These Highlights Do Not Include All The Information Needed To Use Xofluza Safely And Effectively. See Full Prescribing Information For Xofluza.

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.

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].

INSTRUCTIONS FOR USE

XOFLUZA^® (zoh-FLEW-zuh)

(baloxavir marboxil)

for oral suspension

This Instruction for Use contains information on how to prepare and take or give XOFLUZA for oral suspension in packets.

Read these Instructions for Use before preparing and taking or giving XOFLUZA for oral suspension. These Instructions for Use do not take the place of talking to your or your child's healthcare provider about your or your child's medical condition or treatment.

Important information you need to know before preparing and taking or giving XOFLUZA for oral suspension

• XOFLUZA is prescribed as a single, one-time dose.
• Wash your hands before and after preparing, taking, or giving XOFLUZA for oral suspension.
• XOFLUZA for oral suspension packets must be mixed with 1 tablespoon (about 15 to 20 mL) of room temperature drinking water.
• Take or give XOFLUZA for oral suspension right away after mixing.
• Check the expiration date and the product for damage before use. Do not use if expired or damaged.
• If you are prescribed the 80 mg dose of XOFLUZA for oral suspension, you will need to take two packets of 40 mg XOFLUZA, one at a time, until your full prescribed dose is taken.
• XOFLUZA for oral suspension can be taken by mouth or given through a feeding tube. Follow your healthcare provider's instructions for giving XOFLUZA through a feeding tube.

Your healthcare provider will prescribe XOFLUZA packets based on your or your child's weight. See the dosing chart below for the prescribed dose and number of XOFLUZA packets needed based on your or your child's weight.

Supplies needed to prepare and take or give XOFLUZA for oral suspension:

• your prescribed dose of XOFLUZA packets
• a tablespoon (about 15 to 20 mL) of room temperature drinking water in a container
• an enteral syringe (if giving XOFLUZA for oral suspension through a feeding tube).

Distributed by:

Genentech USA, Inc., A Member of the Roche Group

1 DNA Way, South San Francisco, CA 94080-4990

XOFLUZA® is a registered trademark of Genentech, Inc.

©2025 Genentech USA, Inc.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Issued: 05/2025

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.

Treatment of an overdose of XOFLUZA should consist of general supportive measures, including monitoring of vital signs and observation of the clinical status of the patient. There is no specific antidote for overdose with XOFLUZA.

Baloxavir is unlikely to be significantly removed by dialysis due to high serum protein binding [see Clinical Pharmacology (12.3)].

• "People at High-Risk for Flu Complications." Refer to U.S. Centers for Disease Control and Prevention "Influenza (Flu)" website.

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 C₂₇H₂₃F₂N₃O₇S, 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.

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.

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)].

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.

• 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)

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)].

Baloxavir marboxil is a prodrug that is almost completely converted to its active metabolite, baloxavir, following oral administration.

Baloxavir pharmacokinetic parameters are presented for healthy adults and adolescents as the mean [% coefficient of variation (%CV)], unless otherwise specified, in Table 5. Absorption, distribution, metabolism, and elimination data for XOFLUZA is presented in Table 6.

No clinically significant differences in the pharmacokinetics of baloxavir were observed based on age, sex, presence of risk factors for complicated influenza, creatinine clearance (CrCl: 50 mL/min and above), or moderate hepatic impairment (Child-Pugh class B). The effect of severe renal or hepatic impairment on baloxavir pharmacokinetics has not been evaluated.

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)].

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)

Baloxavir marboxil is an antiviral drug with activity against influenza virus [see Microbiology (12.4)].

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 complications¹ [see Clinical Studies (14.1, 14.2, and 14.3].

• 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)

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)

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)

• Tablets: 40 mg and 80 mg. (3)
• For oral suspension (packets): 30 mg and 40 mg per packet in about 15-20 mL of drinking water. (3)
• For oral suspension (bottles): 40 mg/20 mL (2 mg/mL) after reconstitution. (3).

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

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)].

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.

Advise the patient to read the FDA-approved patient labeling (Patient Information).

XOFLUZA is supplied as tablets (40 mg and 80 mg), granules (30 mg and 40 mg) that are reconstituted into a for oral suspension (packets) and as granules that are reconstituted into a for oral suspension (bottles) [40 mg/20 mL (2 mg/mL)] . The single oral dose to be administered depends on body weight [see Dosage and Administration (2.2)].

