Xofluza

Baloxavir marboxil.

XOFLUZA (baloxavir marboxil) is an antiviral 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]thiepin11-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)methylmethyl carbonate. The empirical formula of baloxavir marboxil is C₂₇H₂₃F₂N₃O₇S.
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.
Excipients/Inactive Ingredients: The inactive ingredients of XOFLUZA are: croscarmellose sodium, hypromellose, lactose monohydrate, microcrystalline cellulose, povidone, sodium stearyl fumarate, talc, and titanium dioxide.

Pharmacology: Mechanism of Action: Baloxavir marboxil is an antiviral drug with activity against influenza virus [see Microbiology as follows].
Pharmacodynamics: 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; and 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.
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 1. (See Tables 1 & 2.)

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No clinically significant differences in the pharmacokinetics of baloxavir were observed based on age, sex, or creatinine clearance (CrCl: 50 mL/min and above), moderate hepatic impairment (Child-Pugh class B). The effect of severe renal or hepatic impairment on baloxavir pharmacokinetics has not been evaluated.
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: Clinical Studies: No clinically significant changes in the pharmacokinetics of baloxavir marboxil and its active metabolite, baloxavir, were observed when coadministered 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 coadministered with baloxavir marboxil: midazolam (CYP3A4 substrate), digoxin (P-gp substrate), rosuvastatin (BCRP substrate), or oseltamivir.
Animal Studies: Polyvalent Cations: In monkeys, a 48% to 63% decrease in baloxavir exposure was observed when XOFLUZA was coadministered with calcium, aluminum, magnesium, or iron. No study has been conducted in humans
In Vitro Studies: Cytochrome P450 (CYP) Enzymes: Both baloxavir marboxil and baloxavir, did not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 and did not induce CYP1A2, CYP2B6, or CYP3A4.
Uridine diphosphate (UDP)-glucuronosyl transferase (UGT) Enzymes: Baloxavir marboxil and 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 does 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.
Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: 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.
Clinical Studies: Treatment of Acute Uncomplicated Influenza - Otherwise Healthy Subjects: 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 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 (see Tables 3 and 4).

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In Trial 2, there was no difference in the time to alleviation of symptoms between subjects (age ≥ 20) 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.
Treatment of Acute Uncomplicated Influenza - High Risk Subjects: Trial 3 (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 definition 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 3, 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 pre-existing 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 5.

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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).
Post-Exposure Prophylaxis of Influenza: Trial 4 was a phase 3, randomized, double-blind, multicenter, placebo-controlled study 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 607 subjects (XOFLUZA N=303, placebo N=304) ≥ 12 years of age were randomized and received a single oral dose of XOFLUZA according to body weight and age, or placebo, on day 1. Subjects received 40 mg or 80 mg of XOFLUZA according to body weight (40 to < 80 kg or ≥ 80 kg, respectively). 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 ≥ 12 years of age in Trial 4 was 40 years; 33 (5%) were ≥ 12 to < 18 years of age, 551 (91%) were ≥ 18 to < 65 years of age, and 23 (4%) were ≥ 65 years of age. All subjects were Asian, 84% were female, and 16% were male. The predominant influenza virus strains in the index patients of this study were the A/H3N2 subtype (49%) and the A/H1N1 subtype (46%), followed by the B subtype (1%).
In subjects that were ≥12 years of age, 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 1% in the XOFLUZA group (see Table 6).

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XOFLUZA treatment resulted in a significant reduction in the risk ratio of patients who were infected with influenza virus and presented with fever compared to placebo using modified Poisson regression for a binary response (p-value: <0.0001).
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) 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: 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 7). In adult and adolescent subjects who had a confirmed influenza virus infection, the overall frequencies of treatment-emergent amino acid substitutions associated with reduced susceptibility to baloxavir were 4.5% (6/134), 10.9% (53/485), and 0.9% (2/224) in influenza A/H1N1, A/H3N2, and B virus infections, respectively, in pooled data from Trials 1, 2, and 3 [see Pharmacology: Clinical Studies as previously mentioned]. In Trial 4, of 374 subjects, including 71 subjects <12 years of age, who received XOFLUZA post-exposure prophylaxis, 49 were viral RNA-positive post-baseline, including 31 subjects who were evaluated for resistance. Of these 31 subjects, influenza virus with substitutions associated with reduced susceptibility to baloxavir was identified in 7/7 subjects who developed clinical influenza (as described for the primary endpoint) and 8/24 other subjects evaluated who did not meet the primary endpoint definition for clinical influenza [see Clinical Studies as previously mentioned]. Selection of influenza viruses with reduced susceptibility to baloxavir has occurred at higher frequencies in pediatric subjects, and such viruses were detected with overall frequencies of 20% (4/20), 27.9% (34/122), and 0% (0/21) in influenza A/H1N1, A/H3N2, and B virus infections, respectively, in pooled data from 3 pediatric treatment trials in subjects <12 years of age. (See Table 7.)

