Ensitrelvir

XOCOVA is indicated for post-exposure prophylaxis of coronavirus disease 2019 (COVID-19) in adults and adolescents 12 years of age and older following contact with an individual who has COVID-19. XOCOVA, a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (M pro : also referred to as 3CL pro or nsp5 protease) inhibitor, is indicated for post-exposure prophylaxis of coronavirus disease 2019 (COVID‑19) in adults and adolescents 12 years of age and older following contact with an individual who has COVID-19. ( 1 )

Tablets: white to light yellow-white, round tablets containing 125 mg of ensitrelvir, debossed with the Shionogi trademark ( ) above the identifier code "711" on one side and with a "125" on the other side. Tablets: 125 mg of ensitrelvir ( 3 ) Image

XOCOVA is contraindicated in patients with a history of clinically significant hypersensitivity reactions to ensitrelvir or any other components of the product. XOCOVA is contraindicated in patients taking drugs that are: Primarily metabolized by CYP3A for which elevated concentrations may be associated with serious and/or life-threatening reactions [see Drug Interactions (7.3) ] and Strong CYP3A inducers because they may significantly reduce ensitrelvir plasma concentrations, leading to the potential loss of virologic response [see Drug Interactions (7.3) ] . History of clinically significant hypersensitivity reactions to ensitrelvir or any other components of the product. ( 4 ) Co-administration with drugs primarily metabolized by CYP3A for which elevated concentrations may be associated with serious and/or life-threatening reactions. ( 4 , 7.3 ) Co-administration with strong CYP3A inducers considered to significantly reduce ensitrelvir plasma concentrations and may be associated with the potential for loss of virologic response. ( 4 , 7.3 )

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.

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

Co-administration of XOCOVA can alter the plasma concentrations of other drugs, and other drugs may alter the plasma concentrations of XOCOVA. Consider the potential for drug interactions prior to and during XOCOVA use and review concomitant medications during XOCOVA use. ( 4 , 5.2 , 7 , 12.3 )

7.1 Potential for XOCOVA to Affect Other Drugs Ensitrelvir is a strong inhibitor of CYP3A and an inhibitor of P-gp and BCRP. Co-administration of XOCOVA with drugs that are primarily metabolized by CYP3A or are transported by P-gp or BCRP may result in increased plasma concentrations of such drugs and increase the risk of adverse events [see Contraindications (4) , Warnings and Precautions (5.2) , Drug Interactions (7.3) , and Clinical Pharmacology (12.3) ] . For drugs that are CYP3A substrates and contraindicated with XOCOVA, initiation of XOCOVA should be considered only after careful evaluation of relevant clinical and pharmacokinetic factors related to the concomitant medication. In addition, re-initiation of contraindicated CYP3A substrates should be considered based on an assessment of the duration of CYP3A inhibition and patient‑specific considerations. Refer to individual drug prescribing information for additional information.

7.2 Potential for Other Drugs to Affect XOCOVA Ensitrelvir is a CYP3A substrate; therefore, drugs that induce CYP3A may decrease ensitrelvir plasma concentrations and reduce XOCOVA therapeutic effect [see Drug Interactions (7.3) and Clinical Pharmacology (12.3) ] . Therefore, use of XOCOVA with strong CYP3A4 inducers is contraindicated [see Contraindications (4) ] . No dose adjustment is recommended when XOCOVA is used concomitantly with moderate or weak CYP3A inducers [see Warnings and Precautions (5.2) ] . Refer to individual drug prescribing information for additional information.