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).

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)].

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)].

NDC 50242-599-01

Xofluza^®

(baloxavir marboxil)

for oral suspension

30 mg per packet

Refer to Instructions for Use inside the carton.

1 packet

Rx only

Genentech

11024214

NDC 50242-617-01

Xofluza^®

(baloxavir marboxil)

for oral suspension

40 mg per packet

Refer to Instructions for Use inside the carton.

1 packet

Rx only

Genentech

11024205

NDC 50242-583-01

Xofluza^®

(baloxavir marboxil)

for oral suspension

40 mg/20 mL (2 mg/mL)

Each mL contains

2 mg baloxavir marboxil

after constitution.

Take volume prescribed as a

single one-time dose.

Discard unused portion.

Use the appropriate

measuring device for your

total prescribed dose.

Take before the suspension

expires (see bottle label).

No preservative.

20 mL total usable volume

after constitution

Rx only

Genentech

11000080

Xofluza^®

(baloxavir marboxil) tablet

40 mg per tablet

NDC 50242-860-01

Contains 40 mg total dose (1 x 40 mg tablet)

Usual dosage:

Take the tablet in this package as a single, one-time dose

Rx only

Genentech

11006600

Xofluza^®

(baloxavir marboxil) tablet

80 mg per tablet

NDC 50242-877-01

Contains 80 mg total dose (1 x 80 mg tablet)

Usual dosage:

Take the tablet in this package as a single, one-time dose

Rx only

Genentech

11006589

Trial T0834 was a phase 3, randomized, double-blind, multicenter, placebo-controlled trial designed to evaluate the efficacy of a single oral dose of XOFLUZA compared with placebo in the prevention of influenza in subjects who were household contacts of influenza-infected patients in Japan. Influenza-infected index patients were required to have onset of symptoms for ≤ 48 hours, and subjects (household contacts) were required to have lived with the influenza-infected index patient for ≥ 48 hours.

A total of 715 subjects (XOFLUZA N=360, placebo N=355) 5 years of age and older were randomized and received a single oral dose of XOFLUZA according to body weight and age, or placebo, on Day 1. Subjects received a single dose of XOFLUZA according to body weight. The primary efficacy endpoint was the proportion of household subjects who were infected with influenza virus and presented with fever and at least one respiratory symptom from day 1 to day 10. Influenza infection was confirmed by RT-PCR, fever was defined as a body temperature (axillary) ≥ 37.5°C, and respiratory symptoms were defined as having a symptom of "cough" or "nasal discharge/nasal congestion" with a severity of moderate or severe as assessed by the subject.

The mean age of subjects that were ≥ 5 years of age in Trial T0834 was 35 years; 108 (15%) were 5 to < 12 years, 33 (5%) were ≥ 12 to < 18 years of age, 551 (77%) were ≥ 18 to < 65 years of age, and 23 (3%) were ≥ 65 years of age. All subjects were Asian, 80% were female, and 20% were male.

In subjects that were 5 years of age and older, there was a statistically significant reduction in the proportion of household contacts (subjects) with laboratory-confirmed clinical influenza from 13% in the placebo group to 2% in the XOFLUZA group (see Table 13).

In the 108 pediatric subjects 5 to less than 12 years of age enrolled in Trial T0834, 57 subjects received XOFLUZA and 51 received placebo. In this age group, the proportion of subjects with laboratory-confirmed clinical influenza was 4% in the XOFLUZA group and 14% in the placebo group.

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.

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.

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)].

Trial T0832 (NCT02949011) was a randomized, double-blind, placebo- and active-controlled trial to evaluate the efficacy and safety of a single oral dose of XOFLUZA compared with placebo or oseltamivir in adult and adolescent subjects 12 years of age or older with influenza who were at high risk of developing influenza-related complications.

A total of 2,182 subjects with signs and symptoms of influenza were randomized to receive a single oral dose of 40 mg or 80 mg of XOFLUZA according to body weight (subjects who weighed 40 to less than 80 kg received 40 mg and subjects who weighed 80 kg and above received 80 mg) (N=729), oseltamivir 75 mg twice daily for 5 days (N=725), or placebo (N=728). Twenty-eight percent of subjects were Asian, 59% were White, and 10% were Black or African American. The mean age was 52 years, and 3% of subjects were less than 18 years of age; 43% of subjects were male and 57% female.

