Baloxavir Marboxil

1 INDICATIONS AND USAGE XOFLUZA is an influenza virus polymerase acidic (PA) endonuclease inhibitor indicated for: Treatment of acute uncomplicated influenza in patients 5 years of age and older who have been symptomatic for no more than 48 hours and who are otherwise healthy or at high risk of developing influenza-related complications . ( 1.1 ) Post-exposure prophylaxis of influenza in patients 5 years of age and older following contact with an individual who has influenza. ( 1.2 ) Limitations of Use Influenza viruses change over time, and factors such as the virus type or subtype, emergence of resistance, or changes in viral virulence could diminish the clinical benefit of antiviral drugs. Consider available information on drug susceptibility patterns for circulating influenza virus strains when deciding whether to use XOFLUZA. ( 1.3 ) 1.1 Treatment of Influenza XOFLUZA is indicated for treatment of acute uncomplicated influenza in patients 5 years of age and older who have been symptomatic for no more than 48 hours and who are otherwise healthy or at high risk of developing influenza-related complications 1 [see Clinical Studies (14.1 , 14.2 , and 14.3 ]. 1.2 Post-Exposure Prophylaxis of Influenza XOFLUZA is indicated for post-exposure prophylaxis of influenza in persons 5 years of age and older following contact with an individual who has influenza [see Clinical Studies (14.4) ]. 1.3 Limitations of Use Influenza viruses change over time, and factors such as the virus type or subtype, emergence of resistance, or changes in viral virulence could diminish the clinical benefit of antiviral drugs. Consider available information on drug susceptibility patterns for circulating influenza virus strains when deciding whether to use XOFLUZA [see Warnings and Precautions (5.2) , Microbiology (12.4) and Clinical Studies (14) ] .

5 WARNINGS AND PRECAUTIONS Hypersensitivity such as anaphylaxis, angioedema, urticaria, and erythema multiforme: Initiate appropriate treatment if an allergic-like reaction occurs or is suspected. ( 5.1 ) Increased incidence of Treatment-Emergent Resistance in Patients Less Than 5 Years of Age: XOFLUZA is not indicated in patients less than 5 years of age due to increased incidence of treatment-emergent resistance in this age group . In clinical trials, incidence of virus with treatment-emergent substitutions associated with reduced susceptibility to baloxavir (resistance) was higher in pediatric subjects younger than 5 years of age than older subjects. ( 5.2 ) Risk of bacterial infection: Serious bacterial infections may begin with influenza-like symptoms or may coexist with, or occur as, a complication of influenza. XOFLUZA has not been shown to prevent such complications. Prescribers should be alert to potential secondary bacterial infections and treat them as appropriate. ( 5.3 ) 5.1 Hypersensitivity Cases of anaphylaxis, urticaria, angioedema, and erythema multiforme have been reported in postmarketing experience with XOFLUZA. Appropriate treatment should be instituted if an allergic-like reaction occurs or is suspected. The use of XOFLUZA is contraindicated in patients with known hypersensitivity to XOFLUZA [see Contraindications (4) and Adverse Reactions (6.2) ]. 5.2 Increased Incidence of Treatment-Emergent Resistance in Patients Less Than 5 Years of Age XOFLUZA is not indicated in patients less than 5 years of age due to increased incidence of treatment-emergent resistance in this age group. In clinical trials, the incidence of virus with treatment-emergent substitutions associated with reduced susceptibility to baloxavir (resistance) was higher in pediatric subjects younger than 5 years of age (40%, 38/96) than in pediatric subjects ≥ 5 years to < 12 years of age (16%, 19/117) or subjects ≥ 12 years of age (7%, 60/842). The potential for transmission of resistant strains in the community has not been determined [see Indications and Usage (1) , Use in Specific Populations (8.4) , and Microbiology (12.4) ]. 5.3 Risk of Bacterial Infections There is no evidence of efficacy of XOFLUZA in any illness caused by pathogens other than influenza viruses. Serious bacterial infections may begin with influenza-like symptoms or may coexist with, or occur as, a complication of influenza. XOFLUZA has not been shown to prevent such complications. Prescribers should be alert to potential secondary bacterial infections and treat them as appropriate.

