HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use XOFLUZA safely and effectively. See full prescribing information for XOFLUZA.

 

XOFLUZATM (baloxavir marboxil) tablets, for oral use Initial U.S. Approval: 2018

 

-----------------------------INDICATIONS AND USAGE--------------------------

XOFLUZATM is a polymerase acidic (PA) endonuclease inhibitor indicated for the treatment of acute uncomplicated influenza in patients 12 years of age

and older who have been symptomatic for no more than 48 hours. (1)

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)

 

------------------------DOSAGE AND ADMINISTRATION----------------------

Take a single dose of XOFLUZA orally within 48 hours of symptom onset with or without food. Avoid co-administration of XOFLUZA with dairy

products, calcium-fortified beverages, polyvalent cation-containing laxatives, antacids, or oral supplements (e.g., calcium, iron, magnesium, selenium, or

zinc). The dose of XOFLUZA depends on weight. (2)

 

Patient Body Weight (kg)	Recommended Oral Dose
40 kg to less than 80 kg	Single dose of 40 mg
At least 80 kg	Single dose of 80 mg

 

---------------------DOSAGE FORMS AND STRENGTHS----------------------

Tablets: 20 mg and 40 mg (3)

-------------------------------CONTRAINDICATIONS------------------------------

XOFLUZA is contraindicated in patients with a history of hypersensitivity to baloxavir marboxil or any of its ingredients. (4)

 

--------------------------WARNINGS AND PRECAUTIONS---------------------

Risk of Bacterial Infection: Serious bacterial infections may begin with

influenza-like symptoms, 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. (5.1)

 

-------------------------------ADVERSE REACTIONS------------------------------

Adverse events reported in at least 1% of adult and adolescent subjects treated with XOFLUZA included diarrhea (3%), bronchitis (2%), nasopharyngitis

(1%), headache (1%) and nausea (1%). (6.1)

 

To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

 

------------------------------DRUG INTERACTIONS-------------------------------

·       Avoid co-administration of XOFLUZA with polyvalent cation-containing laxatives, antacids, or oral supplements (e.g., calcium, iron, magnesium,

selenium, or zinc). (7.1)

·       Live attenuated influenza vaccines may be affected by antivirals. (7.2)

 

--------------------------USE IN SPECIFIC POPULATIONS---------------------

·       Safety and efficacy in patients less than 12 years of age or weighing less than 40 kg have not been established. (8.4)

 

See 17 for PATIENT COUNSELING INFORMATION and

FDA-approved patient labeling.

 

Revised: 10/2018

 

 

 

FULL PRESCRIBING INFORMATION: CONTENTS*

 

1   INDICATIONS AND USAGE

2   DOSAGE AND ADMINISTRATION

3   DOSAGE FORMS AND STRENGTHS

4   CONTRAINDICATIONS

5   WARNINGS AND PRECAUTIONS

5.1  Bacterial Infections

6   ADVERSE REACTIONS

6.1  Clinical Trials Experience

7   DRUG INTERACTIONS

7.1 Drugs Affecting Baloxavir Concentrations

7.2 Vaccines

8   USE IN SPECIFIC POPULATIONS

8.1  Pregnancy

8.2  Lactation

8.4  Pediatric Use

8.5 Geriatric Use

 

 

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1  Mechanism of Action

12.2  Pharmacodynamics

12.3  Pharmacokinetics

12.4  Microbiology

13 NONCLINICAL TOXICOLOGY

13.1  Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

* Sections or subsections omitted from the full prescribing information are not listed.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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FULL PRESCRIBING INFORMATION

 

1    INDICATIONS AND USAGE

XOFLUZATM is indicated for the treatment of acute uncomplicated influenza in patients 12 years of age and older who have been symptomatic for no more than 48 hours.

 

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 Microbiology (12.4) and Clinical Studies (14.1)].

 

 

2    DOSAGE AND ADMINISTRATION

 

Initiate treatment with XOFLUZA within 48 hours of influenza symptom onset. XOFLUZA is taken orally as a single dose and may be taken with or without food. However, co-administration 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), Clinical Pharmacology (12.3)].

