Clinical Pharmacology Corner: FDA Approves XOFLUZA (Baloxavir Marboxil)

FDA Approves XOFLUZA (Baloxavir Marboxil) for Acute Uncomplicated Influenza in Patients 12 Years of Age and Older Who Have Been Symptomatic for No More than 48 Hours

On October 24, 2018, the U.S. Food and Drug Administration (FDA) approved XOFLUZA (baloxavir marboxil) 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. The approved recommended dosage of XOFLUZA is based on body weight: 

• Single dose of 40 mg for patients 40 kg to < 80 kg
• Single dose of 80 mg for patients ≥ 80 kg

Initiate treatment with XOFLUZA within 48 hours of influenza symptom onset. XOFLUZA can be taken with or without food, however, avoid co-administration with dairy products, calcium-fortified beverages, polyvalent cation-containing laxatives, antacids, or oral supplements (e.g., calcium, iron, magnesium, selenium, or zinc). 

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.

Mechanism of Action (MOA) and Pharmacokinetics (PK)

• MOA: Baloxavir marboxil is a polymerase acidic (PA) endonuclease inhibitor.  
• General PK: Baloxavir marboxil is a prodrug that is almost completely converted to its active metabolite, baloxavir, following oral administration. 
• Absorption: Baloxavir median T_max is 4 hrs.  
• Distribution: Baloxavir volume of distribution is 1180 L. Protein binding is approximately 93%. 
• Elimination: Baloxavir terminal half-life is 79.1 hrs and clearance is 10.3 L/hr. 
• Metabolism: Baloxavir is primarily metabolized by UGT1A3 with minor contribution from CYP3A4. 
• Excretion: Following administration of radiolabeled baloxavir marboxil, 80.1% of total radioactivity was excreted in feces, and 14.7% in urine (3.3% as baloxavir).  

Drug Interactions

• Avoid co-administration of XOFLUZA with polyvalent cation-containing laxatives, antacids, or oral supplements (e.g., calcium, iron, magnesium, selenium, or zinc) as they may decrease plasma concentrations of baloxavir which may reduce XOFLUZA efficacy. 
• The effectiveness of live attenuated influenza vaccines may be affected by antivirals. Co-administration of XOFLUZA with inactivated or intranasal live attenuated influenza vaccines have not been evaluated.  

Use in Specific Populations

As body weight increases, baloxavir exposure decreases. No clinically significant difference in exposure was observed between body weight groups following the approved recommended weight-based dosage.

  

There were no clinically significant differences in the pharmacokinetics of baloxavir based on age, sex, race/ethnicity (Asians vs. non-Asians), renal function (CLcr ≥ 50 mL/min), or moderate hepatic impairment (Child-Pugh class B). The effect of severe renal or hepatic impairment on baloxavir pharmacokinetics is unknown. 

Efficacy and Safety

Efficacy of XOFLUZA was demonstrated in two randomized controlled double-blinded clinical trials conducted in two different influenza seasons in otherwise healthy subjects with acute uncomplicated influenza. The primary endpoint was time to alleviation of symptoms. Additional information regarding efficacy trials can be found in the full prescribing information linked below.

Adverse events reported in at least 1% of adult and adolescent subjects treated with XOFLUZA included diarrhea (3%), bronchitis (2%), nasopharyngitis (1%), headache (1%) and nausea (1%). 

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Full prescribing information is available at https://go.usa.gov/xPPnA. 

Visit Drugs@FDA at http://go.usa.gov/cMsjT for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval. 

A non-comprehensive list of examples of clinical substrates, inhibitors and inducers for metabolic and transporter system related interactions may be found at https://go.usa.gov/xXY9C.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online athttp://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), or by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.