6 ADVERSE REACTIONS Adverse events reported in at least 1% of adult and adolescent influenza subjects treated with XOFLUZA included diarrhea (3%), bronchitis (3%), nausea (2%), sinusitis (2%), and headache (1%). ( 6.1 ) Adverse events reported in at least 5% of pediatric subjects (5 to < 12 years) treated with XOFLUZA included vomiting (5%) and diarrhea (5%). To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 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 XOFLUZA is based on data from 2,079 subjects, 5 years of age and older in 5 controlled clinical trials who received XOFLUZA. Of these subjects, 1,943 were adults and adolescents (≥ 12 years of age) and 136 were in the pediatric age group (5 to < 12 years of age) [see Clinical Studies (14) ] . Treatment of Acute Uncomplicated Influenza Adult and Adolescent Subjects (≥ 12 Years of Age): The safety of XOFLUZA in adult and adolescent subjects is based on data from 3 placebo-controlled trials in which a total of 1,640 subjects received XOFLUZA: 1,334 (81%) subjects were 18 to 64 years of age, 209 (13%) subjects were adults 65 years of age or older, and 97 (6%) subjects were adolescents 12 to 17 years of age. These trials included otherwise healthy adults and adolescents (N=910) and subjects at high risk of developing complications associated with influenza (N=730). Of these, 1,440 subjects received XOFLUZA at the recommended dose [see Clinical Studies (14.1 , 14.2) ]. Trial T0821 was a phase 2 dose-finding placebo-controlled trial where otherwise healthy adult subjects 20 to 64 years of age received single oral dose of XOFLUZA or placebo. Trial T0831 was a placebo- and active-controlled trial in otherwise healthy adults and adolescents 12 to 64 years of age; subjects received weight-based XOFLUZA or placebo as a single oral dose on Day 1 or oseltamivir twice a day for 5 days. Trial T0832 was a randomized, double-blind, placebo- and active-controlled trial where adults and adolescents at high risk of influenza complications 12 years of age and older received either XOFLUZA, placebo or oseltamivir. Table 4 displays the most common adverse events (regardless of causality assessment) reported in at least 1% of adult and adolescent subjects who received XOFLUZA at the recommended dose in Trials T0821, T0831, and T0832. Table 4 Incidence of Adverse Events Occurring in at Least 1% of Adult and Adolescent Subjects Receiving XOFLUZA in the Acute Uncomplicated Influenza Trials T0821, T0831, and T0832 Adverse Event XOFLUZA (N=1,440) Placebo (N=1,136) Diarrhea 3% 4% Bronchitis 3% 4% Nausea 2% 3% Sinusitis 2% 3% Headache 1% 1% Pediatric Subjects (5 to < 12 Years of Age): In an active-controlled, double-blind trial Trial CP40563 in pediatric subjects, a total of 79 subjects 5 to less than 12 years of age, received the recommended weight-based dosage of XOFLUZA, and 39 subjects received oseltamivir. Of the 118 subjects 5 to less than 12 years of age in Trial CP40563, 15 subjects in the XOFLUZA arm and 4 subjects in the oseltamivir arm were at high risk of developing influenza complications. The most frequently reported AEs (≥ 5%) in all subjects in the XOFLUZA treatment arm were vomiting (5%) and diarrhea (5%). Vomiting was reported in 18% of subjects in the oseltamivir arm [see Clinical Studies (14.3 ]. There are limited safety data in patients 5 to <12 years at high risk of developing influenza complications. Post-Exposure Prophylaxis of Influenza In a placebo-controlled clinical trial, Trial T0834, conducted in adults, and pediatric subjects ≥ 5 years of age, a total of 360 subjects received XOFLUZA, of which 291 (81%) were adults ≥ 18 years; 12 (3%) subjects were adolescents ≥ 12 to 17 years and 57 (16%) were pediatric subjects 5 to < 12 years of age. The safety profile was similar in pediatric patients aged 5 to < 12 years old as that reported in adults and adolescents 12 years of age and older [see Clinical Studies (14.4) ]. 6.2 Postmarketing Experience The following adverse reactions have been identified during postmarketing use of XOFLUZA. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to XOFLUZA exposure. Immune System Disorders: Anaphylactic reactions, anaphylactic shock, anaphylactoid reactions, hypersensitivity reactions, angioedema (swelling of face, eyelids, tongue and lips) Skin and Subcutaneous Tissue Disorders: Rash, urticaria, erythema multiforme Gastrointestinal Disorders: Vomiting, hematochezia, melena, colitis Psychiatric Disorders: Delirium, abnormal behavior, hallucinations