7.3 Established and Other Potentially Significant Drug Interactions Table 1 provides examples of drugs that are contraindicated with XOCOVA [see Contraindications (4) and Warnings and Precautions (5.2) ] . Table 1 is provided as a guide and is not a comprehensive list of all possible drugs that may interact with XOCOVA. The healthcare provider should consult other appropriate resources, such as the prescribing information for the interacting drug, for comprehensive information on dosing and monitoring with concomitant use of a strong CYP3A inhibitor, like XOCOVA [see Drug Interactions (7.1) ]. Table 1 Drugs Contraindicated with XOCOVA due to Risk of Potentially Serious or Fatal Interaction [see Contraindications (4) ] Drug Class Drug(s) within Class Effect on Drug Concentration Clinical Comment Antiarrhythmics quinidine ↑ antiarrhythmic Co-administration is contraindicated due to potential for cardiac arrhythmias. Anticancer drugs apalutamide, enzalutamide ↓ ensitrelvir Co-administration is contraindicated due to potential loss of virologic response. Anticonvulsants carbamazepine See Clinical Pharmacology (12.3) , phenytoin ↓ ensitrelvir Co-administration is contraindicated due to potential loss of virologic response. Antigout agents colchicine ↑ colchicine Co-administration is contraindicated due to potential for serious and/or life-threatening reactions in patients with renal and/or hepatic impairment. Antimycobacterials rifampin ↓ ensitrelvir Co-administration is contraindicated due to potential loss of virologic response. Antipsychotics lurasidone, pimozide ↑ lurasidone, pimozide Co-administration is contraindicated due to serious and/or life-threatening reactions, such as cardiac arrhythmias. Cardiovascular drugs eplerenone, ivabradine ↑ eplerenone, ivabradine Co-administration is contraindicated. Cystic fibrosis transmembrane conductance regulator potentiators lumacaftor/ivacaftor ↓ ensitrelvir Co-administration is contraindicated due to potential loss of virologic response. Ergot derivatives dihydroergotamine, ergotamine, methylergonovine ↑ dihydroergotamine, ergotamine, methylergonovine Co-administration is contraindicated due to potential for acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues, including the central nervous system. Herbal products (for depression) St. John's wort ↓ ensitrelvir Co-administration is contraindicated due to potential loss of virologic response. HMG-CoA reductase inhibitors (statins) simvastatin ↑ simvastatin Co-administration is contraindicated. Discontinue use of simvastatin at least 12 hours prior to initiation of XOCOVA. Immunosuppressants voclosporin ↑ voclosporin Co-administration is contraindicated due to potential for acute and/or chronic nephrotoxicity. Microsomal triglyceride transfer protein (MTTP) inhibitors lomitapide ↑ lomitapide Co-administration is contraindicated due to potential for hepatotoxicity and gastrointestinal adverse reactions. Mineralocorticoid receptor antagonists finerenone ↑ finerenone Co-administration is contraindicated due to potential for serious adverse reactions, including hyperkalemia, hypotension, and hyponatremia. Sedatives triazolam ↑ triazolam Co-administration is contraindicated.

Lactation: Advise not to breastfeed during XOCOVA use and for 2 weeks after the final dose. ( 8.2 )

8.1 Pregnancy Risk Summary Based on animal reproduction studies, XOCOVA may cause fetal harm when administered to a pregnant woman. Embryofetal toxicity (including skeletal malformations and embryofetal lethality) was observed in rabbits during the period of organogenesis at ensitrelvir exposures 7 times the human exposures at the recommended human dose (RHD). In rats, fetal growth retardation, low fetal body weight, and skeletal variations were observed during the period of organogenesis at ensitrelvir exposures 9 times the RHD. In addition, lethality, low body weight, and retardation of morphological development were observed in pre-weaning pups during gestation and lactation at ensitrelvir exposures 9 times the RHD (see Data ) . Advise pregnant women and females of reproductive potential that XOCOVA may cause fetal harm. The available clinical data on the use of XOCOVA during pregnancy are insufficient to identify a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a risk of birth defects, loss, and other adverse outcomes. In the general population in the United States, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In an embryofetal development study in pregnant rabbits, ensitrelvir was administered at oral doses of 30, 100, or 300 mg/kg/day on gestation days (GD) 6-19. Embryofetal lethality, skeletal malformations and variations, abortion, and post-implantation loss were observed with maternal toxicity (decreased food consumption and body weight and body weight gain) at doses ≥100 mg/kg/day. Malformations of the axial skeleton included fused sternebra, branched rib, fused cervical centrum, supernumerary thoracic vertebra, fused thoracic arch, and fused caudal centrum. Skeletal variations included splitting of the thoracic centrum and increased frequencies of full supernumerary rib and/or supernumerary lumbar vertebra. No effects were observed at 30 mg/kg/day, which is estimated to be 3 times the human exposure at the RHD based on the area under the curve (AUC). In a second embryofetal development study in pregnant rabbits, ensitrelvir was administered at 300 mg/kg/day on GD 6-9, 10-12, 13-15, and 16-19. Similar malformations of the axial skeleton were observed, with most of the abnormalities present in animals dosed on GD 6-9; maternal toxicity (presenting as low food consumption) was also present during each segmented dosing period. In an embryofetal development study in pregnant rats, ensitrelvir was administered at oral doses of 20, 60, or 1000 mg/kg/day on GD 6-17. A delay in fetal development (as measured by decreased bone ossification and fetal body weight), as well as an increased incidence of short supernumerary rib, were observed at 1000 mg/kg/day. Decreased food consumption and body weight were also observed at this dose. No effects were observed at 60 mg/kg/day, which is estimated to be 5 times the human exposure at the RHD based on AUC. In a pre- and postnatal development study, ensitrelvir was administered to pregnant rats at oral doses of 20, 60, or 1000 mg/kg/day from GD 6 to postnatal day (PND) 20. Lethality, low body weight, and retardation of morphological development (delayed eyelid opening and sexual maturation) were observed at the highest dose of 1000 mg/kg/day, accompanied by maternal toxicity (total litter loss, decreased body weight and body weight gain, and decreased food consumption). No effects were observed at 60 mg/kg/day, which is estimated to be 5 times the human exposure at the RHD based on AUC.

