XOCOVA

5 WARNINGS AND PRECAUTIONS Embryofetal toxicity: Based on animal data, XOCOVA may cause fetal harm. Advise pregnant women and females of reproductive potential that XOCOVA may cause fetal harm. Advise females of reproductive potential to use effective contraception during XOCOVA use and for 2 weeks after the final dose. ( 5.1 , 8.1 , 8.3 ) The concomitant use of XOCOVA and certain other drugs may result in potentially significant drug interactions. Consult the Full Prescribing Information prior to and during treatment for potential drug interactions. ( 5.2 , 7 ) Hypersensitivity reactions, including anaphylaxis, anaphylactic shock, and angioedema, have been reported with XOCOVA. If signs and symptoms of a clinically significant hypersensitivity reaction occur, immediately discontinue XOCOVA and initiate appropriate treatment. ( 5.3 ) 5.1 Embryofetal Toxicity Based on animal reproduction studies, XOCOVA may cause fetal harm when administered to a pregnant woman. In rabbits, embryofetal toxicity (including skeletal malformations and embryofetal lethality) was observed in rabbit offspring following exposure of pregnant rabbits to ensitrelvir at 7 times the human exposures at the recommended human dose (RHD). Likewise in rats, fetal growth retardation, low fetal body weight, skeletal variations, offspring lethality, low body weight in offspring, and retardation of morphological development were observed following exposure during gestation and lactation at exposures 9 times the human exposures at the RHD [see Use in Specific Populations (8.1) ] . Advise pregnant women and females of reproductive potential that XOCOVA may cause fetal harm. Verify pregnancy status of females of reproductive potential prior to initiating XOCOVA. Advise females of reproductive potential to use effective contraception during XOCOVA use and for 2 weeks after the final dose [see Use in Specific Populations (8.1 , 8.3) ] . 5.2 Risk of Serious Adverse Reactions Due to Drug Interactions XOCOVA is a strong CYP3A inhibitor and an inhibitor of P-gp and BCRP. In patients receiving or initiating medications metabolized by CYP3A or transported by P-gp or BCRP, XOCOVA may increase plasma concentrations of those medications and may potentially lead to severe, life-threatening, or fatal events from increased exposure of concomitant medications. In addition, medications that induce CYP3A may decrease concentrations of ensitrelvir, leading to loss of therapeutic effect of XOCOVA. Prior to prescribing XOCOVA, review all medications taken by the patient to assess potential drug-drug interactions and determine if concomitant medications require a dose adjustment, interruption, and/or additional monitoring (e.g., calcineurin inhibitors) [see Contraindications (4) and Drug Interactions (7) ] . Consider the benefit of XOCOVA and whether the risk of potential drug-drug interactions can be appropriately managed [see Drug Interactions (7) ] . 5.3 Hypersensitivity Reactions Including Anaphylaxis Hypersensitivity reactions, including anaphylaxis, anaphylactic shock, and angioedema, have been reported with XOCOVA [see Adverse Reactions (6.2) ] . If signs and symptoms of a clinically significant hypersensitivity reaction occur, immediately discontinue XOCOVA and initiate appropriate treatment.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hypersensitivity reactions including anaphylaxis [see Warnings and Precautions (5.3) ] The most common adverse events (regardless of causality) occurring in ≥1% of the XOCOVA group and at a greater frequency compared to placebo were headache, diarrhea, and cough. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Shionogi Inc. at 1-800-849-9707 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The overall safety profile of XOCOVA is based on data from 2,831 adults and adolescents exposed to the recommended dosage and duration of XOCOVA in controlled clinical trials. Trial SCORPIO-PEP was a randomized, double-blind, placebo-controlled trial in which 1,190 subjects received oral XOCOVA (375 mg [Day 1]/125 mg [Days 2-5]) and 1,187 subjects received oral placebo (Days 1-5). The most common adverse events (regardless of causality) occurring in ≥1% of the XOCOVA group and at a greater frequency compared to placebo were headache (2.9% and 2.6%, respectively), diarrhea (1.7% and 1.3%, respectively), and cough (1.1% and 0.6%, respectively). The proportion of subjects who discontinued study intervention due to an adverse event was <0.1% in both the XOCOVA and placebo groups. Laboratory Abnormalities: Asymptomatic hemoglobin declines from baseline of >2 g/dL occurred in 3% of XOCOVA recipients versus 1% of placebo recipients. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of XOCOVA outside of the United States. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune system disorders: Anaphylaxis (including anaphylactic shock), angioedema, hypersensitivity, urticaria