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Baloxavir Marboxil

Class: Antivirals, Miscellaneous
VA Class: AM800
Chemical Name: Carbonic acid, [[(12aR)-12-[(11S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl]-3,4,6,8,12,12a-hexahydro-6,8-dioxo-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl]oxy]methyl methyl ester
Molecular Formula: C27H23F2N3O7S
CAS Number: 1985606-14-1
Brands: Xofluza

Medically reviewed by Drugs.com. Last updated on Aug 19, 2019.

Warning

Special Alerts:

For information on the use of this drug in patients with coronavirus disease 2019 (COVID-19), see the document “Assessment of the Evidence for COVID-19-Related Treatments” on ASHP's COVID-19 Resource Center. To view this document, please click here: [Web]

Introduction

Antiviral; prodrug of baloxavir, a polymerase acidic (PA) endonuclease inhibitor active against influenza A and B.1 2 4 5

Uses for Baloxavir Marboxil

Treatment of Seasonal Influenza A and B Virus Infections

Treatment of acute, uncomplicated influenza caused by influenza A or B viruses in adults and adolescents ≥12 years of age who have been symptomatic for ≤48 hours.1 2 Efficacy if administered >48 hours after symptom onset not evaluated.137

Data not available to date regarding use for treatment of severe or complicated influenza in either hospitalized patients or outpatients.137 Data also not available to date regarding use for prophylaxis of influenza.137

CDC, Advisory Committee on Immunization Practices (ACIP), IDSA, and AAP recommend that antiviral treatment be initiated as soon as possible in all individuals with suspected or confirmed influenza who require hospitalization or have severe, complicated, or progressive illness (regardless of vaccination status or underlying illness).105 112 116 137 144 Early empiric antiviral treatment also recommended in individuals with suspected or confirmed influenza of any severity if they are at high risk of developing influenza-related complications because of age or underlying medical conditions (regardless of vaccination status).105 112 116 137 144 This includes children <5 years of age (especially those <2 years of age), adults ≥65 years of age, individuals of any age with certain chronic medical or immunosuppressive conditions, women who are pregnant or ≤2 weeks postpartum, individuals <19 years of age receiving long-term aspirin therapy, American Indians, Alaskan natives, morbidly obese individuals with body mass index (BMI) ≥40, and residents of any age in nursing homes or other long-term care facilities.112 116 137 144

CDC, ACIP, IDSA, and AAP also state that empiric antiviral treatment can be considered in previously healthy, symptomatic individuals with suspected or confirmed influenza who are not known to be at increased risk of developing severe or complicated illness (regardless of vaccination status), if such treatment can be initiated within 48 hours of illness onset.105 112 116 137 144 Although these individuals typically do not require treatment, early empiric antiviral treatment might provide some benefit (e.g., shortened duration of illness).112 116 144 Use clinical judgment to make decisions regarding use of antivirals in such individuals; antivirals not needed in those already beginning to recover.137 144

If indicated, initiate antiviral treatment as soon as possible after illness onset (ideally within 48 hours);105 112 116 137 144 do not delay initiation of treatment while waiting for laboratory confirmation.105 112 116 137 144

For treatment of suspected or confirmed severe, complicated influenza in hospitalized patients or outpatients, oseltamivir is the preferred antiviral because of lack of data regarding use of other influenza antivirals (zanamivir, peramivir, baloxavir marboxil) in such patients.137 Oseltamivir also preferred antiviral for treatment of suspected or confirmed influenza in women who are pregnant or ≤2 weeks postpartum.116 142

For treatment of suspected or confirmed acute, uncomplicated influenza in otherwise healthy outpatients, CDC, IDSA, and others state that any age-appropriate influenza antiviral (oseltamivir, zanamivir, peramivir, baloxavir marboxil) can be used if not contraindicated.112 116 137

Consider viral surveillance data available from local and state health departments and CDC when selecting an antiviral for treatment of seasonal influenza.1 116 137 144 Strains of circulating influenza viruses and the antiviral susceptibility of these strains constantly evolve;144 emergence of resistant strains may decrease effectiveness of influenza antivirals.1

CDC issues recommendations concerning use of antivirals for treatment of influenza, and these recommendations are updated as needed during each influenza season.137 Information regarding influenza surveillance and updated recommendations for treatment of seasonal influenza are available from CDC at [Web].