 

Adults and Adolescents (12 years of age and older)

 

The recommended dose of XOFLUZA in patients 12 years of age or older with acute uncomplicated influenza is a single weight-based dose as follows:

 

Table 1          Recommended XOFLUZA Dosage in Adults and Adolescents 12 Years and Older

 

Patient Body Weight (kg)	Recommended Oral Dose
40 kg to less than 80 kg	Single Dose of 40 mg
At least 80 kg	Single Dose of 80 mg

 

 

3    DOSAGE FORMS AND STRENGTHS

 

XOFLUZA 20 mg Tablets are white to light yellow, oblong shaped film-coated tablets debossed with     “

 

XOFLUZA 40 mg Tablets are white to light yellow, oblong shaped film-coated tablets debossed with “BXM40” on one side.

 

 

4    CONTRAINDICATIONS

 

XOFLUZA is contraindicated in patients with a history of hypersensitivity to baloxavir marboxil or any of its

ingredients.

 

 

 

 

 

 

 

 

 

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5    WARNINGS AND PRECAUTIONS

 

5.1    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, may coexist with, or occur as a complication of influenza. XOFLUZA has not been shown to prevent such complications. Prescribers should be alert to potential secondary bacterial infections and treat them as appropriate.

 

 

6    ADVERSE REACTIONS

 

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 safety profile of XOFLUZA is based on data from 2 placebo-controlled trials, in which a total of

910 subjects received XOFLUZA: 834 (92%) were adults (18 years and older) and 76 (8%) were adolescents (12 to less than 18 years). Of these, 710 subjects received XOFLUZA at the recommended dose. In Trial 1, adult subjects 20 to 64 years of age received a single oral dose of XOFLUZA or placebo. In Trial 2, adult subjects 20 to 64 years of age received XOFLUZA, placebo as a single oral dose on Day 1, or oseltamivir twice a day for 5 days, and adolescent subjects 12 to less than 20 years of age received XOFLUZA or placebo as a single oral dose.

 

Table 2 displays the most common adverse events (regardless of causality assessment) reported in at least 1% of adult and adolescent subjects who received XOFLUZA at the recommended dose in Trials 1 and 2.

 

Table 2             Incidence of Adverse Events Occurring in Greater Than or Equal to 1% of Subjects Receiving XOFLUZA in the Acute Uncomplicated Influenza Trials

Adverse Event	XOFLUZA (N = 710)	Placebo (N = 409)
Diarrhea	3%	5%
Bronchitis	2%	4%
Nausea	1%	1%
Nasopharyngitis	1%	1%
Headache	1%	2%

 

 

7    DRUG INTERACTIONS

 

7.1  Effect of Other Drugs on XOFLUZA

 

Co-administration with polyvalent cation-containing products may decrease plasma concentrations of baloxavir which may reduce XOFLUZA efficacy. Avoid co-administration of XOFLUZA with 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.

 

 

 

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8    USE IN SPECIFIC POPULATIONS

 

8.1    Pregnancy

 

Risk Summary

 

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

 

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

 

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

 

Pregnant women are at higher risk of severe complications from influenza, which may lead to adverse pregnancy and/or fetal outcomes including maternal death, stillbirth, birth defects, preterm delivery, low birth weight and small for gestational age.

 

Data

 

Animal Data

 

Baloxavir marboxil was administered orally to pregnant rats (20, 200, or 1,000 mg/kg/day from gestation day 6 to 17) and rabbits (30, 100, or 1,000 mg/kg/day from gestation day 7 to 19). No adverse embryo-fetal effects were observed in rats up to the highest dose of baloxavir marboxil (1,000 mg/kg/day), resulting in systemic baloxavir exposure (AUC) of approximately 5 times the exposure at the MRHD. In rabbits, fetal skeletal variations occurred at a maternally toxic dose (1,000 mg/kg/day) resulting in 2 abortions out of

19 pregnancies. No adverse maternal or embryo-fetal effects were observed in rabbits at the middle dose (100 mg/kg/day) resulting in systemic baloxavir exposure (AUC) approximately 7 times the exposure at the MRHD.

 

In the prenatal and postnatal development study in rats, baloxavir marboxil was administered orally at 20, 200, or 1,000 mg/kg/day from gestation day 6 to postpartum/lactation day 20. No significant effects were observed in the offspring at maternal systemic baloxavir exposure (AUC) approximately 5 times the exposure at the MRHD.

 

8.2    Lactation

 

Risk Summary

 

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

 

Data

 

In a lactation study, baloxavir and its related metabolites were excreted in the milk of lactating rats administered baloxavir marboxil (1 mg/kg) on postpartum/lactation day 11, with peak milk concentration approximately 5 times that of maternal plasma concentrations occurring 2 hours post-dose. No effects of

 

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baloxavir marboxil on growth and postnatal development were observed in nursing pups at the highest oral dose tested in rats.  Maternal systemic exposure was approximately 5 times the baloxavir exposure in humans at the MRHD.