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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 substitutions E119V and R292K, A/H7N9 virus with the NA substitution R292K (A/H3N2 numbering), and type B virus with the NA substitutions R152K and 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.

Treatment of Influenza: XOFLUZA 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 and who are: otherwise healthy, or at high risk of developing influenza-related complications [see Pharmacology: Clinical Studies: Treatment of Acute Uncomplicated Influenza - High Risk Subjects under Actions].
Post-Exposure Prophylaxis of Influenza: XOFLUZA is indicated for post-exposure prophylaxis of influenza in persons 12 years of age and older following contact with an individual who has influenza [see Pharmacology: Clinical Studies: Post-Exposure Prophylaxis of Influenza under Actions].
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 and Pharmacology: Clinical Studies under Actions].

Dosage and Administration Overview: Initiate treatment with XOFLUZA.
XOFLUZA should be taken as soon as possible after influenza symptom onset or exposure to influenza 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 Effect of Other Drugs on XOFLUZA under Interactions and Pharmacology: Pharmacokinetics under Actions].
Recommended Dosage: 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 of 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 Table 8. (See Table 8.)

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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 Pharmacology: Pharmacokinetics under Actions].

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 Hypersensitivity under Precautions].

Hypersensitivity: Cases of anaphylaxis, urticaria, angioedema, and erythema multiforme have been reported in post-marketing 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 and Postmarketing Experience under Adverse Reactions].
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.
Use in Children: Treatment of Acute Uncomplicated Influenza in Pediatric Patients: The safety and effectiveness of XOFLUZA for the treatment of acute uncomplicated influenza 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 Pharmacology: Clinical Studies: Treatment of Acute Uncomplicated Influenza - Otherwise Healthy Subjects under Actions]. 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 in Trial 2 was comparable to that observed 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 Pharmacology: Clinical Studies: Treatment of Acute Uncomplicated Influenza - Otherwise Healthy Subjects under Actions]. Adverse events reported in adolescents in both trials were similar to those reported in adults [see Clinical Trials Experience under Adverse Reactions].
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 under Actions].
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 Pharmacology: Clinical Studies: Post-Exposure Prophylaxis of Influenza under Actions]. 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 Pharmacology: Clinical Studies: Post-Exposure Prophylaxis of Influenza under Actions]. Adverse events reported in adolescent subjects were similar to those reported in adults in the same trial [see Clinical Trials Experience under Adverse Reactions].
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.
Use in the Elderly: 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 Pharmacology: Clinical Studies: Treatment of Acute Uncomplicated Influenza - High Risk Subjects under Actions]. In Trial 3, 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.

Pregnancy: Risk Summary: There are no adequate and well-controlled studies with 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 as follows). 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 as follows).
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.
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 as follows). 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.

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 1,943 subjects 12 years of age and older in 4 controlled clinical trials who received XOFLUZA [see Pharmacology: Clinical Studies under Actions].
Treatment of Acute Uncomplicated Influenza: The safety of XOFLUZA in adult and adolescent subjects is based on data from 3 placebo-controlled trials in which a total of 1,640 subjects received XOFLUZA: 1,334 subjects (81%) were 18 to 64 years of age, 209 subjects (13%) were adults 65 years of age or older and 97 subjects (6%) were adolescents 12 to 17 years of age. These trials included otherwise healthy adults and adolescents (N=910) and subjects at high risk of developing complications associated with influenza (N=730). Of these, 1,440 subjects received XOFLUZA at the recommended dose [see Pharmacology: Clinical Studies under Actions]. Trial 1 was a phase 2 dose-finding placebo-controlled trial where otherwise healthy adult subjects 20 to 64 years of age received single oral dose of XOFLUZA or placebo. Trial 2 was a placebo- and active-controlled trial in otherwise healthy adults and adolescents 12 to 64 years of age; subjects received weight-based XOFLUZA or placebo as a single oral dose on Day 1 or oseltamivir twice a day for 5 days. Trial 3 was a randomized, double-blind, placebo- and active-controlled trial where adults and adolescents at high risk of influenza complications 12 years of age and older received either XOFLUZA, placebo or oseltamivir.
Table 9 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, 2 and 3. (See Table 9.)

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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 Pharmacology: Clinical Studies: Post-Exposure Prophylaxis of Influenza under Actions].
Postmarketing Experience: The following adverse reactions have been identified during post-marketing 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.

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 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).
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.

Do not store above 30°C, store in the original package in order to protect from moisture.

Advise the patient to read the NPRA-approved Patient Information Leaflet (RiMUP).
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 & Administration].
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 & Administration and Effect of Other Drugs on XOFLUZA under Interactions].
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 in blister card containing one tablet of 40 mg to be taken as a single 40 mg dose and blister card containing four tablets of 20 mg to be taken together as a single 80 mg dose [see Presentation and Storage].
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 and Hypersensitivity under Precautions].
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 Vaccines under Interactions].

Antivirals

J05AX25 - baloxavir marboxil ; Belongs to the class of other antivirals. Used as a direct acting antiviral in the systemic treatment of viral infections.

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