Baloxavir Marboxil Dosage and Administration

Administration

Oral Administration

Administer orally without regard to meals.1

Avoid taking with dairy products; calcium-fortified beverages; aluminum-, calcium-, or magnesium-containing antacids; polyvalent cation-containing laxatives; or multivitamins or dietary supplements containing calcium, iron, magnesium, selenium, or zinc.1 (See Specific Drugs under Interactions.)

Dosage

Pediatric Patients

Treatment of Seasonal Influenza A and B Virus Infections
Acute, Uncomplicated Influenza A or B Virus Infections
Oral

Adolescents ≥12 years of age weighing 40 to <80 kg: Single 40-mg dose given within 48 hours after symptom onset.1

Adolescents ≥12 years of age weighing ≥80 kg: Single 80-mg dose given within 48 hours after symptom onset.1

Adults

Treatment of Seasonal Influenza A and B Virus Infections
Acute, Uncomplicated Influenza A or B Virus Infections
Oral

Adults weighing 40 to <80 kg: Single 40-mg dose given within 48 hours after symptom onset.1

Adults weighing ≥80 kg: Single 80-mg dose given within 48 hours after symptom onset.1

Special Populations

No special population dosage recommendations at this time.1

Cautions for Baloxavir Marboxil

Contraindications

  • Known hypersensitivity to baloxavir marboxil or any ingredient in the formulation.1

Warnings/Precautions

Bacterial Infections

When making treatment decisions in patients with suspected influenza, consider possibility of primary or concomitant bacterial infection.1

Serious bacterial infections may begin with influenza-like symptoms or may coexist with or occur as complications of influenza.1 No evidence that baloxavir prevents such complications.1 If a bacterial infection occurs, treat as appropriate.1

No evidence that baloxavir is effective for illness caused by any organisms other than influenza viruses.1

Influenza Vaccination

Influenza antivirals are not a substitute for annual vaccination with a seasonal influenza vaccine (influenza virus vaccine inactivated, influenza vaccine live intranasal, influenza vaccine recombinant).112 116 144

Although influenza virus vaccine inactivated or influenza vaccine recombinant may be administered to individuals receiving influenza antivirals,100 134 such antivirals may inhibit the vaccine virus contained in influenza vaccine live intranasal and decrease efficacy of this influenza vaccine.1 100 134 (See Specific Drugs under Interactions.)

Specific Populations

Pregnancy

Data not available regarding use of baloxavir marboxil in pregnant women.1

No adverse embryofetal effects were observed in reproduction studies in rats and rabbits.1

Pregnant women are at increased risk for severe complications from influenza,1 142 which may lead to adverse pregnancy and/or fetal outcomes including maternal death, stillbirths, birth defects, preterm delivery, low birthweight, and small size for gestational age.1

CDC states baloxavir marboxil not recommended for treatment of influenza in pregnant women because of lack of safety and efficacy data in such patients.142 Oseltamivir is the preferred antiviral for treatment of suspected or confirmed influenza in women who are pregnant or ≤2 weeks postpartum.116 137 142

Lactation

Not known whether distributes into human milk, affects milk production, or has any effects on breast-fed infants.1 Distributed into milk in rats.1

Manufacturer states consider benefits of breast-feeding and importance of baloxavir marboxil to the woman; also consider potential adverse effects on the breast-fed child from the drug or the underlying maternal condition.1

CDC states baloxavir marboxil not recommended for treatment of influenza in nursing women because of lack of safety data in such patients.142

Pediatric Use

Safety and efficacy not established in pediatric patients <12 years of age.1

Safety and efficacy in adolescents ≥12 years of age similar to that reported in adults.1

