Baloxavir (Monograph)

Brand name: Xofluza
Drug 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

Medically reviewed by Drugs.com on Sep 25, 2023. Written by ASHP.

Introduction

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

Uses for Baloxavir

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, including those who are otherwise healthy and those who are at high risk for influenza-related complications. Efficacy if administered >48 hours after symptom onset not evaluated.

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

For treatment of suspected or confirmed acute, uncomplicated seasonal influenza in otherwise healthy outpatients, CDC, IDSA, and others state that any age-appropriate influenza antiviral (oral oseltamivir, inhaled zanamivir, oral baloxavir marboxil, IV peramivir) can be used if not contraindicated. CDC states may consider early empiric antiviral treatment in outpatients with suspected influenza (e.g., influenza-like illness such as fever with either cough or sore throat) based on clinical judgement if such treatment can be initiated within 48 hours of illness onset.

For treatment of suspected or confirmed seasonal influenza in hospitalized patients or outpatients with severe, complicated, or progressive illness (e.g., pneumonia, exacerbation of underlying chronic medical conditions), CDC states oseltamivir is the preferred influenza antiviral because of lack of data regarding use of other influenza antivirals in such patients. CDC states baloxavir marboxil not recommended for treatment of influenza in hospitalized patients.

Consider that influenza and coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have overlapping signs and symptoms and coinfection with influenza A or B viruses and SARS-CoV-2 can occur. Although laboratory testing can help distinguish between influenza virus infection and SARS-CoV-2 infection, CDC recommends initiating empiric influenza treatment in patients with suspected influenza who are hospitalized, have severe, complicated, or progressive illness, or are at high risk for influenza complication without waiting for results of influenza testing, SARS-CoV-2 testing, or multiplex molecular assays that detect influenza A and B viruses and SARS-CoV- 2.

Consider viral surveillance data available from local and state health departments and CDC when selecting an antiviral for treatment of seasonal influenza. Strains of circulating influenza viruses and the antiviral susceptibility of these strains constantly evolve, and emergence of resistant strains may decrease effectiveness of influenza antivirals. Although circulating influenza A and B viruses during recent years have been susceptible to baloxavir, consult most recent information on susceptibility of circulating viruses when selecting an antiviral for treatment of influenza.

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

Prevention of Seasonal Influenza A and B Virus Infections

Postexposure prophylaxis of influenza A or B virus infection in adults and adolescents ≥12 years of age who are contacts of an individual with influenza.

Annual vaccination with seasonal influenza virus vaccine, as recommended by CDC's Advisory Committee on Immunization Practices (ACIP), is the primary means of preventing seasonal influenza and its severe complications. Prophylaxis with an appropriate antiviral active against circulating influenza strains is considered an adjunct to vaccination for control and prevention of influenza in certain individuals.

Base decisions regarding use of antivirals for prophylaxis of seasonal influenza on the risk for influenza-related complications in the exposed individual, the type and duration of contact, recommendations from local or public health authorities, and clinical judgment. In general, use influenza antiviral prophylaxis only if it can be initiated within 48 hours after the most recent exposure.

CDC and others do not recommend routine use of influenza antivirals for postexposure prophylaxis in individuals exposed to influenza; may consider such prophylaxis in certain situations in exposed individuals at high risk for influenza-related complications for whom influenza vaccine is contraindicated, unavailable, or expected to have low efficacy (e.g., immunocompromised individuals).

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

Related/similar drugs

Tamiflu, oseltamivir, amantadine, Vicks DayQuil Severe Cold & Flu, Xofluza, Coricidin HBP Cold & Flu, Afluria

Baloxavir Dosage and Administration

Administration

Oral Administration

Administer orally without regard to meals.

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

Commercially available as tablets or as granules for oral suspension that must be suspended in water prior to administration.

Granules for Oral Suspension

Baloxavir marboxil granules for oral suspension are intended for use in patients unable to easily swallow tablets or those requiring enteral administration.

Prior to dispensing, add 20 mL of drinking or sterile water to a bottle containing baloxavir marboxil granules and swirl the bottle to ensure the granules are evenly suspended; do not shake the bottle. Each bottle provides an oral suspension containing 40 mg/20 mL (2 mg/mL) of the drug. Depending on the required dosage, prepare 1 or 2 bottles of the oral suspension.

Does not contain preservatives and must be administered within 10 hours following preparation. May store oral suspension at room temperature (20–25°C) for up to 10 hours after preparation; discard if not used within 10 hours or if stored at a temperature >25°C. Mark the expiration date and time on the bottle at the time of preparation.

Provide a measuring device (e.g., oral syringe, measuring cup) with the oral suspension.

Enteral administration (i.e., feeding tube): Draw the dose of oral suspension into an enteral syringe; flush the feeding tube with 1 mL of water before and after enteral administration of the dose.

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

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

Prevention of Seasonal Influenza A and B Virus Infections

Oral

Adolescents ≥12 years of age weighing <80 kg: Single 40-mg dose given within 48 hours after contact with an individual with influenza.

Adolescents ≥12 years of age weighing ≥80 kg: Single 80-mg dose given within 48 hours after contact with an individual with influenza.

Adults

Treatment of Seasonal Influenza A and B Virus Infections

Acute, Uncomplicated Influenza A or B Virus Infections

Oral

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

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

Prevention of Seasonal Influenza A and B Virus Infections

Oral

Adults weighing <80 kg: Single 40-mg dose given within 48 hours after contact with an individual with influenza.

Adults weighing ≥80 kg: Single 80-mg dose given within 48 hours after contact with an individual with influenza.

Special Populations

No special population dosage recommendations provided by the manufacturer for geriatric individuals or patients with impaired hepatic or renal function.

