XOFLUZA

Baloxavir marboxil is an influenza virus PA endonuclease inhibitor. The active component of XOFLUZA is baloxavir marboxil. The chemical name of baloxavir marboxil is ({(12aR)-12-[(11S)-7,8-Difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl]-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl}oxy)methyl methyl carbonate. The empirical formula of baloxavir marboxil is C 27 H 23 F 2 N 3 O 7 S, and the chemical structure is shown below. Baloxavir marboxil has a molecular mass of 571.55 grams per mole and a partition coefficient (log P) of 2.26. It is freely soluble in dimethylsulfoxide, soluble in acetonitrile, slightly soluble in methanol and ethanol, and practically insoluble in water. XOFLUZA is supplied as tablets and for oral suspension (in packets and in bottles). XOFLUZA tablets are white to light yellow, film-coated for oral administration . The 40 mg film-coated tablet contains 40 mg of baloxavir marboxil, and the 80 mg film-coated tablet contains 80 mg of baloxavir marboxil. The inactive ingredients of XOFLUZA tablets are: croscarmellose sodium, hypromellose, lactose monohydrate, microcrystalline cellulose, povidone K25, sodium stearyl fumarate, talc, and titanium dioxide. XOFLUZA for oral suspension (packets) is supplied as white to light yellow granules in a packet. Each packet contains either 30 mg or 40 mg of baloxavir marboxil. The granules must be reconstituted in about 15 to 20 mL of room temperature drinking water. The inactive ingredients are: hypromellose, maltitol, mannitol, povidone K25, silicon dioxide, sodium chloride, strawberry flavor, sucralose, and talc. XOFLUZA for oral suspension (bottles) is supplied as white to light yellow granules in an amber glass bottle. Each bottle contains 40 mg (nominal) of baloxavir marboxil. The granules must be reconstituted with 20 mL of drinking water or sterile water to yield a 2 mg/mL greyish white, white to light yellow opaque suspension with strawberry flavor. The inactive ingredients are: hypromellose, maltitol, mannitol, povidone K25, silicon dioxide, sodium chloride, strawberry flavor, sucralose, and talc. Chemical Structure

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) ] .

