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    Polymerase Acidic (PA) Endonuclease Inhibitor Antivirals

    DEA CLASS

    Rx

    DESCRIPTION

    Antiviral drug that targets the influenza virus-specific enzyme polymerase acidic (PA) protein
    Used for treatment of acute uncomplicated influenza and for post-exposure influenza prophylaxis
    Not a substitute for an annual influenza virus vaccination

    COMMON BRAND NAMES

    Xofluza

    HOW SUPPLIED

    Baloxavir/Baloxavir Marboxil Oral Gran F/Recon: 1mL, 2mg
    Xofluza Oral Tab: 20mg, 40mg, 80mg

    DOSAGE & INDICATIONS

    For the treatment of acute uncomplicated influenza A virus infection or influenza B virus infection in patients who are otherwise healthy or at high risk of developing influenza-related complications.
    Oral dosage
    Adults weighing 80 kg or more

    80 mg PO as a single dose within 48 hours of symptom onset.[63687]

    Adults less than 80 kg

    40 mg PO as a single dose within 48 hours of symptom onset.

    Children and Adolescents 12 to 17 years weighing 80 kg or more

    80 mg PO as a single dose within 48 hours of symptom onset.

    Children and Adolescents 12 to 17 years weighing less than 80 kg

    40 mg PO as a single dose within 48 hours of symptom onset.

    For post-exposure seasonal influenza prophylaxis.
    Oral dosage
    Adults weighing 80 kg or more

    80 mg PO as a single dose administered as soon as possible after contact with an individual who has influenza.

    Adults weighing less than 80 kg

    40 mg PO as a single dose administered as soon as possible after contact with an individual who has influenza.

    Children and Adolescents 12 to 17 years weighing 80 kg or more

    80 mg PO as a single dose administered as soon as possible after contact with an individual who has influenza.

    Children and Adolescents 12 to 17 years weighing less than 80 kg

    40 mg PO as a single dose administered as soon as possible after contact with an individual who has influenza.

    MAXIMUM DOSAGE

    Adults

    weight 80 kg or more: 80 mg PO.
    weight less than 80 kg: 40 mg PO.

    Geriatric

    weight 80 kg or more: 80 mg PO.
    weight less than 80 kg: 40 mg PO.

    Adolescents

    weight 80 kg or more: 80 mg PO.
    weight less than 80 kg: 40 mg PO.

    Children

    12 years and weight 80 kg or more: 80 mg PO.
    12 years and weight less than 80 kg: 40 mg PO.
    1 to 11 years: Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Oral Administration

    Administer with or without food.
    Avoid administration with polyvalent cation-containing products such as dairy products, calcium-fortified beverages, laxatives, antacids, or oral supplements (e.g., calcium, iron, magnesium, selenium, zinc).[63687]

    Oral Liquid Formulations

    Intended for use in patients who have difficulty swallowing tablets or those who require enteral administration.
    Gently swirl before use. Do not shake.
    Administer using a calibrated measuring device.
    Instruct caregiver or patient that the total prescribed dose may require more than 1 bottle (for patients weighing 80 kg or more).
    Do not mix with soft food or another liquid.
    The patient should sit in an upright position and should not be lying down.
     
    Reconstitution
    Gently tap the bottom of the bottle to loosen the granules.
    Constitute with 20 mL of drinking water or sterile water.
    Gently swirl the suspension to ensure the granules are evenly suspended. Do not shake.
    Storage: Prepare the suspension at the time of dispensing. Administration must occur within 10 hours after constitution as the product does not contain a preservative. Store at room temperature 20 degrees C to 25 degrees C (68 degrees F to 77 degrees F) and keep in original bottle. Write the expiration time and date on the bottle label.
     
    Enteral Administration
    Draw up the suspension with an enteral syringe.
    Flush with 1 mL of water before and after enteral administration.

    STORAGE

    Xofluza:
    - Discard unused portion. Do not store for later use.
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    - Store in original container
    - Store reconstituted product in accordance with package insert instructions
    - Store reconstituted suspension no longer than 10 hours at room temperature 20 to 25 degrees C (68 to 77 degrees F) when reconstituted with drinking or sterile water
    - The suspension must be discarded if no used within 10 hours of preparation or if it has been stored above 25 degrees C (77 degrees F).

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Baloxavir marboxil is contraindicated for use in patients with a known allergic reaction to the drug or any of its components. Cases of anaphylaxis, angioedema, urticaria, and erythema multiforme have been reported during postmarketing use of the drug. If anaphylaxis or a serious allergic reaction develops during treatment, institute appropriate therapy.