Geriatric Use

Clinical studies to date have not included patients ≥65 years of age;1 2 insufficient data to determine whether geriatric patients respond differently than younger adults.1

Common Adverse Effects

GI effects (nausea, diarrhea), bronchitis, nasopharyngitis, headache.1

Interactions for Baloxavir Marboxil

Active metabolite of baloxavir marboxil, baloxavir, is metabolized principally by UGT1A3 and, to a minor extent, by CYP3A4.1

Baloxavir marboxil and baloxavir do not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, or 2D6 and do not induce CYP1A2, 2B6, or 3A4 in vitro.1

Baloxavir marboxil and baloxavir do not inhibit UGT1A1, 1A3, 1A4, 1A6, 1A9, 2B7, or 2B15 in vitro.1 Baloxavir does not inhibit organic anion transport polypeptide (OATP) 1B1, OATP1B3, organic cation transporter (OCT) 1, OCT2, organic anion transporter (OAT) 1, OAT3, multidrug and toxin extrusion (MATE) 1, or MATE2K.1

Baloxavir marboxil and baloxavir are substrates of P-glycoprotein (P-gp) in vitro.1

Specific Drugs

Drug

Interaction

Comments

Antacids, aluminum-, calcium-, or magnesium-containing

May decrease baloxavir concentrations and decrease efficacy1

Avoid concomitant administration with baloxavir marboxil1

Calcium supplements

May decrease baloxavir concentrations and decrease efficacy1

Avoid concomitant administration with baloxavir marboxil1

Digoxin

No effect on pharmacokinetics of digoxin1

Influenza vaccines

Influenza virus vaccine inactivated and influenza vaccine recombinant: Influenza antivirals not expected to affect vaccine efficacy;100 134 not specifically studied with baloxavir marboxil1

Influenza vaccine live intranasal: Influenza antivirals may inhibit the vaccine virus and decrease vaccine efficacy;1 100 134 not specifically studied with baloxavir marboxil1

Influenza virus vaccine inactivated and influenza vaccine recombinant: May administer concomitantly with or any time before or after influenza antivirals100 134

Influenza vaccine live intranasal: Do not administer until ≥48 hours after influenza antivirals discontinued;100 134 137 if feasible, do not administer influenza antivirals until ≥14 days after the vaccine; if influenza antiviral given within 2 weeks after the vaccine, repeat vaccine dose ≥48 hours after the antiviral;134 alternatively, revaccinate using age-appropriate inactivated or recombinant influenza vaccine100 134

Iron preparations

May decrease baloxavir concentrations and decrease efficacy1

Avoid concomitant administration with baloxavir marboxil1

Itraconazole

No effect on pharmacokinetics of baloxavir marboxil or baloxavir1

Laxatives containing polyvalent cations

May decrease baloxavir concentrations and decrease efficacy1

Avoid concomitant administration with baloxavir marboxil1

Midazolam

No effect on pharmacokinetics of midazolam1

Multivitamins

May decrease baloxavir concentrations and decrease efficacy1

Avoid concomitant administration with baloxavir marboxil1

Oseltamivir

No effect on pharmacokinetics of oseltamivir, baloxavir marboxil, or baloxavir1

Probenecid

No effect on pharmacokinetics of baloxavir marboxil or baloxavir1

Rosuvastatin

No effect on pharmacokinetics of rosuvastatin1

Baloxavir Marboxil Pharmacokinetics

Absorption

Bioavailability

Following oral administration of baloxavir marboxil, rapidly and almost completely converted to active metabolite, baloxavir,1 4 6 7 by esterases in GI lumen, liver, and blood.4 7

Median time to peak plasma concentrations of baloxavir after oral administration of baloxavir marboxil is 4 hours.1 4 6 7

Food

Food decreases peak plasma concentrations and AUC of baloxavir by approximately 48 and 36%, respectively.1 6

Baloxavir may form chelates with polyvalent cations (e.g., aluminum, calcium, iron, magnesium, selenium, zinc);1 systemic baloxavir exposures may be decreased if baloxavir marboxil is administered with dairy products, calcium-fortified beverages, or other foods, drugs, or preparations containing polyvalent cations.1 (See Specific Drugs under Interactions.)

