Xofluza: Package Insert / Prescribing Info

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 complications1 [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)].

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

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.

XOFLUZA Tablets:

• 40 mg: white to light yellow, oblong-shaped, film-coated, debossed with "BXM40" on one side.
• 80 mg: white to light yellow, oblong shaped, film-coated, debossed with "BXM80" on one side.

XOFLUZA for Oral Suspension (Packets):

• 30 mg: white to light yellow granules with strawberry flavor (each packet contains 30 mg baloxavir marboxil).
• 40 mg: white to light yellow granules with strawberry flavor (each packet contains 40 mg baloxavir marboxil).

XOFLUZA for Oral Suspension (Bottles):

• 40 mg/20 mL (2 mg/mL) of baloxavir marboxil after reconstitution with 20 mL of drinking water or sterile water. The granules are white to light yellow. The reconstituted product is a greyish white, white to light yellow opaque suspension with strawberry flavor.

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.

6.1 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)].

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

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.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

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.

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

12.3 Pharmacokinetics

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.

12.4 Microbiology

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14.1 Treatment of Acute Uncomplicated Influenza—Otherwise Healthy Subjects (12 Years of Age and Older)

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.

14.2 Treatment of Acute Uncomplicated Influenza—High Risk Subjects (12 Years of Age and Older)

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).

14.3 Treatment of Acute Uncomplicated Influenza—Otherwise Healthy and High-Risk Pediatric Subjects (5 to < 12 Years of Age)

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).

14.4 Post-Exposure Prophylaxis of Influenza (5 Years of Age and Older)

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.

XOFLUZA Tablets

XOFLUZA for Oral Suspension (Packets)

XOFLUZA for Oral Suspension (Bottles)

Important Dosing Information

Instruct patients to begin treatment with XOFLUZA as soon as possible at the first appearance of influenza symptoms, within 48 hours of onset of symptoms. Instruct patients to start taking XOFLUZA for prevention as soon as possible after exposure [see Dosage and Administration (2.2)].

XOFLUZA can be taken with or without food, but advise patients not to take with dairy products, calcium-fortified beverages, polyvalent cation-containing laxatives, antacids, or oral supplements (e.g., calcium, iron, magnesium, selenium, or zinc) [see Dosage and Administration (2.2) and Drug Interactions (7.1)].

Advise patients to follow the healthcare provider's dosing recommendation for a single, one-time dose of XOFLUZA. XOFLUZA is dosed based on weight and is available as tablets, and for oral suspension (packets and bottles). XOFLUZA for oral suspension in a packet is not made into a suspension but rather mixed with a small amount of room temperature drinking water to aid administration.

Tablets: Provided as a blister card containing either one tablet of 40 mg, or one tablet of 80 mg as a single dose [see Dosage and Administration (2.2)].

For Oral Suspension:

• Provided in a packet containing either 30 mg or 40 mg baloxavir marboxil. Advise patients or caregivers to read and follow the Instructions for Use for details on the preparation and administration (oral or via enteral feeding tube). XOFLUZA for oral suspension (packets) should be taken immediately after mixing and fully dispersing with water because the product does not contain a preservative [see Dosage and Administration (2.2, 2.3), and How Supplied/Storage and Handling (16)].
• Provided in a bottle containing 40 mg/20 mL (2 mg/mL) after reconstitution by the healthcare provider. Advise the patients and/or caregiver to use a measuring device (oral syringe) to measure their prescribed dose. Counsel patients and/or caregivers how to use the measuring device (oral syringe) provided and inform patients that they may need to draw up XOFLUZA for oral suspension (bottles) multiple times using the oral syringe to receive the full dosage. The suspension should be taken as soon as possible but no later than 10 hours after reconstitution by the healthcare provider because the product does not contain a preservative [see Dosage and Administration (2.2, 2.4), and How Supplied/Storage and Handling (16)].

Hypersensitivity

Advise patients and/or caregivers of the risk of severe allergic reactions such as anaphylaxis, angioedema, urticaria, and erythema multiforme. Instruct patients and/or caregivers to seek immediate medical attention if an allergic-like reaction occurs or is suspected [see Contraindications (4) and Warnings and Precautions (5.1)].

Influenza Vaccines

Because of the potential for antivirals to decrease the effectiveness of live attenuated influenza vaccines, advise patients to consult their healthcare provider prior to receiving a live attenuated influenza vaccine after taking XOFLUZA [see Drug Interactions (7.2)].