Treatment of Acute Uncomplicated Influenza or Post-Exposure Prophylaxis in Adults and Adolescents (12 Years of Age and Older)

XOFLUZA should be taken 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 12 years of age or older is a single weight-based dose displayed in Tables 1 and 2.

Constituting XOFLUZA for Oral Suspension

Prepare the suspension at the time of dispensing. Administration must occur within 10 hours after constitution because the product does not contain a preservative.

1. Gently tap the bottom of the bottle to loosen the granules.
2. Constitute XOFLUZA for oral suspension with 20 mL of drinking water or sterile water.
3. Gently swirl the suspension to ensure that the granules are evenly suspended. Do not shake.
4. Write the expiration time and date on the bottle label in the space provided (10 hours from constitution time).

Important Information for the Healthcare Provider

• Provide caregiver or patient with a measuring device (e.g., oral syringe, measuring cup) to deliver the prescribed dose of the suspension for oral use. For enteral administration (i.e., feeding tube), draw up suspension with an enteral syringe. 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 may require more than one bottle (e.g., for adults and adolescents weighing at least 80 kg).

Treatment of Acute Uncomplicated Influenza

Post-Exposure Prophylaxis of Influenza

The safety of XOFLUZA in adult and adolescent subjects is based on data from one placebo-controlled clinical trial in which 374 subjects, of which 303 were adult and adolescent subjects ≥ 12 years, received XOFLUZA: eight (3%) subjects were adults 65 years of age or older, and 12 (4%) subjects were adolescents 12 to 17 years of age. The most frequently reported AE in the total study population was nasopharyngitis which occurred in 6% of subjects who received XOFLUZA and 7% on placebo [see Clinical Studies (14.3)].

Risk Summary

There are no adequate and well-controlled studies with XOFLUZA in pregnant women to inform a drug-associated risk of adverse developmental outcomes. There are risks to the mother and fetus associated with influenza virus infection in pregnancy [see Clinical Considerations]. In animal reproduction studies, no adverse developmental effects were observed in rats or rabbits with oral administration of baloxavir marboxil at exposures approximately 5 (rats) and 7 (rabbits) times the systemic baloxavir exposure at the maximum recommended human dose (MRHD) [see Data].

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%–4% and 15%–20%, respectively.

Clinical Considerations

Data

Risk Summary

There are no data on the presence of baloxavir marboxil in human milk, the effects on the breastfed infant, or the effects on milk production. Baloxavir and its related metabolites were present in the milk of lactating rats [see Data]. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for XOFLUZA and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.

Data

In a lactation study, baloxavir and its related metabolites were excreted in the milk of lactating rats administered baloxavir marboxil (1 mg/kg) on postpartum/lactation day 11, with peak milk concentration approximately 5 times that of maternal plasma concentrations occurring 2 hours post-dose. No effects of baloxavir marboxil on growth and postnatal development were observed in nursing pups at the highest oral dose tested in rats. Maternal systemic exposure was approximately 5 times the baloxavir exposure in humans at the MRHD.

Treatment of Acute Uncomplicated Influenza in Pediatric Subjects

The safety and effectiveness of XOFLUZA for the treatment of acute uncomplicated influenza in pediatric subjects 12 years of age and older weighing at least 40 kg is supported by one randomized, double-blind, controlled trial in otherwise healthy subjects (Trial 2) and one trial in subjects at high risk of developing influenza-related complications (Trial 3) [see Clinical Studies (14.1)]. A total of 117 otherwise healthy adolescents 12-17 years old were randomized and received either XOFLUZA (N=76) or placebo (N=41) in Trial 2; 38 adolescents aged 12 to 17 years at high risk for influenza complications were randomized and received either XOFLUZA (N=21) or placebo (N=17) in Trial 3. The median time to alleviation of symptoms in influenza-infected adolescent subjects aged 12 to 17 years in Trial 2 was comparable to that observed in adults. In Trial 3, the median time to improvement of symptoms in the limited number of influenza-infected adolescent subjects aged 12 to 17 years was similar in the XOFLUZA and placebo arms [see Clinical Studies (14.1)]. Adverse events reported in adolescents in both trials were similar to those reported in adults [see Adverse Reactions (6.1)].

The safety and efficacy of XOFLUZA in pediatric subjects less than 12 years of age have not been established for the treatment of acute uncomplicated influenza. For information on baloxavir resistance in subjects less than 12 years of age [see Microbiology (12.4)].

Post-Exposure Prophylaxis of Influenza in Pediatric Subjects

The safety and effectiveness of XOFLUZA for post-exposure prophylaxis in adolescents (12 years to < 18 years) is supported by one randomized, double-blind, controlled trial conducted in Japan (Trial 4) [see Clinical Studies (14.3)]. Subjects in this trial were randomized in a 1:1 ratio to receive XOFLUZA or placebo. A total of 12 subjects from ≥ 12 to < 18 years of age received XOFLUZA. The incidence of RT-PCR-confirmed symptomatic influenza was similar in the XOFLUZA and placebo arms in the limited number of adolescent subjects aged 12 to 17 years of age [see Clinical Studies (14.3)]. Adverse events reported in adolescent subjects were similar to those reported in adults in the same trial [see Adverse Reactions (6.1)].