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies with XOFLUZA in pregnant women to inform a drug-associated risk of adverse developmental outcomes. There are risks to the mother and fetus associated with influenza virus infection in pregnancy (see Clinical Considerations ). In animal reproduction studies, no adverse developmental effects were observed in rats or rabbits with oral administration of baloxavir marboxil at exposures approximately 5 (rats) and 7 (rabbits) times the systemic baloxavir exposure at the maximum recommended human dose (MRHD) (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%–4% and 15%–20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Pregnant women are at higher risk of severe complications from influenza, which may lead to adverse pregnancy and/or fetal outcomes, including maternal death, stillbirth, birth defects, preterm delivery, low birth weight, and small for gestational age. Data Animal Data Baloxavir marboxil was administered orally to pregnant rats (20, 200, or 1,000 mg/kg/day from gestation day 6 to 17) and rabbits (30, 100, or 1,000 mg/kg/day from gestation day 7 to 19). No adverse embryo-fetal effects were observed in rats up to the highest dose of baloxavir marboxil (1,000 mg/kg/day), resulting in systemic baloxavir exposure (AUC) of approximately 5 times the exposure at the MRHD. In rabbits, fetal skeletal variations occurred at a maternally toxic dose (1,000 mg/kg/day) resulting in 2 abortions out of 19 pregnancies. No adverse maternal or embryo-fetal effects were observed in rabbits at the middle dose (100 mg/kg/day) resulting in systemic baloxavir exposure (AUC) approximately 7 times the exposure at the MRHD. In the prenatal and postnatal development study in rats, baloxavir marboxil was administered orally at 20, 200, or 1,000 mg/kg/day from gestation day 6 to postpartum/lactation day 20. No significant effects were observed in the offspring at maternal systemic baloxavir exposure (AUC) approximately 5 times the exposure at the MRHD. 8.2 Lactation Risk Summary There are no data on the presence of baloxavir marboxil in human milk, the effects on the breastfed infant, or the effects on milk production. Baloxavir and its related metabolites were present in the milk of lactating rats (see Data ) . The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for XOFLUZA and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition. Data In a lactation study, baloxavir and its related metabolites were excreted in the milk of lactating rats administered baloxavir marboxil (1 mg/kg) on postpartum/lactation day 11, with peak milk concentration approximately 5 times that of maternal plasma concentrations occurring 2 hours post-dose. No effects of baloxavir marboxil on growth and postnatal development were observed in nursing pups at the highest oral dose tested in rats. Maternal systemic exposure was approximately 5 times the baloxavir exposure in humans at the MRHD. 8.4 Pediatric Use Treatment of Acute Uncomplicated Influenza in Adolescent Subjects (≥ 12 Years of Age) The safety and effectiveness of XOFLUZA for the treatment of acute uncomplicated influenza in adolescent subjects 12 years of age and older weighing at least 40 kg is supported by one randomized, double-blind, controlled trial in otherwise healthy subjects Trial T0831 and one trial in subjects at high risk of developing influenza-related complications Trial T0832 [see Clinical Studies (14.1) ]. A total of 117 otherwise healthy adolescents 12 to17 years of age were randomized and received either XOFLUZA (N=76) or placebo (N=41) in Trial T0831; 38 adolescents 12 to 17 years of age at high risk for influenza complications were randomized and received either XOFLUZA (N=21) or placebo (N=17) in Trial T0832. The median time to alleviation of symptoms in influenza-infected adolescent subjects aged 12 to 17 years in Trial T0831 was comparable to that observed in adults. In Trial T0832, the median time to improvement of symptoms in the limited number of influenza-infected adolescent subjects aged 12 to 17 years was similar in the XOFLUZA and placebo arms [see Clinical Studies (14.1) ]. Adverse events reported in adolescents in both trials were similar to those reported in adults [see Adverse Reactions (6.1) ]. Treatment of Acute Uncomplicated Influenza in Pediatric Subjects (5 to < 12 Years of Age) The safety and effectiveness of XOFLUZA in pediatric subjects 5 to less than 12 years of age is supported by one randomized, double-blind, controlled trial Trial CP40563 with a primary endpoint of safety. In this trial, 118 pediatric subjects were randomized and treated in a 2:1 ratio and received either XOFLUZA (N=79) or oseltamivir (N=39). Efficacy was extrapolated from adults and adolescents based on