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Baloxavir Marboxil
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General dosing information:
Seasonal influenza virus:
Novel influenza A viruses associated with severe human disease, including avian influenza virus:
80 mg PO as a single dose within 48 hours of symptom onset.[63687]
40 mg PO as a single dose within 48 hours of symptom onset.[63687]
80 mg PO as a single dose within 48 hours of symptom onset.[63687]
40 mg PO as a single dose within 48 hours of symptom onset.[63687]
2 mg/kg PO as a single dose within 48 hours of symptom onset.[63687]
80 mg PO as a single dose administered as soon as possible after contact with an individual who has influenza.[63687]
40 mg PO as a single dose administered as soon as possible after contact with an individual who has influenza.[63687]
80 mg PO as a single dose administered as soon as possible after contact with an individual who has influenza.[63687]
40 mg PO as a single dose administered as soon as possible after contact with an individual who has influenza.[63687]
2 mg/kg PO as a single dose administered as soon as possible after contact with an individual who has influenza.[63687]
80 mg PO as a single dose for outpatients with uncomplicated, mild-to-moderate illness who present within 48 hours of symptom onset.[62315] [62336]
40 mg PO as a single dose for outpatients with uncomplicated, mild-to-moderate illness who present within 48 hours of symptom onset.[62315] [62336]
80 mg PO as a single dose for outpatients with uncomplicated, mild-to-moderate illness who present within 48 hours of symptom onset.[62315] [62336]
40 mg PO as a single dose for outpatients with uncomplicated, mild-to-moderate illness who present within 48 hours of symptom onset.[62315] [62336]
weight 80 kg or more: 80 mg PO.
weight less than 80 kg: 40 mg PO.
weight 80 kg or more: 80 mg PO.
weight less than 80 kg: 40 mg PO.
weight 80 kg or more: 80 mg PO.
weight less than 80 kg: 40 mg PO.
5 to 12 years and weight 80 kg or more: 80 mg PO.
5 to 12 years and weight 20 to 79 kg: 40 mg PO.
5 to 12 years and weight less than 20 kg: 2 mg/kg PO.
1 to 4 years: Safety and efficacy have not been established.
Safety and efficacy have not been established.
Safety and efficacy have not been established.
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.[63687]
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.[63687]
† Off-label indication
Baloxavir marboxil is an oral antiviral drug given as a single weight-based dose. It is approved to treat uncomplicated influenza infection in patients 5 years and older who have been symptomatic for no more than 48 hours and who are otherwise healthy or are at high risk of developing influenza-related complications. Baloxavir is also approved for postexposure influenza prophylaxis in patients 5 years and older. Baloxavir is active against both influenza A and B viruses. It is the first drug approved that targets the influenza virus-specific enzyme polymerase acidic (PA) protein, which is located within the viral RNA polymerase complex. By inhibiting the endonuclease activity of the PA protein, the drug prevents viral gene transcription and ultimately viral replication. Baloxavir is not a substitute for an annual influenza virus vaccination. Instead, antiviral drugs are considered adjuncts to the prevention and control of influenza; annual influenza vaccination remains the main option for reducing the impact of influenza.[62315][63687]
For storage information, see the specific product information within the How Supplied section.
Reconstitution
Enteral Administration
Gastrointestinal adverse reactions reported in adults and adolescents during clinical trials with baloxavir marboxil include diarrhea (3%) and nausea (2%). Diarrhea and vomiting were reported in 5% of patients 5 to 11 years receiving baloxavir in clinical trials. Other adverse reactions reported during postmarketing use include hematochezia, melena, and colitis.[63687]
Dermatologic and immune system adverse reactions reported during postmarketing use of baloxavir marboxil include cases of anaphylactic shock, anaphylactic and anaphylactoid reactions, hypersensitivity reactions, angioedema (swelling of face, eyelids, and tongue), rash, urticaria, and erythema multiforme.[63687]
Headache was reported in 1% of adults and adolescents during clinical trials with baloxavir marboxil. Other adverse reactions reported during postmarketing use include delirium, abnormal behavior, and hallucinations.[63687]
Respiratory adverse reactions reported in adults and adolescents during clinical trials with baloxavir marboxil include bronchitis (3%) and sinusitis (2%).[63687]
Antiviral medications with activity against influenza, such as baloxavir marboxil, are not substitutes for receipt of an annual influenza vaccination; these medications should be used as an adjunct to the vaccine in the control of influenza. Interaction studies with baloxavir marboxil and influenza vaccines have not been conducted. Concurrent administration may interfere with the viral replication necessary after administration of the live attenuated influenza vaccine for the proper development of immunity.[63687]
Serious bacterial infections may begin with influenza-type symptoms or may coexist with or occur as complications of influenza. There are no data to suggest baloxavir marboxil is effective in preventing such complications or treating a viral infection other than influenza virus A and B. Baloxavir marboxil is most effective when initiated within 48 hours of symptom onset.[63687]