High risk factors were based on the Centers for Disease Control and Prevention definition¹ of health factors known to increase the risk of developing serious complications from influenza. The majority of subjects had underlying asthma or chronic lung disease, diabetes, heart disease, morbid obesity, or were 65 years of age or older.

In Trial T0832, 1,158 of the 2,182 enrolled subjects had influenza confirmed by RT-PCR and were included in the efficacy analysis (XOFLUZA N=385, placebo N=385, or oseltamivir N=388). Among subjects in whom only one type/subtype of influenza virus was identified, 50% were infected with subtype A/H3N2, 43% were infected with type B, and 7% were infected with subtype A/H1N1.

Eligible subjects had an axillary temperature of at least 38°C, at least one moderate or severe respiratory symptom (cough, nasal congestion, or sore throat), and at least one moderate or severe systemic symptom (headache, feverishness or chills, muscle or joint pain, or fatigue), and all were treated within 48 hours of symptom onset. Subjects participating in the trial were required to self-assess their influenza symptoms as "none," "mild," "moderate," or "severe" twice daily. A total of 215 subjects (19%) had preexisting symptoms (cough, muscle or joint pain, or fatigue) associated with their underlying high-risk condition that were worsened due to influenza infection. The primary efficacy endpoint was time to improvement of influenza symptoms (cough, sore throat, headache, nasal congestion, feverishness or chills, muscle or joint pain, and fatigue). This endpoint included alleviation of new symptoms and improvement of any preexisting symptoms that had worsened due to influenza. A statistically significant improvement in the primary endpoint was observed for XOFLUZA when compared with placebo (see Table 12).

There was no statistically significant difference in the median time to improvement of influenza symptoms in the subjects who received XOFLUZA (73 hours) and those who received oseltamivir (81 hours). The median time to improvement of influenza symptoms in the limited number of adolescent subjects aged 12 to 17 years infected with influenza virus was similar for subjects who received XOFLUZA (188 hours) or placebo (191 hours) (N=13 and N=12, respectively).

For subjects infected with type B virus, the median time to improvement of influenza symptoms was 75 hours in the XOFLUZA group (95% CI of 67, 90) compared to 101 hours in the placebo group (95% CI of 83, 116).

Two randomized, controlled, double-blinded clinical trials conducted in two different influenza seasons evaluated efficacy and safety of XOFLUZA in otherwise healthy subjects with acute uncomplicated influenza.

In Trial T0821, a placebo-controlled phase 2 dose-finding trial, a single oral dose of XOFLUZA was compared with placebo in 400 adult subjects 20 to 64 years of age in Japan. All subjects in Trial T0821 were Asian, the majority of subjects were male (62%), and the mean age was 38 years. In this trial, among subjects who received XOFLUZA and had influenza virus typed, influenza A/H1N1 was the predominant strain (63%), followed by influenza B (25%), and influenza A/H3N2 (12%).

In Trial T0831 (NCT02954354), a phase 3, randomized, double-blind, active- and placebo-controlled trial, XOFLUZA was studied in 1,436 otherwise healthy adults and adolescents with signs and symptoms of influenza in the U.S. and Japan. Subjects were 12 to 64 years of age and weighed at least 40 kg. Adults aged 20 to 64 years received weight-based XOFLUZA (subjects who weighed 40 to less than 80 kg received 40 mg and subjects who weighed 80 kg and above received 80 mg) (N=612) or placebo as a single oral dose on day 1 (N=310) or oseltamivir twice a day for 5 days (N=514). Subjects in the XOFLUZA and placebo arms received a placebo for the duration of oseltamivir dosing after XOFLUZA or placebo dosing in that arm. Adolescent subjects 12 to less than 20 years of age received weight-based XOFLUZA or placebo as a single oral dose.

Seventy-eight percent of subjects in Trial T0831 were Asian, 17% were White, and 4% were Black or African American. The mean age was 34 years, and 11% of subjects were less than 20 years of age; 54% of subjects were male and 46% female. In Trial T0831, 1,062 of 1,436 enrolled subjects had influenza confirmed by RT-PCR and were included in the efficacy analysis (XOFLUZA N=455, placebo N=230, or oseltamivir N=377). Among subjects who received XOFLUZA and had influenza virus typed, influenza A/H3N2 was the predominant strain (90%), followed by influenza B (9%), and influenza A/H1N1 (2%).