comparable PK exposures in adults, adolescents and pediatric subjects 5 to less than 12 years of age. The median time to alleviation of signs and symptoms in influenza-infected subjects was comparable in the XOFLUZA and oseltamivir arms. Adverse events reported with XOFLUZA in pediatric subjects were similar to those observed in adults and adolescents except for vomiting and diarrhea, which were both more commonly reported in pediatric subjects [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.1) ]. Post-Exposure Prophylaxis of Influenza in Pediatric and Adolescent Subjects (5 to < 18 Years of Age) The safety and effectiveness of XOFLUZA for post-exposure prophylaxis in pediatric and adolescent subjects 5 to less than 18 years of age is supported by one randomized, double-blind, controlled trial conducted in Japan Trial T0834 [see Clinical Studies (14.3) ]. Subjects in this trial were randomized in a 1:1 ratio to receive XOFLUZA or placebo. A total of 69 subjects from 5 to <18 years of age in Trial T0834 received XOFLUZA. The incidence of RT-PCR-confirmed symptomatic influenza in pediatric subjects 5 to <18 years of age was similar to that observed in adult subjects [see Clinical Pharmacology (12.3) , and Clinical Studies (14.3) ]. Efficacy was extrapolated from adults based on comparable PK exposures in adults, adolescents and pediatric subjects 5 to <18 years of age. Adverse events reported in pediatric and adolescent subjects were similar to those reported in adults in the same trial [see Adverse Reactions (6.1) ]. Pediatric Subjects (< 5 Years of Age) The safety and effectiveness of XOFLUZA for treatment and post-exposure prophylaxis of influenza in pediatric subjects less than 5 years of age, including neonates, have not been established [see Warnings and Precautions (5.2) and Microbiology (12.4) ]. 8.5 Geriatric Use The safety and effectiveness of XOFLUZA in subjects 65 years of age and older has been established and is supported by one randomized, double-blind, controlled trial [see Clinical Studies (14.2) ] . In Trial T0832, of 730 XOFLUZA-treated subjects at high risk of influenza-related complications, 209 (29%) subjects were 65 years of age and older. The median time to improvement of influenza symptoms in subjects 65 years of age and older was 70 hours in subjects who received XOFLUZA (N=112) and 88 hours in those who received placebo (N=102). The safety profile observed for this population was similar to that reported in the overall trial population except for nausea, which was reported in 6% of elderly subjects compared to 1% of subjects from 18 to 64 years of age.

8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies with XOFLUZA in pregnant women to inform a drug-associated risk of adverse developmental outcomes. There are risks to the mother and fetus associated with influenza virus infection in pregnancy (see Clinical Considerations ). In animal reproduction studies, no adverse developmental effects were observed in rats or rabbits with oral administration of baloxavir marboxil at exposures approximately 5 (rats) and 7 (rabbits) times the systemic baloxavir exposure at the maximum recommended human dose (MRHD) (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%–4% and 15%–20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Pregnant women are at higher risk of severe complications from influenza, which may lead to adverse pregnancy and/or fetal outcomes, including maternal death, stillbirth, birth defects, preterm delivery, low birth weight, and small for gestational age. Data Animal Data Baloxavir marboxil was administered orally to pregnant rats (20, 200, or 1,000 mg/kg/day from gestation day 6 to 17) and rabbits (30, 100, or 1,000 mg/kg/day from gestation day 7 to 19). No adverse embryo-fetal effects were observed in rats up to the highest dose of baloxavir marboxil (1,000 mg/kg/day), resulting in systemic baloxavir exposure (AUC) of approximately 5 times the exposure at the MRHD. In rabbits, fetal skeletal variations occurred at a maternally toxic dose (1,000 mg/kg/day) resulting in 2 abortions out of 19 pregnancies. No adverse maternal or embryo-fetal effects were observed in rabbits at the middle dose (100 mg/kg/day) resulting in systemic baloxavir exposure (AUC) approximately 7 times the exposure at the MRHD. In the prenatal and postnatal development study in rats, baloxavir marboxil was administered orally at 20, 200, or 1,000 mg/kg/day from gestation day 6 to postpartum/lactation day 20. No significant effects were observed in the offspring at maternal systemic baloxavir exposure (AUC) approximately 5 times the exposure at the MRHD.