 

8.4    Pediatric Use

 

The safety and effectiveness of XOFLUZA for the treatment of influenza have been established in pediatric patients 12 years of age and older weighing at least 40 kg [see Adverse Reactions (6.1) and Clinical Studies (14)]. The safety and effectiveness of XOFLUZA have not been established in pediatric patients less than 12 years of age.

 

The use of XOFLUZA in pediatric patients 12 years of age and older weighing at least 40 kg is supported by one randomized, double-blind, controlled trial [see Clinical Studies (14)]. In this phase 3 trial, 118 adolescents were randomized to receive either XOFLUZA (N=80) or placebo (N=38). The median time to alleviation of symptoms in adolescent subjects was 54 hours compared to 93 hours for subjects who received placebo. Adverse reactions reported in adolescents were similar to those reported in adults [see Adverse Reactions (6.1)].

 

8.5    Geriatric Use

 

Clinical trials of XOFLUZA did not include subjects 65 years of age and older to determine whether they respond differently from younger subjects.

 

 

 

10    OVERDOSAGE

 

There have been no reports of XOFLUZA overdoses. 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)].

 

 

 

11    DESCRIPTION

 

XOFLUZA (baloxavir marboxil) is an antiviral PA endonuclease inhibitor. XOFLUZA is supplied as white to light yellow film-coated tablets for oral administration.

 

The active component of XOFLUZA is baloxavir marboxil. Baloxavir marboxil has a molecular weight of

571.55 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.

 

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.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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The inactive ingredients of XOFLUZA are: croscarmellose sodium, hypromellose, lactose monohydrate, microcrystalline cellulose, povidone, sodium stearyl fumarate, talc, and titanium dioxide.

 

 

 

12    CLINICAL PHARMACOLOGY

 

12.1    Mechanism of Action

 

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

 

12.2    Pharmacodynamics

 

Cardiac Electrophysiology

 

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

No change in the baloxavir exposure-response (time to alleviation of symptoms) relationship was observed at the recommended dosing.

 

12.3    Pharmacokinetics

 

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

 

In the phase 3 trial, at the recommended dose of 40 mg for subjects weighing less than 80 kg, the mean (CV%) values of baloxavir Cmax and AUC0-inf were 96.4 ng/mL (45.9%) and 6160 ng·hr/mL (39.2%), respectively. At the recommended dose of 80 mg for subjects weighing 80 kg and more, the mean (CV%) values of baloxavir Cmax and AUC0-inf were 107 ng/mL (47.2%) and 8009 ng·hr/mL (42.4%), respectively. Refer to Table 3 for pharmacokinetic parameters of baloxavir in healthy subjects.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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Table 3             Pharmacokinetic Parameters of Plasma Baloxavir

 

Absorption
Tmax (hr)a	4
Effect of food (relative to fasting)b	Cmax: ↓48%, AUC0-inf; ↓36%
Distribution
% Bound to human serum proteinsc	92.9 - 93.9
Ratio of blood cell to blood	48.5% - 54.4%
Volume of distribution (V/F, L)d	1180 (20.8%)
Elimination
Major route of elimination	Metabolism
Clearance (CL/F, L/hr)d	10.3 (22.5%)
t1/2 (hr) d, e	79.1 (22.4%)
Metabolism
Metabolic pathwaysf	UGT1A3, CYP3A4
Excretion
% of dose excreted in urineg	14.7 (Total radioactivity), 3.3 (Baloxavir)
% of dose excreted in fecesg	80.1 (Total radioactivity)

a Median

b Meal: approximately 400 to 500 kcal including 150 kcal from fat

c in vitro

d Geometric mean (geometric CV%)

e Apparent terminal elimination half-life

f Baloxavir is primarily metabolized by UGT1A3 with minor contribution from CYP3A4

g Ratio of radioactivity to radio-labeled [14C]-baloxavir marboxil dose in mass balance study

 

Specific Populations

 

There were no clinically significant differences in the pharmacokinetics of baloxavir based on age (adolescents as compared to adults), or sex.

 

Patients with Renal Impairment

 

A population pharmacokinetic analysis did not identify a clinically meaningful effect of renal function on the pharmacokinetics of baloxavir in patients with creatinine clearance (CrCl) 50 mL/min and above. The effects of severe renal impairment on the pharmacokinetics of baloxavir marboxil or its active metabolite, baloxavir, have not been evaluated.