Pregnant and postpartum patients are at significantly higher risk for serious complications from influenza infection as compared with nonpregnant people; therefore, timely use of antiviral therapy is recommended for the treatment of influenza. However, the Centers for Disease Control and Prevention (CDC) and the American College of Obstetricians and Gynecologists (ACOG) do not recommend the use of baloxavir marboxil during pregnancy due to the lack of safety and efficacy data; oseltamivir is the preferred treatment in pregnant patients. No data are available regarding the use of baloxavir marboxil during human pregnancy. In animal studies, adverse developmental effects were not observed in rats or rabbits with systemic drug exposures of approximately 5- and 7-times, respectively, the exposure at the maximum recommended human dose.[63687] [62315] [70419]
It is not known if baloxavir marboxil is excreted in human milk, or if the drug has an adverse effect on milk production or a breastfed infant. Due to the lack of safety data, the CDC does not recommend baloxavir in breast-feeding mothers.[62315] Zanamivir and oseltamivir may be potential alternatives to consider during breast-feeding. However, patient factors, local susceptibility patterns, and specific microbial susceptibility should be assessed before choosing an alternative. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.[46966] [46967] [63687]
Baloxavir is not indicated in neonates, infants, and children younger than 5 years of age due to increased incidence of treatment emergent resistance in this age group. In clinical trials, the incidence of virus with treatment-emergent substitutions associated with reduced susceptibility to baloxavir (resistance) was higher in patients younger than 5 years (43%, 36/83) than in patients 5 to 11 years (16%, 19/117) or patients 12 years and older (7%, 60/842). The potential for transmission of resistant strains in the community has not been determined.[63687]
Baloxavir, the active metabolite of baloxavir marboxil, is responsible for the drugs antiviral activity. Baloxavir inhibits the endonuclease activity of polymerase acidic (PA) protein, an influenza virus-specific enzyme in the viral RNA polymerase complex. By blocking the PA protein, baloxavir prevents viral gene transcription and ultimately influenza virus replication.[63687]
Influenza viruses are classified into 3 distinct types, influenza A, B, and C, with influenza infections being attributed to either the influenza A virus or influenza B virus. Influenza A is further divided into subtypes based on their hemagglutinin (H or HA) and neuraminidase (N or NA) activity. At least 16 distinct HAs (H1 to H16) and 9 NAs (N1 to N9) have been described. In 2009, a novel influenza A H1N1 virus (previously referred to as swine influenza) was identified; this virus is included in season influenza A viruses. Human cases of influenza illness from the avian H5N1 virus (commonly known as avian flu) have been reported since 1997. Human infections with avian H7N9, H5N2, H5N8, H9N2, H7N7, and H7N3 viruses have also been described.[36906] [62337]
Based on data from an MDCK-cell-based plaque reduction assay, the median 50% effective concentrations (EC50) of baloxavir are 0.73 nM (n = 31; range 0.2 to 1.85 nM) for subtype A/H1N1 strains, 0.83 nM (n = 33; range 0.35 to 2.63 nM) for subtype A/H3N2 strains, and 5.97 nM (n = 30; range 2.67 to 14.23 nM) for type B strains. A virus titer reduction assay found the 90% effective concentration (EC90) values against avian subtypes A/H5N1 and A/H7N9 to be in the range of 0.8 to 3.16 nM. A relationship between antiviral activity in cell culture and clinical efficacy (i.e., inhibition of influenza virus replication) in humans has not been established.
Influenza A virus isolates with reduced susceptibility to baloxavir have been selected in cell cultures. Amino acid substitutions in the PA protein of the viral RNA polymerase complex that confer reduced susceptibility to baloxavir include I38T (A/H1N1 and A/H3N2), E198K and E18G (AH1N1), and E199G (A/H3N2). In clinical studies in patients with confirmed influenza virus infection, the incidence of treatment-emergent amino acid substitutions associated with reduced susceptibility to baloxavir was 4.5% (n = 6 of 134) in influenza A/H1N1 virus, 10.9% (n = 53 of 485) in influenza A/H3N2 virus, and 0.9% (n = 2 of 224) in influenza B virus. In a post-exposure prophylaxis trial (Trial T0834), 27 patients were evaluated for resistance. Of these, influenza virus with substitutions associated with reduced susceptibility to baloxavir was identified in 6 of 6 patients who developed clinical influenza and 7 of 21 patients who did not meet the primary endpoint definition for clinical influenza. Selection of influenza viruses with reduced susceptibility to baloxavir has occurred in higher frequencies in pediatric patients with overall frequencies of 20.1% (n = 6 of 29) in influenza A/H1N1 virus, 34.5% (n = 49 of 142) in influenza A/H3N2 virus, and 0% (n = 0 of 30) in influenza B virus in pooled data from pediatric treatment trials in patients younger than 12 years. Specific amino acid substitutions were E23G/K/R, A37T, I38F/N/S/T for influenza A/H1N1 virus; E23G/K, A37T, I38M/T, E199G for influenza A/H3N2 virus; and T20K, I38T for influenza B virus.