8.4 Pediatric Use Treatment of Acute Uncomplicated Influenza in Adolescent Subjects (≥ 12 Years of Age) The safety and effectiveness of XOFLUZA for the treatment of acute uncomplicated influenza in adolescent subjects 12 years of age and older weighing at least 40 kg is supported by one randomized, double-blind, controlled trial in otherwise healthy subjects Trial T0831 and one trial in subjects at high risk of developing influenza-related complications Trial T0832 [see Clinical Studies (14.1) ]. A total of 117 otherwise healthy adolescents 12 to17 years of age were randomized and received either XOFLUZA (N=76) or placebo (N=41) in Trial T0831; 38 adolescents 12 to 17 years of age at high risk for influenza complications were randomized and received either XOFLUZA (N=21) or placebo (N=17) in Trial T0832. The median time to alleviation of symptoms in influenza-infected adolescent subjects aged 12 to 17 years in Trial T0831 was comparable to that observed in adults. In Trial T0832, the median time to improvement of symptoms in the limited number of influenza-infected adolescent subjects aged 12 to 17 years was similar in the XOFLUZA and placebo arms [see Clinical Studies (14.1) ]. Adverse events reported in adolescents in both trials were similar to those reported in adults [see Adverse Reactions (6.1) ]. Treatment of Acute Uncomplicated Influenza in Pediatric Subjects (5 to < 12 Years of Age) The safety and effectiveness of XOFLUZA in pediatric subjects 5 to less than 12 years of age is supported by one randomized, double-blind, controlled trial Trial CP40563 with a primary endpoint of safety. In this trial, 118 pediatric subjects were randomized and treated in a 2:1 ratio and received either XOFLUZA (N=79) or oseltamivir (N=39). Efficacy was extrapolated from adults and adolescents based on comparable PK exposures in adults, adolescents and pediatric subjects 5 to less than 12 years of age. The median time to alleviation of signs and symptoms in influenza-infected subjects was comparable in the XOFLUZA and oseltamivir arms. Adverse events reported with XOFLUZA in pediatric subjects were similar to those observed in adults and adolescents except for vomiting and diarrhea, which were both more commonly reported in pediatric subjects [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.1) ]. Post-Exposure Prophylaxis of Influenza in Pediatric and Adolescent Subjects (5 to < 18 Years of Age) The safety and effectiveness of XOFLUZA for post-exposure prophylaxis in pediatric and adolescent subjects 5 to less than 18 years of age is supported by one randomized, double-blind, controlled trial conducted in Japan Trial T0834 [see Clinical Studies (14.3) ]. Subjects in this trial were randomized in a 1:1 ratio to receive XOFLUZA or placebo. A total of 69 subjects from 5 to <18 years of age in Trial T0834 received XOFLUZA. The incidence of RT-PCR-confirmed symptomatic influenza in pediatric subjects 5 to <18 years of age was similar to that observed in adult subjects [see Clinical Pharmacology (12.3) , and Clinical Studies (14.3) ]. Efficacy was extrapolated from adults based on comparable PK exposures in adults, adolescents and pediatric subjects 5 to <18 years of age. Adverse events reported in pediatric and adolescent subjects were similar to those reported in adults in the same trial [see Adverse Reactions (6.1) ]. Pediatric Subjects (< 5 Years of Age) The safety and effectiveness of XOFLUZA for treatment and post-exposure prophylaxis of influenza in pediatric subjects less than 5 years of age, including neonates, have not been established [see Warnings and Precautions (5.2) and Microbiology (12.4) ].