    Vaccination

    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]

    Infection, viral infection

    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]

    Pregnancy

    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. When deciding on treatment, health care providers are advised to consider that pregnant women are at higher risk of severe complications from influenza, which may result in adverse pregnancy or fetal outcomes (i.e., maternal death, stillbirth, birth defects, preterm delivery, low birth weight, small gestational age).[63687] The CDC does not recommend baloxavir during pregnancy due to the lack of safety data; oseltamivir is the preferred treatment in pregnant women.[62315]

    Breast-feeding

    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]

    ADVERSE REACTIONS

    Moderate

    melena / Delayed / Incidence not known
    colitis / Delayed / Incidence not known
    hallucinations / Early / Incidence not known
    delirium / Early / Incidence not known

    Mild

    pharyngitis / Delayed / 6.0-6.0
    diarrhea / Early / 3.0-3.0
    nausea / Early / 2.0-2.0
    sinusitis / Delayed / 2.0-2.0
    headache / Early / 1.0-1.0
    vomiting / Early / Incidence not known

    DRUG INTERACTIONS

    Aluminum Hydroxide: (Major) Do not administer baloxavir with products that contain aluminum hydroxide. Polyvalent cations, such as aluminum, can chelate with baloxavir; thereby reducing its absorption.
    Aluminum Hydroxide; Magnesium Carbonate: (Major) Do not administer baloxavir with products that contain aluminum hydroxide. Polyvalent cations, such as aluminum, can chelate with baloxavir; thereby reducing its absorption. (Major) Do not administer baloxavir with products that contain magnesium carbonate. Polyvalent cations, such as magnesium, can chelate with baloxavir, reducing its absorption.
    Aluminum Hydroxide; Magnesium Hydroxide: (Major) Do not administer baloxavir with products that contain aluminum hydroxide. Polyvalent cations, such as aluminum, can chelate with baloxavir; thereby reducing its absorption. (Major) Do not administer baloxavir with products that contain magnesium hydroxide. Polyvalent cations, such as magnesium, can chelate with baloxavir, reducing its absorption.
    Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Major) Do not administer baloxavir with products that contain aluminum hydroxide. Polyvalent cations, such as aluminum, can chelate with baloxavir; thereby reducing its absorption. (Major) Do not administer baloxavir with products that contain magnesium hydroxide. Polyvalent cations, such as magnesium, can chelate with baloxavir, reducing its absorption.
    Aluminum Hydroxide; Magnesium Trisilicate: (Major) Do not administer baloxavir with products that contain aluminum hydroxide. Polyvalent cations, such as aluminum, can chelate with baloxavir; thereby reducing its absorption. (Major) Do not administer baloxavir with products that contain magnesium trisilicate. Polyvalent cations, such as magnesium, can chelate with baloxavir, reducing its absorption.
    Calcium (oral): (Major) Do not administer baloxavir with products that contain calcium. Polyvalent cations, such as calcium, can chelate with baloxavir, reducing its absorption.
    Calcium Acetate: (Major) Do not administer baloxavir with products that contain calcium. Polyvalent cations, such as calcium, can chelate with baloxavir, reducing its absorption.
    Calcium Carbonate: (Major) Do not administer baloxavir with products that contain calcium. Polyvalent cations, such as calcium, can chelate with baloxavir, reducing its absorption.
    Calcium Carbonate; Famotidine; Magnesium Hydroxide: (Major) Do not administer baloxavir with products that contain calcium. Polyvalent cations, such as calcium, can chelate with baloxavir, reducing its absorption.
    Calcium Carbonate; Magnesium Hydroxide: (Major) Do not administer baloxavir with products that contain calcium. Polyvalent cations, such as calcium, can chelate with baloxavir, reducing its absorption.
    Calcium Carbonate; Magnesium Hydroxide; Simethicone: (Major) Do not administer baloxavir with products that contain calcium. Polyvalent cations, such as calcium, can chelate with baloxavir, reducing its absorption.
    Calcium Carbonate; Risedronate: (Major) Do not administer baloxavir with products that contain calcium. Polyvalent cations, such as calcium, can chelate with baloxavir, reducing its absorption.
    Calcium Carbonate; Simethicone: (Major) Do not administer baloxavir with products that contain calcium. Polyvalent cations, such as calcium, can chelate with baloxavir, reducing its absorption.
    Calcium Gluconate: (Major) Do not administer baloxavir with products that contain calcium. Polyvalent cations, such as calcium, can chelate with baloxavir, reducing its absorption.
    Calcium; Vitamin D: (Major) Do not administer baloxavir with products that contain calcium. Polyvalent cations, such as calcium, can chelate with baloxavir, reducing its absorption.
    Carbetapentane; Guaifenesin; Phenylephrine: (Major) Do not administer baloxavir with products that contain zinc. Polyvalent cations, such as zinc, can chelate with baloxavir, reducing its absorption.
    Carbetapentane; Phenylephrine: (Major) Do not administer baloxavir with products that contain zinc. Polyvalent cations, such as zinc, can chelate with baloxavir, reducing its absorption.
    Chlorpheniramine; Pseudoephedrine: (Major) Do not administer baloxavir with products that contain zinc. Polyvalent cations, such as zinc, can chelate with baloxavir, reducing its absorption.
    Chromium: (Major) Do not administer baloxavir with products that contain calcium. Polyvalent cations, such as calcium, can chelate with baloxavir, reducing its absorption.
    Hetastarch; Dextrose; Electrolytes: (Major) Do not administer baloxavir with products that contain calcium. Polyvalent cations, such as calcium, can chelate with baloxavir, reducing its absorption.
    Iron Sucrose, Sucroferric Oxyhydroxide: (Major) Do not administer baloxavir with products that contain oral iron sucrose, sucroferric oxyhydroxide. Polyvalent cations, such as iron, can chelate with baloxavir, reducing its absorption.
    Live Attenuated Influenza Vaccine (intranasal): (Major) Do not administer the intranasal live attenuated influenza vaccine (LAIV) 2 weeks before or 17 days after administration of baloxavir, unless medically indicated. Inactivated influenza vaccines may be used, as appropriate. Because of its antiviral properties, baloxavir may interfere with the efficacy of live attenuated influenza vaccines. Therefore, live influenza virus vaccines are not recommended during treatment with baloxavir. Consult currently recommended guidance on the use of antiviral drugs against influenza.
    Magnesium Citrate: (Major) Do not administer baloxavir with products that contain magnesium citrate. Polyvalent cations, such as magnesium, can chelate with baloxavir, reducing its absorption.
    Magnesium Hydroxide: (Major) Do not administer baloxavir with products that contain magnesium hydroxide. Polyvalent cations, such as magnesium, can chelate with baloxavir, reducing its absorption.
    Pyridoxine, Vitamin B6: (Major) Do not administer baloxavir with products that contain calcium. Polyvalent cations, such as calcium, can chelate with baloxavir, reducing its absorption.
    Selenium: (Major) Do not administer baloxavir with selenium. Polyvalent cations, such as selenium, can chelate with baloxavir, reducing its absorption.
    Zinc Salts: (Major) Do not administer baloxavir with products that contain zinc. Polyvalent cations, such as zinc, can chelate with baloxavir, reducing its absorption.
    Zinc: (Major) Do not administer baloxavir with products that contain zinc. Polyvalent cations, such as zinc, can chelate with baloxavir, reducing its absorption.