Cross-resistance between baloxavir and neuraminidase inhibitors (i.e., oseltamivir, peramivir, zanamivir) or M2 proton channel inhibitors (i.e., amantadine, rimantadine) is not expected. Baloxavir is active against neuraminidase inhibitor-resistant strains. Similarly, oseltamivir is active against viruses with reduced susceptibility to baloxavir. Consider concurrently available surveillance information on influenza drug susceptibility patterns and treatment effects when deciding on it and which anti-influenza medication to use.[63687]
Revision Date: 06/06/2024, 11:56:42 AMBaloxavir marboxil is administered orally. Once in systemic circulation, the drug is hydrolyzed to form baloxavir (the active metabolite). Baloxavir is 92.9% to 93.9% bound to human plasma proteins and has a volume of distribution of 1,180 L and a blood cell to blood ratio of 48.5% to 54.4%. The primary metabolic pathway is via uridine diphosphate glucuronosyl transferase (UGT1A3) with secondary contributions from CYP3A4. The terminal elimination half-life is 79.1 hours.[63687]
Affected cytochrome P450 isoenzymes and drug transporters: P-glycoprotein (P-gp)
Both baloxavir marboxil and baloxavir are substrates of the drug transporter P-gp.[63687]
Peak baloxavir concentrations are achieved 4 hours after oral administration. The systemic drug exposure (AUC) for the 40 mg dose is 5,520 ng x hour/mL and the AUC for the 80 mg dose is 6,930 ng x hour/mL. The maximum plasma concentration (Cmax) for the 40 mg dose is 68.9 ng/mL and the Cmax for the 80 mg dose is 82.5 ng/mL. When administered with food, the AUC is decreased by 36% and the Cmax is decreased by 48%.[63687]
In animal studies, a 48% to 63% decrease in baloxavir exposure was observed when coadministered with calcium, aluminum, magnesium, or iron. No studies have been conducted in humans.[63687]
The effects of severe hepatic impairment on the pharmacokinetics of baloxavir marboxil or its active metabolite have not been evaluated. No clinically meaningful differences were identified when comparing baloxavir pharmacokinetics in patients with normal and moderate hepatic impairment (Child-Pugh B).[63687]
The effects of severe renal impairment on the pharmacokinetics of baloxavir marboxil or its active metabolite have not been evaluated. No clinically meaningful differences were observed when baloxavir marboxil was administered to patients with creatinine clearance 50 mL/minute or higher.[63687]
After the approved recommended dosage, baloxavir exposures are similar in pediatric subjects (5 to 11 years) compared to adult subjects.[63687]
No clinically significant differences in the pharmacokinetics of baloxavir were observed based on sex.[63687]
Systemic exposure (AUC) of baloxavir is approximately 35% lower in non-Asian as compared with Asians; however, this difference is not considered clinically significant.[63687]
As body weight increases, systemic exposure (AUC) of baloxavir decreases; however, when dosed with the recommended weight-based dosing, no clinically significant difference in AUC was observed between body weight groups (i.e., less than 80 kg vs. 80 kg or more).[63687]
Pregnant and postpartum patients are at significantly higher risk for serious complications from influenza infection as compared with nonpregnant people; therefore, timely use of antiviral therapy is recommended for the treatment of influenza. However, the Centers for Disease Control and Prevention (CDC) and the American College of Obstetricians and Gynecologists (ACOG) do not recommend the use of baloxavir marboxil during pregnancy due to the lack of safety and efficacy data; oseltamivir is the preferred treatment in pregnant patients. No data are available regarding the use of baloxavir marboxil during human pregnancy. In animal studies, adverse developmental effects were not observed in rats or rabbits with systemic drug exposures of approximately 5- and 7-times, respectively, the exposure at the maximum recommended human dose.[63687] [62315] [70419]
It is not known if baloxavir marboxil is excreted in human milk, or if the drug has an adverse effect on milk production or a breastfed infant. Due to the lack of safety data, the CDC does not recommend baloxavir in breast-feeding mothers.[62315] Zanamivir and oseltamivir may be potential alternatives to consider during breast-feeding. However, patient factors, local susceptibility patterns, and specific microbial susceptibility should be assessed before choosing an alternative. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.[46966] [46967] [63687]
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