 

Patients with Hepatic Impairment

 

In a clinical study comparing pharmacokinetics of baloxavir in subjects with moderate hepatic impairment (Child-Pugh class B) to subjects with normal hepatic function, no clinically meaningful differences in the pharmacokinetics of baloxavir were observed.

 

The pharmacokinetics in patients with severe hepatic impairment have not been evaluated.

 

Body Weight

 

Body weight had a significant effect on the pharmacokinetics of baloxavir (as body weight increases, baloxavir exposure decreases). When dosed with the recommended weight-based dosing, no clinically significant difference in exposure was observed between body weight groups.

 

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.

 

 

 

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Drug Interaction Studies

 

Clinical Studies

 

No clinically significant changes in the pharmacokinetics of baloxavir marboxil and its active metabolite, baloxavir, were observed when co-administered with itraconazole (combined strong CYP3A and P-gp inhibitor), probenecid (UGT inhibitor), or oseltamivir.

 

No clinically significant changes in the pharmacokinetics of the following drugs were observed when co- administered with baloxavir marboxil: midazolam (CYP3A4 substrate), digoxin (P-gp substrate), rosuvastatin (BCRP substrate), or oseltamivir.

 

In Vitro Studies Where Drug Interaction Potential Was Not Further Evaluated Clinically

 

Cytochrome P450 (CYP) Enzymes: Baloxavir marboxil and its active metabolite, baloxavir, did not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6. Baloxavir marboxil and its active metabolite, baloxavir, did not induce CYP1A2, CYP2B6, or CYP3A4.

 

Uridine diphosphate (UDP)-glucuronosyl transferase (UGT) Enzymes:Baloxavir marboxil and its active metabolite, baloxavir, did not inhibit UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, or UGT2B15.

 

Transporter Systems: Both baloxavir marboxil and baloxavir are substrates of P-glycoprotein (P-gp). Baloxavir did not inhibit organic anion transporting polypeptides (OATP) 1B1, OATP1B3, organic cation transporter (OCT) 1, OCT2, organic anion transporter (OAT) 1, OAT3, multidrug and toxin extrusion (MATE) 1, or MATE2K.

 

Potential for Interactions with Polyvalent Cations: Baloxavir may form a chelate with polyvalent cations such as calcium, aluminum, or magnesium in food or medications. A significant decrease in baloxavir exposure was observed when XOFLUZA was co-administered with calcium, aluminum, magnesium, or iron in monkeys. No study has been conducted in humans.

 

12.4    Microbiology

 

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) of baloxavir was

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=19; range: 0.20-1.85 nM) for subtype A/H1N1 strains, 0.68 nM (n=19; range: 0.35-1.87 nM) for subtype A/H3N2 strains, and 5.28 nM (n=21; range: 3.33-13.00 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 1.64 and 0.80 nM, respectively. The relationship between antiviral activity in cell culture and clinical response to treatment in humans has not been established.

 

 

 

 

 

 

 

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Resistance

 

Cell culture: Influenza A virus isolates with reduced susceptibility to baloxavir were selected by serial passage of virus in cell culture in the presence of increasing concentrations of baloxavir. Reduced susceptibility of influenza A virus to baloxavir was conferred by amino acid substitutions I38T (A/H1N1 and A/H3N2) and E199G (A/H3N2) in the PA protein of the viral RNA polymerase complex.

 

Clinical studies: Influenza A and B viruses with treatment-emergent amino acid substitutions at positions associated with reduced susceptibility to baloxavir in cell culture were observed in clinical studies (Table 4). The overall incidence of treatment-emergent amino acid substitutions associated with reduced susceptibility to baloxavir in Trials 1 and 2 was 2.7% (5/182) and 11% (39/370), respectively.

 

Table 4             Treatment-Emergent Amino Acid Substitutions in PA Associated with Reduced Susceptibility to Baloxavir

Influenza Type/Subtype	A/H1N1	A/H3N2	B
Amino Acid Substitution	E23K/R, I38F/T	E23G/K, A37T, I38M/T, E199G	I38T

 

None of the treatment-emergent substitutions associated with reduced susceptibility to baloxavir were identified in virus from pre-treatment respiratory specimens in the clinical studies. Strains containing substitutions known to be associated with reduced susceptibility to baloxavir were identified in approximately 0.05% of PA sequences in the National Center for Biotechnology Information/GenBank database (queried August 2018).

