real-world safety comparisons remain limited. This retrospective cohort study evaluated acute clinical event risks over a 29-day follow-up using community pharmacy records from Japanese patients newly prescribed either drug between January and September 2023. Hazard ratios (HRs) were estimated using multivariable Cox proportional hazard models. The analysis included 2051 patients prescribed molnupiravir and 563 prescribed ensitrelvir. Patients prescribed molnupiravir were older and had a higher prevalence of comorbidities than those prescribed ensitrelvir. However, after multivariable adjustment, no significant differences in the risk of major symptoms, such as diarrhea or vertigo, or overall add-on drug prescription were observed between the patient groups. An exception was anti-inflammatory drugs, with a significantly higher risk in the molnupiravir group (adjusted HR: 3.44, 95% confidence interval: 1.07–11.06). These results indicate that while short-term acute clinical event profiles were broadly comparable between molnupiravir and ensitrelvir in routine practice, the differences in add-on prescriptions, combined with the observational study design and limited statistical power in sub-analyses, highlight persistent clinical uncertainty. Our findings provide real-world evidence complementary to that from randomized controlled trials and emphasize the need for larger future studies.