Distribution

Extent

Baloxavir and its related metabolites are distributed into milk in rats;1 not known whether distributed into human milk.1

Plasma Protein Binding

Approximately 93–94% in vitro.1

Elimination

Metabolism

Following oral administration, baloxavir marboxil rapidly hydrolyzed by esterases to the active metabolite, baloxavir.1 4 6 Baloxavir is then metabolized principally by UGT1A3 and, to a lesser extent, by CYP3A4.1

Elimination Route

Approximately 80% of an oral dose of baloxavir marboxil is eliminated in feces as baloxavir;1 4 <15% eliminated in urine.1 4

Half-life

Baloxavir: Mean apparent terminal elimination half-life is approximately 80 hours.1 4 7

Special Populations

Hepatic impairment: Pharmacokinetics not affected in patients with moderate impairment (Child-Pugh class B).1 Not evaluated in those with severe impairment (Child-Pugh class C).1

Renal impairment: Pharmacokinetics not affected in patients with CLcr ≥50 mL/minute.1 Not evaluated in those with severe renal impairment.1

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).1

Actions and Spectrum

  • Baloxavir marboxil is a prodrug of baloxavir, a polymerase acidic (PA) endonuclease inhibitor antiviral.1 2 4 5 Inactive until hydrolyzed in vivo to baloxavir.1 2 4

  • Baloxavir selectively inhibits cap-dependent endonuclease activity of the PA subunit of the viral RNA polymerase complex and prevents transcription of influenza viral messenger RNA, which is required for viral replication.1 2 4 5

  • Mechanism of action against influenza viruses differs from that of neuraminidase inhibitor antivirals (oseltamivir, peramivir, zanamivir) and adamantane derivative antivirals (amantadine, rimantadine).4

  • Active in vitro against laboratory and clinical isolates of influenza A and B viruses, and has been active against some influenza strains resistant to neuraminidase inhibitors (oseltamivir, peramivir, zanamivir).1 5

  • Has been active in vitro against some avian influenza A viruses, including some strains of avian influenza A (H5N1) and (H7N9).1 5

  • Influenza A viruses with reduced susceptibility to baloxavir have been produced in vitro.1 5 In addition, influenza A and B viruses with treatment-emergent amino acid substitutions associated with reduced in vitro susceptibility to baloxavir reported in some patients treated with baloxavir marboxil.1 2 4

  • Influenza viruses with reduced susceptibility to baloxavir have amino acid substitutions in the PA protein of the viral RNA polymerase complex.1 5

  • Cross-resistance between baloxavir and neuraminidase inhibitors (oseltamivir, peramivir, zanamivir) or adamantane derivatives (amantadine, rimantadine) not expected.1 However, influenza viruses with amino acid substitutions in the PA protein of the viral RNA polymerase complex that confer resistance to baloxavir may also have substitutions that confer resistance to neuraminidase inhibitors or adamantane derivatives.1

Advice to Patients

  • Importance of reading patient information provided by the manufacturer.1

  • Importance of initiating baloxavir marboxil as soon as possible after first appearance of influenza symptoms (≤48 hours after symptom onset).1

  • Advise patients that baloxavir marboxil may be taken with or without food, but should not be taken with dairy products or calcium-fortified beverages or with antacids, laxatives, multivitamins, or dietary supplements containing polyvalent cations (e.g., calcium, iron, magnesium, selenium, zinc).1

  • Advise patients that influenza antivirals such as baloxavir marboxil may decrease effectiveness of influenza virus vaccine live;1 importance of consulting clinician before receiving the live intranasal influenza vaccine.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Baloxavir Marboxil

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

20 mg

Xofluza

Genentech

40 mg

Xofluza

Genentech

AHFS DI Essentials™. © Copyright 2020, Selected Revisions August 19, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Genentech USA, Inc. Xofluza (baloxavir marboxil) tablets prescribing information. South San Francisco, CA: 2018 Oct.