 

Prescribers should consider currently available surveillance information on influenza virus drug susceptibility patterns and treatment effects when deciding whether to use XOFLUZA.

 

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 substitution E119V, A/H7N9 virus with the NA substitution R292K (A/H3N2 numbering), and type B virus with the NA substitution 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.

 

 

 

13    NONCLINICAL TOXICOLOGY

 

13.1    Carcinogenesis, Mutagenesis, Impairment of Fertility

 

Carcinogenesis

 

Carcinogenicity studies have not been performed with baloxavir marboxil.

 

 

 

 

 

 

 

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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.

 

 

 

14    CLINICAL STUDIES

 

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 active- and placebo-controlled trial, XOFLUZA was studied in

1,436 adult and adolescent subjects 12 to 64 years of age weighing at least 40 kg in the U.S. and Japan. Adults ages 20 to 64 years received XOFLUZA or placebo as a single oral dose on Day 1 or oseltamivir twice a day for 5 days.  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 XOFLUZA or placebo as a single oral dose.

 

In Trial 2, subjects weighing less than 80 kg received XOFLUZA at a dose of 40 mg and subjects weighing 80 kg or more received an 80 mg 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, 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, 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 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 5 and 6).

 

 

 

 

 

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Table 5             Time to Alleviation of Symptoms after Single Dose in Adult Subjects with Acute Uncomplicated Influenza in Trial 1 (Median Hours)

 

 

 

 

 

 

 

 

XOFLUZA 40 mg (95% CI1) N = 100 Placebo (95% CI1) N = 100     Adults (20 to 64 Years of Age) 50 hours2   (45, 64)   78 hours   (68, 89)

1CI: Confidence interval

2XOFLUZA treatment resulted in a statistically significant shorter time to alleviation of symptoms compared to placebo using the Gehan-Breslow’s generalized Wilcoxon test (p-value: 0.014, adjusted for multiplicity). The primary analysis using the Cox Proportional Hazards Model did not reach

statistical significance (p-value: 0.165).

 

 

 

Table 6             Time to Alleviation of Symptoms after Single Dose in Subjects 12 Years of Age and Older with Acute Uncomplicated Influenza in Trial 2 (Median Hours)

 

 

 

 

 

 

 

 

XOFLUZA 40 mg or 80 mg1 (95% CI2) N = 455 Placebo (95% CI2) N = 230     Subjects (≥ 12 Years of Age) 54 hours3   (50, 59)   80 hours   (73, 87)

1Dosing was based on weight. Subjects weighing < 80 kg received a single 40 mg dose and subjects ≥ 80 kg received a single 80 mg dose.

2CI: Confidence interval

3XOFLUZA treatment resulted in a statistically significant shorter time to alleviation of symptoms compared to placebo using the Peto-Prentice’s generalized Wilcoxon test (p-value: <0.001).

 

 

 

In Trial 2, there was no difference in the time to alleviation of symptoms between subjects 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 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.

 

 

 

16    HOW SUPPLIED/STORAGE AND HANDLING

 

XOFLUZA Tablets:

 

·                 20 mg white to light yellow, oblong shaped film-coated tablets debossed with     “772” on one side and “20” on the other side available as:

 

o   2 x 20 mg tablets per blister card in secondary packaging: NDC 50242-828-02

o   4 x 20 mg tablets per blister card in secondary packaging: NDC 50242-828-04

 

 

 

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·                 40 mg white to light yellow, oblong shaped film-coated tablets debossed with “BXM40” on one side available as:

 

o   1 x 40 mg tablet per blister card in secondary packaging: NDC 50242-860-01

o   2 x 40 mg tablets per blister card in secondary packaging: NDC 50242-860-02

Store XOFLUZA in its blister package at 20ºC to 25ºC (68ºF to 77ºF); excursions permitted to 15ºC to 30ºC (59ºF to 86ºF) [see USP Controlled Room Temperature].

 

 

 

17    PATIENT COUNSELING INFORMATION

 

Advise the patient to read the FDA-approved patient labeling (Patient Information). 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. 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) and Drug Interactions (7.1)].

 

Influenza Vaccines

 

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

 

 

 

Distributed by:

Genentech USA, Inc.

A Member of the Roche Group

1 DNA Way

South San Francisco, CA 94080-4990

 

Manufactured by: Shionogi & Co., Ltd. 2-5-1 Mishima, Settsu

Osaka 566-0022, Japan

 

XOFLUZA™ is a trademark of Genentech, Inc.

 

© 2018 Genentech USA, Inc.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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