The safety and efficacy of XOFLUZA for post-exposure prophylaxis of influenza in pediatric subjects less than 12 years of age have not been established.

Cardiac Electrophysiology

At twice the expected exposure from recommended dosing, XOFLUZA did not prolong the QTc interval.

Exposure-Response Relationships

When XOFLUZA is dosed by weight, as recommended (40 mg in patients weighing 40–80 kg; 80 mg in patients weighing at least 80 kg), no difference in baloxavir exposure-response (time to alleviation of influenza symptoms in the otherwise healthy population or time to improvement of influenza symptoms in the high risk population) relationship has been observed.

Body Weight

Baloxavir exposure decreases as body weight increases. No clinically significant difference in exposure was observed between body weight groups following the approved recommended dosage.

Race/Ethnicity

Based on a population pharmacokinetic analysis, baloxavir exposure is approximately 35% lower in non-Asians as compared to Asians; this difference is not considered clinically significant when the recommended dose was administered.

Drug Interaction Studies

Mechanism of Action

Baloxavir marboxil is a prodrug that is converted by hydrolysis to baloxavir, the active form that exerts anti-influenza virus activity. Baloxavir inhibits the endonuclease activity of the polymerase acidic (PA) protein, an influenza virus-specific enzyme in the viral RNA polymerase complex required for viral gene transcription, resulting in inhibition of influenza virus replication. The 50% inhibitory concentration (IC50) values of baloxavir ranged from 1.4 to 3.1 nM (n=4) for influenza A viruses and 4.5 to 8.9 nM (n=3) for influenza B viruses in a PA endonuclease assay. Viruses with reduced susceptibility to baloxavir have amino acid substitutions in the PA protein.

Antiviral Activity

The antiviral activity of baloxavir against laboratory strains and clinical isolates of influenza A and B viruses was determined in an MDCK cell-based plaque reduction assay. The median 50% effective concentration (EC50) values of baloxavir were 0.73 nM (n=31; range: 0.20–1.85 nM) for subtype A/H1N1 strains, 0.83 nM (n=33; range: 0.35–2.63 nM) for subtype A/H3N2 strains, and 5.97 nM (n=30; range: 2.67–14.23 nM) for type B strains. In an MDCK cell-based virus titer reduction assay, the 90% effective concentration (EC90) values of baloxavir against avian subtypes A/H5N1 and A/H7N9 were in the range of 0.80 to 3.16 nM. The relationship between antiviral activity in cell culture and clinical response to treatment in humans has not been established.

Resistance

Cross-Resistance

Cross-resistance between baloxavir and neuraminidase (NA) inhibitors, or between baloxavir and M2 proton pump inhibitors (adamantanes), is not expected because these drugs target different viral proteins. Baloxavir is active against NA inhibitor-resistant strains, including A/H1N1 and A/H5N1 viruses with the NA substitution H275Y (A/H1N1 numbering), A/H3N2 virus with the NA substitutions E119V or R292K, A/H7N9 virus with the NA substitution R292K (A/H3N2 numbering), and type B virus with the NA substitutions R152K or D198E (A/H3N2 numbering). The NA inhibitor oseltamivir is active against viruses with reduced susceptibility to baloxavir, including A/H1N1 virus with PA substitutions E23K or I38F/T, A/H3N2 virus with PA substitutions E23G/K, A37T, I38M/T, or E199G, and type B virus with the PA substitution I38T. Influenza virus may carry amino acid substitutions in PA that reduce susceptibility to baloxavir and at the same time carry resistance-associated substitutions for NA inhibitors and M2 proton pump inhibitors. The clinical relevance of phenotypic cross-resistance evaluations has not been established.

Immune Response

Interaction studies with influenza vaccines and baloxavir marboxil have not been conducted.

Carcinogenesis

Carcinogenicity studies have not been performed with baloxavir marboxil.

Mutagenesis

Baloxavir marboxil and the active metabolite, baloxavir, were not mutagenic in in vitro and in in vivo genotoxicity assays, which included bacterial mutation assays in S. typhimurium and E. coli, micronucleus tests with cultured mammalian cells, and in the rodent micronucleus assay.

Impairment of Fertility

In a fertility and early embryonic development study in rats, doses of baloxavir marboxil at 20, 200, or 1,000 mg/kg/day were administered to females for 2 weeks before mating, during mating, and until day 7 of pregnancy. Males were dosed for 4 weeks before mating and throughout mating. There were no effects on fertility, mating performance, or early embryonic development at any dose level, resulting in systemic drug exposure (AUC) approximately 5 times the MRHD.

Adults and Adolescents (Aged 12 Years 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 1, 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 1 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 2 (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 ages 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 2 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 2, 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 1 and 2, 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 1) or positive influenza reverse transcription polymerase chain reaction (RT-PCR) (Trial 2) 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 7 and 8).

In Trial 2, 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 2, 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 1 and 38 subjects in Trial 2. In the influenza B subset in Trial 1, 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 2, 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.