2. Hayden FG, Sugaya N, Hirotsu N et al. Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents. N Engl J Med. 2018; 379:913-923. http://www.ncbi.nlm.nih.gov/pubmed/30184455?dopt=AbstractPlus

3. Anon. Antiviral drugs for treatment and prophylaxis of seasonal influenza. Med Lett Drugs Ther. 2019; 61:1-4. http://www.ncbi.nlm.nih.gov/pubmed/30681660?dopt=AbstractPlus

4. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 210854Orig1s000: Clinical review(s). From FDA website. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210854Orig1s000MedR.pdf

5. Noshi T, Kitano M, Taniguchi K et al. In vitro characterization of baloxavir acid, a first-in-class cap-dependent endonuclease inhibitor of the influenza virus polymerase PA subunit. Antiviral Res. 2018; 160:109-117. http://www.ncbi.nlm.nih.gov/pubmed/30316915?dopt=AbstractPlus

6. Koshimichi H, Ishibashi T, Kawaguchi N et al. Safety, Tolerability, and Pharmacokinetics of the Novel Anti-influenza Agent Baloxavir Marboxil in Healthy Adults: Phase I Study Findings. Clin Drug Investig. 2018; 38:1189-1196. http://www.ncbi.nlm.nih.gov/pubmed/30288682?dopt=AbstractPlus

7. Koshimichi H, Tsuda Y, Ishibashi T et al. Population Pharmacokinetic and Exposure-Response Analyses of Baloxavir Marboxil in Adults and Adolescents Including Patients With Influenza. J Pharm Sci. 2018; http://www.ncbi.nlm.nih.gov/pubmed/30557562?dopt=AbstractPlus

8. Kawaguchi N, Koshimichi H, Ishibashi T et al. Evaluation of Drug-Drug Interaction Potential between Baloxavir Marboxil and Oseltamivir in Healthy Subjects. Clin Drug Investig. 2018; 38:1053-1060. http://www.ncbi.nlm.nih.gov/pubmed/30203386?dopt=AbstractPlus

100. Grohskopf LA, Sokolow LZ, Broder KR et al. Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices - United States, 2018-19 Influenza Season. MMWR Recomm Rep. 2018; 67:1-20. Additional background information may be available at CDC website at https://www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/flu.html. http://www.ncbi.nlm.nih.gov/pubmed/28841201?dopt=AbstractPlus

105. American Academy of Pediatrics. Red Book: 2018-2021 Report of the Committee on Infectious Diseases. 31st ed. Itasca, IL: American Academy of Pediatrics; 2018: 476-90.

112. Committee on Infectious Diseases. Recommendations for Prevention and Control of Influenza in Children, 2018-2019. Pediatrics. 2018; 142 http://www.ncbi.nlm.nih.gov/pubmed/30177511?dopt=AbstractPlus

116. Uyeki TM, Bernstein HH, Bradley JS et al. Clinical Practice Guidelines by the Infectious Diseases Society of America: 2018 Update on Diagnosis, Treatment, Chemoprophylaxis, and Institutional Outbreak Management of Seasonal Influenza. Clin Infect Dis. 2019; 68:e1-e47. http://www.ncbi.nlm.nih.gov/pubmed/30566567?dopt=AbstractPlus

134. Kroger AT, Duchin J, Vazquez M. General best practice guidelines for immunization. Best practices guidance of the Advisory Committee on Immunization Practices (ACIP). From CDC website. Accessed 2019 Apr 15. Updates may be available at CDC website. https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/downloads/general-recs.pdf

137. Centers for Disease Control and Prevention. Influenza antiviral medications: summary for clinicians. From CDC website. Accessed 2019 Apr 15. http://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm

142. Centers for Disease Control and Prevention. Recommendations for obstetric health care providers related to use of antiviral medications in the treatment and prevention of influenza. From CDC website. Accessed 2019 Apr 15.

144. Fiore AE , Fry A, Shay D et al. Antiviral agents for the treatment and chemoprophylaxis of influenza --- recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2011; 60:1-24.

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