Xofluza (baloxavir marboxil)

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.

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.

The most common side effects of Xofluza in adults and adolescents include:

• diarrhea
• bronchitis
• common cold symptoms (nasopharyngitis)
• headache
• nausea

Xofluza is not effective in treating infections other than influenza. Other kinds of infections can appear like flu or occur along with flu and may need different kinds of treatment. Tell your healthcare provider if you feel worse or develop new symptoms during or after treatment with Xofluza or if your flu symptoms do not start to get better.

These are not all the possible side effects of Xofluza. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800 FDA-1088.

Initiate treatment with Xofluza within 48 hours of influenza symptom onset. Xofluza is taken orally as a single dose 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.

Adults and Adolescents (12 years of age and older)

The recommended dose of Xofluza in patients 12 years of age or older with acute uncomplicated influenza is a single weight-based dose as follows:

• 40 kg to less than 80 kg: Single Dose of 40 mg
• At least 80 kg: Single Dose of 80 mg

Effect of Other Drugs on Xofluza

Co-administration with polyvalent cation-containing products may decrease plasma concentrations of baloxavir which may reduce Xofluza efficacy. Avoid co-administration of Xofluza with polyvalent cationcontaining 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.

Pregnancy Risk Summary

There are no available data on 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. 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).

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.

Breastfeeding mothers

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. 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.

How does (baloxavir marboxil) Xofluza work?

Baloxavir marboxil is a prodrug that is converted by hydrolysis to baloxavir, the active form that exerts antiinfluenza 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) of baloxavir was 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=19; range: 0.20-1.85 nM) for subtype A/H1N1 strains, 0.68 nM (n=19; range: 0.35-1.87 nM) for subtype A/H3N2 strains, and 5.28 nM (n=21; range: 3.33-13.00 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 1.64 and 0.80 nM, respectively. The relationship between antiviral activity in cell culture and clinical response to treatment in humans has not been established.