In both Trials T0821 and T0831, eligible subjects had an axillary temperature of at least 38˚C, at least one moderate or severe respiratory symptom (cough, nasal congestion, or sore throat), and at least one moderate or severe systemic symptom (headache, feverishness or chills, muscle or joint pain, or fatigue), and all were treated within 48 hours of symptom onset. Subjects participating in the trial were required to self-assess their influenza symptoms as "none," "mild," "moderate," or "severe" twice daily. The primary efficacy population was defined as those with a positive rapid influenza diagnostic test (Trial T0821) or positive influenza reverse transcription polymerase chain reaction (RT-PCR) (Trial T0831) at trial entry.

The primary endpoint of both trials, time to alleviation of symptoms, was defined as the time when all seven symptoms (cough, sore throat, nasal congestion, headache, feverishness, myalgia, and fatigue) had been assessed by the subject as none or mild for a duration of at least 21.5 hours.

In both trials, XOFLUZA treatment at the recommended dose resulted in a statistically significant shorter time to alleviation of symptoms compared with placebo in the primary efficacy population (Tables 10 and 11).

In Trial T0831, there was no difference in the time to alleviation of symptoms between subjects (age ≥ 20 years) who received XOFLUZA (54 hours) and those who received oseltamivir (54 hours). For adolescent subjects (12 to 17 years of age) in Trial T0831, the median time to alleviation of symptoms for subjects infected with influenza and who received XOFLUZA (N=63) was 54 hours (95% CI of 43, 81) compared to 93 hours (95% CI of 64, 118) in the placebo arm (N=27).

The number of subjects who received XOFLUZA at the recommended dose and who were infected with influenza type B virus was limited, including 24 subjects in Trial T0821 and 38 subjects in Trial T0831. In the influenza B subset in Trial T0821, the median time to alleviation of symptoms in subjects who received 40 mg XOFLUZA was 63 hours (95% CI of 43, 70) compared to 83 hours (95% CI of 58, 93) in subjects who received placebo. In the influenza B subset in Trial T0831, the median time to alleviation of symptoms in subjects who received 40 mg or 80 mg XOFLUZA was 93 hours (95% CI of 53, 135) compared to 77 hours (95% CI of 47, 189) in subjects who received placebo.

Trial CP40563 (NCT03629184) was a randomized, double-blind, multicenter, active-controlled trial, designed to evaluate the safety, efficacy, and pharmacokinetics of a single oral dose of XOFLUZA compared with oseltamivir in otherwise healthy pediatric subjects (including subjects aged 5 to < 12 years of age) with influenza-like symptoms. Eligible subjects had a tympanic temperature of at least 38°C and at least one respiratory symptom of either cough or nasal congestion.

A total of 118 subjects 5 to less than 12 years of age were randomized and received a single one-time oral dose of XOFLUZA (N=79) based on body weight (2 mg/kg for subjects weighing < 20 kg or 40 mg for subjects weighing ≥ 20 kg) or oseltamivir (N=39) for 5 days (dose based on body weight). Subjects at high risk of developing complications associated with influenza were included in the trial [16% (19/118)]. The primary objective was to compare the safety of a single one-time dose of XOFLUZA with 5 days of oseltamivir administered twice daily. The secondary efficacy endpoint included time to alleviation of influenza signs and symptoms, which was defined as the time when all of the following were met for at least 21.5 hours: cough and nasal symptoms were assessed by the caregiver as no problem or minor problem, subject was able to return to normal daily activity, and subject was afebrile (temperature ≤ 37.2°C). However, the trial was not powered to detect statistically significant differences in this secondary endpoint.

Of the 118 randomized subjects 5 to less than 12 years of age in Trial CP40563, 94 subjects had influenza confirmed by RT-PCR at baseline or during the trial; 89% percent of subjects were White, 3% Black or African American and 8% Other/unknown/multiple races. The mean age was 8 years [SD=1.97]; 56% of subjects were female and 44% male. The predominant influenza virus strain in this trial was the A/H3N2 subtype (67%), followed by A/H1N1 (20%) and type B (9%).

The median time to alleviation of influenza signs and symptoms was 138 hours in the XOFLUZA arm (95% CI of 117, 163) and 126 hours in the oseltamivir arm (95% CI of 96, 166).