Cautions for Baloxavir

Contraindications

• History of hypersensitivity to baloxavir marboxil or any ingredient in the formulation.

Warnings/Precautions

Sensitivity Reactions

Serious allergic reactions, including anaphylaxis, anaphylactic or anaphylactoid reactions, angioedema (face, eyelids, tongue, lips), urticaria, and erythema multiforme, reported during postmarketing experience. Rash also reported.

Initiate appropriate treatment if an allergic-like reaction occurs or is suspected.

Bacterial Infections

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

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

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

Immunocompromised Individuals

Data not available regarding efficacy and safety of baloxavir marboxil for treatment of influenza in individuals with severe immunosuppression. Emergence of resistance to baloxavir may be a concern because duration of influenza virus replication may be prolonged in such patients.

CDC does not recommend baloxavir marboxil monotherapy for treatment of influenza in individuals with severe immunosuppression.

Influenza Vaccination

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

Although influenza antivirals, including baloxavir marboxil, may be used concomitantly with or any time before or after influenza virus vaccine inactivated or influenza vaccine recombinant, such antivirals may inhibit the vaccine virus contained in influenza vaccine live intranasal and decrease efficacy of the live vaccine. (See Specific Drugs under Interactions.)

Specific Populations

Pregnancy

No adequate and well-controlled studies using baloxavir marboxil in pregnant women to inform a drug-associated risk of adverse developmental outcomes.

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

Pregnant women are at increased risk for severe complications from influenza, 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.

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

Lactation

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

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.

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

Pediatric Use

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

Treatment of acute, uncomplicated influenza in adolescents ≥12 years of age weighing ≥40 kg: Safety and efficacy established in a phase 3, randomized, double-blind, placebo-controlled study. Safety profile was similar to that reported in adults.

Postexposure prophylaxis of influenza in adolescents ≥12 years of age: Safety and efficacy supported by a randomized, double-blind, placebo-controlled trial conducted in Japan that included 12 individuals 12–17 years of age who received the drug. Adverse effects were similar to those reported in adults who received the drug.

Geriatric Use

Safety and efficacy in adults ≥65 years of age for treatment of acute, uncomplicated influenza established and supported by a randomized, double-blind, controlled trial that included 209 adults in this age group at high risk of influenza-related complications who were treated with the drug. Safety profile in adults ≥65 years of age was similar to that reported in the overall trial population, with the exception of nausea (reported in 6% of adults ≥65 years of age compared with 1% of those 18–64 years of age).

Common Adverse Effects

GI effects (nausea, diarrhea), bronchitis, sinusitis, headache.

Drug Interactions

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

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

Baloxavir marboxil and baloxavir do not inhibit UGT1A1, 1A3, 1A4, 1A6, 1A9, 2B7, or 2B15 in vitro. 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.

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

Specific Drugs

Baloxavir Pharmacokinetics

Absorption

Bioavailability

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

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

Baloxavir exposure decreases as body weight increases. No clinically important difference in exposures observed between body weight groups when the recommended weight-based baloxavir marboxil dosage is used (40-mg dose in those weighing <80 kg or 80-mg dose in those weighing ≥80 kg).

Food

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

Baloxavir may form chelates with polyvalent cations (e.g., aluminum, calcium, iron, magnesium, selenium, zinc); 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. (See Specific Drugs under Interactions.)

Distribution

Extent

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

Plasma Protein Binding

Approximately 93–94% in vitro.

Elimination

Metabolism

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

Elimination Route

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

Half-life

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

Special Populations

Based on a population pharmacokinetic analysis, baloxavir exposure is approximately 35% lower in non-Asians compared with Asians; this difference not considered clinically important when recommended baloxavir marboxil dosage used.

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

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

Stability

Storage

Oral

Granules for Oral Suspension

20–25°C (may be exposed to 15–30°C).

Following suspension in drinking or sterile water, may store in original bottle at room temperature (20–25°C) for up to 10 hours. Discard if not used within 10 hours or if stored at >25°C.

Tablets

20–25°C (may be exposed to 15–30°C).

Actions and Spectrum

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

• 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.

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

• 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).

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

• Influenza A viruses with reduced susceptibility to baloxavir have been produced in vitro. 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.

• Viral surveillance data indicate almost all influenza A (H1N1)pdm09, influenza A (H3N2), and influenza B viruses circulating during recent influenza seasons have been susceptible to baloxavir in vitro; reduced in vitro susceptibility to baloxavir reported only rarely in influenza A (H1N1)pdm09 and influenza A (H3N2) circulating during recent influenza seasons.

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

• Cross-resistance between baloxavir and neuraminidase inhibitors (oseltamivir, peramivir, zanamivir) or adamantane derivatives (amantadine, rimantadine) not expected. 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.

Advice to Patients

• Importance of reading patient information provided by the manufacturer.

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

• Postexposure prophylaxis of influenza: Importance of initiating baloxavir marboxil as soon as possible after exposure.

• 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).

• Importance of taking baloxavir marboxil as a single dose as prescribed (either as a tablet or oral suspension).

• If the oral suspension is used, advise patients and/or caregivers that the total prescribed dose may require 1 or 2 bottles of the oral suspension, depending on patient's weight. Importance of administering the oral suspension as soon as possible, but no later than 10 hours after preparation. Expiration date and time should appear on the bottle(s) of oral suspension.

• Advise patients and/or caregivers of the risk of severe allergic reactions (e.g., anaphylaxis, angioedema, urticaria, erythema multiforme) and importance of seeking immediate medical attention if an allergic-like reaction occurs or is suspected.

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

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

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

• Importance of informing patients of other important precautionary information. (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.

Reload page with references included

Frequently asked questions

• What is the difference between Xofluza and Tamiflu?
• How long does it take for Xofluza to work?

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