Treatment and Post-Exposure Prophylaxis of Influenza Take XOFLUZA as a single dose as soon as possible and within 48 hours of influenza symptom onset for treatment of acute uncomplicated influenza or following contact with an individual who has influenza. XOFLUZA may be taken with or without food. ( 2.1 , 2.2 ) Patient Body Weight Recommended Single Oral Dose in Patients 5 Years of Age and Older (Tablets) 20 kg to less than 80 kg One 40 mg tablet (blister card contains one 40 mg tablet) At least 80 kg One 80 mg tablet (blister card contains one 80 mg tablet) Patient Body Weight Recommended Single Oral Dose in Patients 5 Years of Age and Older For Oral Suspension (Packets) 15 kg to less than 20 kg One 30 mg packet 20 kg to less than 80 kg One 40 mg packet At least 80 kg 80 mg (two 40 mg packets) Patient Body Weight Recommended Single Oral Dose in Patients 5 Years of Age and Older For Oral Suspension (Bottles) Less than 20 kg 2 mg/kg 20 kg to less than 80 kg 40 mg (20 mL) At least 80 kg 80 mg (40 mL) Refer to the Full Prescribing Information for additional information on the recommended dosage and preparation of XOFLUZA for oral suspension (bottles) or for oral suspension (packets) for both for oral or enteral use in patients 5 years of age and older. ( 2.2 , 2.3 ) 2.1 Dosage and Administration Overview XOFLUZA is available in two dosage forms: XOFLUZA tablets (40 mg and 80 mg). XOFLUZA for oral suspension is available in two different presentations: packets (30 mg and 40 mg) and bottles (2 mg/mL). If the patient weighs less than 15 kg, XOFLUZA for oral suspension in bottle is the recommended presentation. Both presentations of the for oral suspension are intended for patients who are unable to or have difficulty swallowing tablets, or those who require enteral administration [see Dosage and Administration (2.2 , 2.3 , 2.4) ] . Take XOFLUZA as soon as possible after influenza symptom onset or exposure to influenza [see Dosage and Administration (2.2) ] . XOFLUZA may be taken with or without food. However, concomitant use of XOFLUZA with dairy products, calcium-fortified beverages, polyvalent cation-containing laxatives, antacids, or oral supplements (e.g., calcium, iron, magnesium, selenium, or zinc) should be avoided [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ]. 2.2 Recommended Dosage Treatment of Acute Uncomplicated Influenza or Post-Exposure Prophylaxis in Adults, and Pediatric Patients (5 Years of Age and Older) Take XOFLUZA as a single dose as soon as possible and within 48 hours of influenza symptom onset for treatment of acute uncomplicated influenza or following contact with an individual who has influenza. The recommended dosage of XOFLUZA in patients 5 years of age or older is a single weight-based dose displayed in Tables 1 , 2 and 3 . Table 1 XOFLUZA Tablets: Recommended Dosage in Adults and Pediatric Patients 5 Years of Age and Older Patient Body Weight Recommended Single Oral Dose (Tablets) Recommended XOFLUZA dosage is based on the patient's weight. 20 kg to less than 80 kg One 40 mg tablet (blister card contains one 40 mg tablet) At least 80 kg One 80 mg tablet (blister card contains one 80 mg tablet) Table 2 XOFLUZA for Oral Suspension (Packets): Recommended Dosage in Adults and Pediatric Patients 5 Years of Age and Older Patient Body Weight Recommended Single Oral Dose (Packets) Recommended XOFLUZA dosage is based on the patient's weight. 15 kg Patients who weigh less than 15 kg should receive XOFLUZA for oral suspension (bottles). to less than 20 kg One 30 mg packet 20 kg to less than 80 kg One 40 mg packet At least 80 kg 80 mg (two 40 mg packets) Table 3 XOFLUZA for Oral Suspension (Bottles): Recommended Dosage in Adults and Pediatric Patients 5 Years of Age and Older Patient Body Weight Recommended Single Oral Dose Recommended XOFLUZA dosage is based on the patient's weight. , Use a measuring device (oral syringe) to measure the prescribed dose for use. (For Oral Suspension in Bottles) Less than 20 kg 2 mg/kg 20 kg to less than 80 kg 40 mg (20 mL) At least 80 kg 80 mg (40 mL Dosage requires two bottles of XOFLUZA for oral suspension. ) 2.3 Preparation of XOFLUZA for Oral Suspension (Packets) by Patient or Caregiver See the XOFLUZA for oral suspension (packets) Instructions for Use for details on the preparation and administration (oral or via enteral feeding tube). For the 30 mg or 40 mg dose, mix in a small container with 1 tablespoon (about 15-20 mL) of room temperature drinking water. Once the supplied XOFLUZA for oral suspension (packets) have fully dispersed in the drinking water, take the entire mixture immediately. For the 80 mg dose, use two 40 mg packets. Prepare each packet as described above for the 40 mg dose and take the packets separately. For enteral administration (i.e., feeding tube), draw up the entire contents with an enteral syringe and administer through a tube that is 4 French or larger. Flush with 1 mL of water before and after enteral administration. 2.4 Preparation of XOFLUZA for Oral Suspension (Bottles) by Healthcare Provider Prior to dispensing to the patient, reconstitute XOFLUZA for oral suspension (bottles) with 20 mL of drinking water or sterile water. After reconstitution, each bottle of XOFLUZA for oral suspension (bottles) contains 40 mg of baloxavir marboxil per 20 mL of volume for a final concentration of 2 mg/mL. The for oral suspension (bottles) can be used for oral or enteral use. Only take the contents of the full bottle(s) of XOFLUZA for oral suspension (bottles) with the use of a measuring device (oral syringe). Ensure the caregiver or patient uses an oral syringe to measure the prescribed dose of XOFLUZA for oral suspension (bottles). Patients may need to draw up XOFLUZA for oral suspension (bottles) multiple times using the oral syringe to receive the full dose. Reconstituting XOFLUZA for Oral Suspension (Bottles) Prepare the for oral suspension (bottles) at the time of dispensing. Administration must occur within 10 hours after reconstitution because this product does not contain a preservative. Gently tap the bottom of the bottle to loosen the granules. Reconstitute XOFLUZA for oral suspension (bottles) with 20 mL of drinking water or sterile water. Gently swirl the suspension to ensure that the granules are evenly suspended. Do not shake. Write the expiration time and date on the bottle label in the space provided (10 hours from reconstitution time). Important Information for the Healthcare Provider Provide caregiver or patient with a measuring device (oral syringe) to deliver the prescribed dose of the for suspension for oral use (bottles). For enteral administration (i.e., feeding tube), draw up for oral suspension (bottles) with an enteral syringe and administer through a tube that is 4 French or larger. Flush with 1 mL of water before and after enteral administration. Instruct the caregiver or patient that the total prescribed dose of XOFLUZA for oral suspension (bottles) may require: Less than one bottle (e.g., for pediatric patients 5 years of age and older who weigh less than 20 kg) One bottle (e.g., for adults and adolescents weighing 20 kg to less than 80 kg), or Two bottles (e.g., for adults and adolescents weighing at least 80 kg).

XOFLUZA is contraindicated in patients with a history of hypersensitivity to baloxavir marboxil or any of its ingredients. Serious allergic reactions have included anaphylaxis, angioedema, urticaria, and erythema multiforme [see Warnings and Precautions (5.1) ]. XOFLUZA is contraindicated in patients with a history of hypersensitivity to baloxavir marboxil or any of its ingredients. ( 4 )

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

Avoid coadministration of XOFLUZA with dairy products, calcium-fortified beverages, polyvalent cation-containing laxatives, antacids, or oral supplements (e.g., calcium, iron, magnesium, selenium, or zinc). ( 2.1 , 7.1 ) Live attenuated influenza vaccines may be affected by antivirals. ( 7.2 ) 7.1 Effect of Other Drugs on XOFLUZA Baloxavir may form a chelate with polyvalent cations such as calcium, aluminum, or magnesium. Coadministration with polyvalent cation-containing products may decrease plasma concentrations of baloxavir [see Clinical Pharmacology (12.3) ], which may reduce XOFLUZA efficacy. Avoid coadministration of XOFLUZA with dairy products, calcium-fortified beverages, polyvalent cation-containing laxatives, antacids, or oral supplements (e.g., calcium, iron, magnesium, selenium, or zinc). 7.2 Vaccines The concurrent use of XOFLUZA with intranasal live attenuated influenza vaccine (LAIV) has not been evaluated. Concurrent administration of antiviral drugs may inhibit viral replication of LAIV and thereby decrease the effectiveness of LAIV vaccination. Interactions between inactivated influenza vaccines and XOFLUZA have not been evaluated.

Storage: Store tablets in their blister package at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Storage: Store granules (bottles) at 20°C to 25°C (68°F to 77°F) and keep in the original bottle; excursions are permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature] . Store reconstituted suspension no longer than 10 hours at 20°C to 25°C (68°F to 77°F) when reconstituted with drinking water or sterile water. The suspension must be discarded if not used within 10 hours of preparation or if suspension has been stored above 25°C (77°F).