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.

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].

INSTRUCTIONS FOR USE

XOFLUZA^® (zoh-FLEW-zuh)

(baloxavir marboxil)

for oral suspension

This Instruction for Use contains information on how to prepare and take or give XOFLUZA for oral suspension in packets.

Read these Instructions for Use before preparing and taking or giving XOFLUZA for oral suspension. These Instructions for Use do not take the place of talking to your or your child's healthcare provider about your or your child's medical condition or treatment.

Important information you need to know before preparing and taking or giving XOFLUZA for oral suspension

• XOFLUZA is prescribed as a single, one-time dose.
• Wash your hands before and after preparing, taking, or giving XOFLUZA for oral suspension.
• XOFLUZA for oral suspension packets must be mixed with 1 tablespoon (about 15 to 20 mL) of room temperature drinking water.
• Take or give XOFLUZA for oral suspension right away after mixing.
• Check the expiration date and the product for damage before use. Do not use if expired or damaged.
• If you are prescribed the 80 mg dose of XOFLUZA for oral suspension, you will need to take two packets of 40 mg XOFLUZA, one at a time, until your full prescribed dose is taken.
• XOFLUZA for oral suspension can be taken by mouth or given through a feeding tube. Follow your healthcare provider's instructions for giving XOFLUZA through a feeding tube.

Your healthcare provider will prescribe XOFLUZA packets based on your or your child's weight. See the dosing chart below for the prescribed dose and number of XOFLUZA packets needed based on your or your child's weight.

Supplies needed to prepare and take or give XOFLUZA for oral suspension:

• your prescribed dose of XOFLUZA packets
• a tablespoon (about 15 to 20 mL) of room temperature drinking water in a container
• an enteral syringe (if giving XOFLUZA for oral suspension through a feeding tube).

Distributed by:

Genentech USA, Inc., A Member of the Roche Group

1 DNA Way, South San Francisco, CA 94080-4990

XOFLUZA® is a registered trademark of Genentech, Inc.

©2025 Genentech USA, Inc.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Issued: 05/2025

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.

Treatment of an overdose of XOFLUZA should consist of general supportive measures, including monitoring of vital signs and observation of the clinical status of the patient. There is no specific antidote for overdose with XOFLUZA.

Baloxavir is unlikely to be significantly removed by dialysis due to high serum protein binding [see Clinical Pharmacology (12.3)].

• "People at High-Risk for Flu Complications." Refer to U.S. Centers for Disease Control and Prevention "Influenza (Flu)" website.

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 C₂₇H₂₃F₂N₃O₇S, 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.

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.

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)].

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.

• 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)

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)].

Baloxavir marboxil is a prodrug that is almost completely converted to its active metabolite, baloxavir, following oral administration.

Baloxavir pharmacokinetic parameters are presented for healthy adults and adolescents as the mean [% coefficient of variation (%CV)], unless otherwise specified, in Table 5. Absorption, distribution, metabolism, and elimination data for XOFLUZA is presented in Table 6.

No clinically significant differences in the pharmacokinetics of baloxavir were observed based on age, sex, presence of risk factors for complicated influenza, creatinine clearance (CrCl: 50 mL/min and above), or moderate hepatic impairment (Child-Pugh class B). The effect of severe renal or hepatic impairment on baloxavir pharmacokinetics has not been evaluated.

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)].

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)

Baloxavir marboxil is an antiviral drug with activity against influenza virus [see Microbiology (12.4)].

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 complications¹ [see Clinical Studies (14.1, 14.2, and 14.3].

• 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)

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)

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)

• Tablets: 40 mg and 80 mg. (3)
• For oral suspension (packets): 30 mg and 40 mg per packet in about 15-20 mL of drinking water. (3)
• For oral suspension (bottles): 40 mg/20 mL (2 mg/mL) after reconstitution. (3).

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

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)].

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.

Advise the patient to read the FDA-approved patient labeling (Patient Information).

XOFLUZA is supplied as tablets (40 mg and 80 mg), granules (30 mg and 40 mg) that are reconstituted into a for oral suspension (packets) and as granules that are reconstituted into a for oral suspension (bottles) [40 mg/20 mL (2 mg/mL)] . The single oral dose to be administered depends on body weight [see Dosage and Administration (2.2)].