8.2 Lactation Risk Summary There are no data on the presence of ensitrelvir in human milk, the effects on the breastfed infant, or the effects on milk production. Ensitrelvir was present in the milk of lactating rats (see Data ) . When a drug is present in animal milk, it is likely that the drug will be present in human milk. Due to the potential for adverse effects in a breastfed child from XOCOVA, advise lactating women not to breastfeed while taking XOCOVA and for at least 2 weeks after the final dose [see Use in Specific Populations (8.4) ] . Data In rats, ensitrelvir was excreted into the milk of lactating rats following a single oral administration of 2 mg/kg. Milk concentrations of ensitrelvir were approximately 2 times that of maternal plasma concentrations, observed 4 hours post-dose. The concentration of ensitrelvir in animal milk does not necessarily predict the concentration of ensitrelvir in human milk.

8.3 Females and Males of Reproductive Potential Based on animal data, XOCOVA may cause fetal harm when administered to pregnant women [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1) ] . Pregnancy Testing Verify pregnancy status of females of reproductive potential prior to initiating XOCOVA. Contraception Females Advise females of reproductive potential to use effective contraception during use of XOCOVA and for 2 weeks after the final dose.

8.4 Pediatric Use The safety and effectiveness of XOCOVA for the post-exposure prophylaxis of COVID-19 in adolescents is supported by results of SCORPIO-PEP, an adequate and well-controlled trial that enrolled adults and adolescents ≥12 years of age. Of the 139 adolescents enrolled in this trial, 72 received XOCOVA. The safety of XOCOVA in adolescents is further supported by data from 16 adolescents who received XOCOVA in another clinical trial. No overall differences in safety, pharmacokinetics, or efficacy of XOCOVA were observed between adolescents and adults [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.1) ] . The safety and effectiveness of XOCOVA have not been established in pediatric patients less than 12 years of age. Juvenile Animal Toxicity Data In a juvenile toxicology study in rats, ensitrelvir was administered orally at 0, 10, 30 or 90 mg/kg for 8 or 9 days, from PND 4-11 or PND 12-20, respectively (PND 4-20 in rats is equivalent to approximately 0 to 2 years in humans). Femur bone shortening (accompanied by decreased body weight) was observed in rats dosed from PND 4-11 at 90 mg/kg, which is estimated to be 14 times the human exposure at the recommended human dose (RHD) in adults based on AUC. These effects were not observed in animals dosed from PND 4-11 with 90 mg/kg followed by a 41-day dose-free period. No effects were observed at 30 mg/kg for animals dosed from PND 4-11, which is estimated to be 8 times the human exposure at the RHD in adults. No effects were observed at 90 mg/kg for animals dosed from PND 12-20, which is estimated to be 12 times the human exposure at the RHD in adults. In another juvenile toxicology study in rats, ensitrelvir was administered orally at 0, 30, 90 or 1000 mg/kg for 8 days from PND 21-28 or PND 29-36, or 9 days from PND 37-45 (PND 21-45 in rats is equivalent to approximately 2 to 12 years in humans). Femur bone shortening (accompanied by decreased body weight and food consumption) was observed in rats dosed from PND 21-28 at 1000 mg/kg which is estimated to be 11 times the human exposure at the RHD in adults based on AUC. These effects were not observed in animals dosed from PND 21-28 with 1000 mg/kg followed by a 22-day dose-free period. No effects were observed at 90 mg/kg, which is estimated to be 6 times the human exposure at the RHD in adults. No effects were observed at 1000 mg/kg for animals dosed from PND 29-36 or PND 37-45, which is estimated to be approximately 10 times the human exposure at the RHD in adults. […]

Ensitrelvir is a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antiviral drug [see Microbiology (12.4) ].