    PREGNANCY AND LACTATION

    Pregnancy

    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. When deciding on treatment, health care providers are advised to consider that pregnant women are at higher risk of severe complications from influenza, which may result in adverse pregnancy or fetal outcomes (i.e., maternal death, stillbirth, birth defects, preterm delivery, low birth weight, small gestational age).[63687] The CDC does not recommend baloxavir during pregnancy due to the lack of safety data; oseltamivir is the preferred treatment in pregnant women.[62315]

    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]

    MECHANISM OF ACTION

    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. 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, 31 patients were evaluated for resistance. Of these, influenza virus with substitutions associated with reduced susceptibility to baloxavir was identified in 7 of 7 patients who developed clinical influenza and 8 of 24 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% (n = 4 of 20) in influenza A/H1N1 virus, 27.9% (n = 34 of 122) in influenza A/H3N2 virus, and 0% (n = 0 of 21) in influenza B virus in pooled data from 3 pediatric treatment trials in patients younger than 12 years. Specific amino acid substitutions were E23K/R, I38F/N/S/T for influenza A/H1N1 virus; E23G/K, A37T, I38M/T, E199G for influenza A/H3N2 virus; and 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]

    PHARMACOKINETICS

    Baloxavir 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]

    Oral Route

    Peak baloxavir concentrations are achieved 4 hours after oral administration. The systemic drug exposure (AUC) for the 40 mg dose is 5520 ng x hour/mL and the AUC for the 80 mg dose is 6930 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%.
     
    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.