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).

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)].

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)].

NDC 50242-599-01

Xofluza^®

(baloxavir marboxil)

for oral suspension

30 mg per packet

Refer to Instructions for Use inside the carton.

1 packet

Rx only

Genentech

11024214

NDC 50242-617-01

Xofluza^®

(baloxavir marboxil)

for oral suspension

40 mg per packet

Refer to Instructions for Use inside the carton.

1 packet

Rx only

Genentech

11024205

NDC 50242-583-01

Xofluza^®

(baloxavir marboxil)

for oral suspension

40 mg/20 mL (2 mg/mL)

Each mL contains

2 mg baloxavir marboxil

after constitution.

Take volume prescribed as a

single one-time dose.

Discard unused portion.

Use the appropriate

measuring device for your

total prescribed dose.

Take before the suspension

expires (see bottle label).

No preservative.

20 mL total usable volume

after constitution

Rx only

Genentech

11000080

Xofluza^®

(baloxavir marboxil) tablet

40 mg per tablet

NDC 50242-860-01

Contains 40 mg total dose (1 x 40 mg tablet)

Usual dosage:

Take the tablet in this package as a single, one-time dose

Rx only

Genentech

11006600

Xofluza^®

(baloxavir marboxil) tablet

80 mg per tablet

NDC 50242-877-01

Contains 80 mg total dose (1 x 80 mg tablet)

Usual dosage:

Take the tablet in this package as a single, one-time dose

Rx only

Genentech

11006589

Trial T0834 was a phase 3, randomized, double-blind, multicenter, placebo-controlled trial designed to evaluate the efficacy of a single oral dose of XOFLUZA compared with placebo in the prevention of influenza in subjects who were household contacts of influenza-infected patients in Japan. Influenza-infected index patients were required to have onset of symptoms for ≤ 48 hours, and subjects (household contacts) were required to have lived with the influenza-infected index patient for ≥ 48 hours.

A total of 715 subjects (XOFLUZA N=360, placebo N=355) 5 years of age and older were randomized and received a single oral dose of XOFLUZA according to body weight and age, or placebo, on Day 1. Subjects received a single dose of XOFLUZA according to body weight. The primary efficacy endpoint was the proportion of household subjects who were infected with influenza virus and presented with fever and at least one respiratory symptom from day 1 to day 10. Influenza infection was confirmed by RT-PCR, fever was defined as a body temperature (axillary) ≥ 37.5°C, and respiratory symptoms were defined as having a symptom of "cough" or "nasal discharge/nasal congestion" with a severity of moderate or severe as assessed by the subject.

The mean age of subjects that were ≥ 5 years of age in Trial T0834 was 35 years; 108 (15%) were 5 to < 12 years, 33 (5%) were ≥ 12 to < 18 years of age, 551 (77%) were ≥ 18 to < 65 years of age, and 23 (3%) were ≥ 65 years of age. All subjects were Asian, 80% were female, and 20% were male.

In subjects that were 5 years of age and older, there was a statistically significant reduction in the proportion of household contacts (subjects) with laboratory-confirmed clinical influenza from 13% in the placebo group to 2% in the XOFLUZA group (see Table 13).

In the 108 pediatric subjects 5 to less than 12 years of age enrolled in Trial T0834, 57 subjects received XOFLUZA and 51 received placebo. In this age group, the proportion of subjects with laboratory-confirmed clinical influenza was 4% in the XOFLUZA group and 14% in the placebo group.

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.

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.

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)].

Trial T0832 (NCT02949011) was a randomized, double-blind, placebo- and active-controlled trial to evaluate the efficacy and safety of a single oral dose of XOFLUZA compared with placebo or oseltamivir in adult and adolescent subjects 12 years of age or older with influenza who were at high risk of developing influenza-related complications.

A total of 2,182 subjects with signs and symptoms of influenza were randomized to receive a single oral dose of 40 mg or 80 mg of XOFLUZA according to body weight (subjects who weighed 40 to less than 80 kg received 40 mg and subjects who weighed 80 kg and above received 80 mg) (N=729), oseltamivir 75 mg twice daily for 5 days (N=725), or placebo (N=728). Twenty-eight percent of subjects were Asian, 59% were White, and 10% were Black or African American. The mean age was 52 years, and 3% of subjects were less than 18 years of age; 43% of subjects were male and 57% female.

High risk factors were based on the Centers for Disease Control and Prevention definition¹ of health factors known to increase the risk of developing serious complications from influenza. The majority of subjects had underlying asthma or chronic lung disease, diabetes, heart disease, morbid obesity, or were 65 years of age or older.

In Trial T0832, 1,158 of the 2,182 enrolled subjects had influenza confirmed by RT-PCR and were included in the efficacy analysis (XOFLUZA N=385, placebo N=385, or oseltamivir N=388). Among subjects in whom only one type/subtype of influenza virus was identified, 50% were infected with subtype A/H3N2, 43% were infected with type B, and 7% were infected with subtype A/H1N1.

Eligible subjects had an axillary temperature of at least 38°C, at least one moderate or severe respiratory symptom (cough, nasal congestion, or sore throat), and at least one moderate or severe systemic symptom (headache, feverishness or chills, muscle or joint pain, or fatigue), and all were treated within 48 hours of symptom onset. Subjects participating in the trial were required to self-assess their influenza symptoms as "none," "mild," "moderate," or "severe" twice daily. A total of 215 subjects (19%) had preexisting symptoms (cough, muscle or joint pain, or fatigue) associated with their underlying high-risk condition that were worsened due to influenza infection. The primary efficacy endpoint was time to improvement of influenza symptoms (cough, sore throat, headache, nasal congestion, feverishness or chills, muscle or joint pain, and fatigue). This endpoint included alleviation of new symptoms and improvement of any preexisting symptoms that had worsened due to influenza. A statistically significant improvement in the primary endpoint was observed for XOFLUZA when compared with placebo (see Table 12).

There was no statistically significant difference in the median time to improvement of influenza symptoms in the subjects who received XOFLUZA (73 hours) and those who received oseltamivir (81 hours). The median time to improvement of influenza symptoms in the limited number of adolescent subjects aged 12 to 17 years infected with influenza virus was similar for subjects who received XOFLUZA (188 hours) or placebo (191 hours) (N=13 and N=12, respectively).

For subjects infected with type B virus, the median time to improvement of influenza symptoms was 75 hours in the XOFLUZA group (95% CI of 67, 90) compared to 101 hours in the placebo group (95% CI of 83, 116).

Two randomized, controlled, double-blinded clinical trials conducted in two different influenza seasons evaluated efficacy and safety of XOFLUZA in otherwise healthy subjects with acute uncomplicated influenza.

In Trial T0821, a placebo-controlled phase 2 dose-finding trial, a single oral dose of XOFLUZA was compared with placebo in 400 adult subjects 20 to 64 years of age in Japan. All subjects in Trial T0821 were Asian, the majority of subjects were male (62%), and the mean age was 38 years. In this trial, among subjects who received XOFLUZA and had influenza virus typed, influenza A/H1N1 was the predominant strain (63%), followed by influenza B (25%), and influenza A/H3N2 (12%).

In Trial T0831 (NCT02954354), a phase 3, randomized, double-blind, active- and placebo-controlled trial, XOFLUZA was studied in 1,436 otherwise healthy adults and adolescents with signs and symptoms of influenza in the U.S. and Japan. Subjects were 12 to 64 years of age and weighed at least 40 kg. Adults aged 20 to 64 years received weight-based XOFLUZA (subjects who weighed 40 to less than 80 kg received 40 mg and subjects who weighed 80 kg and above received 80 mg) (N=612) or placebo as a single oral dose on day 1 (N=310) or oseltamivir twice a day for 5 days (N=514). Subjects in the XOFLUZA and placebo arms received a placebo for the duration of oseltamivir dosing after XOFLUZA or placebo dosing in that arm. Adolescent subjects 12 to less than 20 years of age received weight-based XOFLUZA or placebo as a single oral dose.

Seventy-eight percent of subjects in Trial T0831 were Asian, 17% were White, and 4% were Black or African American. The mean age was 34 years, and 11% of subjects were less than 20 years of age; 54% of subjects were male and 46% female. In Trial T0831, 1,062 of 1,436 enrolled subjects had influenza confirmed by RT-PCR and were included in the efficacy analysis (XOFLUZA N=455, placebo N=230, or oseltamivir N=377). Among subjects who received XOFLUZA and had influenza virus typed, influenza A/H3N2 was the predominant strain (90%), followed by influenza B (9%), and influenza A/H1N1 (2%).

In both Trials T0821 and T0831, eligible subjects had an axillary temperature of at least 38˚C, at least one moderate or severe respiratory symptom (cough, nasal congestion, or sore throat), and at least one moderate or severe systemic symptom (headache, feverishness or chills, muscle or joint pain, or fatigue), and all were treated within 48 hours of symptom onset. Subjects participating in the trial were required to self-assess their influenza symptoms as "none," "mild," "moderate," or "severe" twice daily. The primary efficacy population was defined as those with a positive rapid influenza diagnostic test (Trial T0821) or positive influenza reverse transcription polymerase chain reaction (RT-PCR) (Trial T0831) at trial entry.

The primary endpoint of both trials, time to alleviation of symptoms, was defined as the time when all seven symptoms (cough, sore throat, nasal congestion, headache, feverishness, myalgia, and fatigue) had been assessed by the subject as none or mild for a duration of at least 21.5 hours.

In both trials, XOFLUZA treatment at the recommended dose resulted in a statistically significant shorter time to alleviation of symptoms compared with placebo in the primary efficacy population (Tables 10 and 11).

In Trial T0831, there was no difference in the time to alleviation of symptoms between subjects (age ≥ 20 years) who received XOFLUZA (54 hours) and those who received oseltamivir (54 hours). For adolescent subjects (12 to 17 years of age) in Trial T0831, the median time to alleviation of symptoms for subjects infected with influenza and who received XOFLUZA (N=63) was 54 hours (95% CI of 43, 81) compared to 93 hours (95% CI of 64, 118) in the placebo arm (N=27).

The number of subjects who received XOFLUZA at the recommended dose and who were infected with influenza type B virus was limited, including 24 subjects in Trial T0821 and 38 subjects in Trial T0831. In the influenza B subset in Trial T0821, the median time to alleviation of symptoms in subjects who received 40 mg XOFLUZA was 63 hours (95% CI of 43, 70) compared to 83 hours (95% CI of 58, 93) in subjects who received placebo. In the influenza B subset in Trial T0831, the median time to alleviation of symptoms in subjects who received 40 mg or 80 mg XOFLUZA was 93 hours (95% CI of 53, 135) compared to 77 hours (95% CI of 47, 189) in subjects who received placebo.

Trial CP40563 (NCT03629184) was a randomized, double-blind, multicenter, active-controlled trial, designed to evaluate the safety, efficacy, and pharmacokinetics of a single oral dose of XOFLUZA compared with oseltamivir in otherwise healthy pediatric subjects (including subjects aged 5 to < 12 years of age) with influenza-like symptoms. Eligible subjects had a tympanic temperature of at least 38°C and at least one respiratory symptom of either cough or nasal congestion.

A total of 118 subjects 5 to less than 12 years of age were randomized and received a single one-time oral dose of XOFLUZA (N=79) based on body weight (2 mg/kg for subjects weighing < 20 kg or 40 mg for subjects weighing ≥ 20 kg) or oseltamivir (N=39) for 5 days (dose based on body weight). Subjects at high risk of developing complications associated with influenza were included in the trial [16% (19/118)]. The primary objective was to compare the safety of a single one-time dose of XOFLUZA with 5 days of oseltamivir administered twice daily. The secondary efficacy endpoint included time to alleviation of influenza signs and symptoms, which was defined as the time when all of the following were met for at least 21.5 hours: cough and nasal symptoms were assessed by the caregiver as no problem or minor problem, subject was able to return to normal daily activity, and subject was afebrile (temperature ≤ 37.2°C). However, the trial was not powered to detect statistically significant differences in this secondary endpoint.

Of the 118 randomized subjects 5 to less than 12 years of age in Trial CP40563, 94 subjects had influenza confirmed by RT-PCR at baseline or during the trial; 89% percent of subjects were White, 3% Black or African American and 8% Other/unknown/multiple races. The mean age was 8 years [SD=1.97]; 56% of subjects were female and 44% male. The predominant influenza virus strain in this trial was the A/H3N2 subtype (67%), followed by A/H1N1 (20%) and type B (9%).

The median time to alleviation of influenza signs and symptoms was 138 hours in the XOFLUZA arm (95% CI of 117, 163) and 126 hours in the oseltamivir arm (95% CI of 96, 166).