By Bryant Froberg, Pharm.D., candidate 2019, Ferris State University College of Pharmacy, L'Anse, Mich.
Influenza infections have a large impact on the United States population and healthcare system. The preliminary burden estimates from the Centers for Disease Control and Prevention (CDC) reports nearly 600,000 hospitalizations and 50,000 deaths can be attributed to influenza this flu season. A large number of these patients will be treated with supportive care and antiviral medications. Neuraminidase inhibitors have been the antiviral class of choice since their approval. This is largely due to the presence of widespread adamantane-resistant influenza and the lack of development of antivirals with novel mechanisms against the virus, until now.1
Xofluza™ (baloxavir maboxil), approved in Oct. 2018, is the first new antiviral flu treatment approved by the Food and Drug Administration (FDA) in almost 20 years. It is an oral medication that has the benefit of only having to be taken as a single dose. Standard dosing is based upon weight with patients between 40 and 80 kg receiving a one-time dose of 40mg. The dose is doubled to 80mg in patients that weigh over 80 kg. There are no recommended dose adjustments for kidney or hepatic dysfunction, but clinical trials excluded patients with a creatinine clearance less than 50 mL/min or Child-Pugh Class C impairment. Administration should be avoided with dairy products, calcium-fortified beverages, polyvalent cation-containing laxatives, antacids, or oral supplements due to decreases in serum concentrations of Xofluza™.2,3
Xofluza™ is an oral prodrug that works by inhibiting the endonuclease activity of polymerase acidic protein. Polymerase acidic protein is an influenza virus-specific enzyme that cleaves the host mRNA caps in order to initiate viral transcription. Without initiation of transcription, the influenza virus replication is inhibited. This inhibition reduces the influenza viral load in the host and decreases the release of cytokines, leading to decreased tissue damage and relief of symptoms.2,3
The safety and efficacy of Xofluza™ was evaluated in one phase II and one phase III trial over two flu seasons. The phase II trial randomized patients to receive placebo or Xofluza™ at a range of doses (10, 20, 40mg). All three doses of Xofluza™ had a significant decrease in the median time to alleviation of symptoms when compared to placebo. The phase III trial randomized patients to receive a single oral dose of baloxavir, oseltamivir for five days, or matching placebos. The results of this trial showed a significant decrease in the median time to alleviation of symptoms when compared to placebo and similar time to alleviation as oseltamivir. Adverse events were similar to placebo with diarrhea, headache and nausea being the most common.4
As with any other antimicrobial agent, resistance development is a concern. Results from clinical trials showed that 2-10 percent of patients tested positive for post-treatment viruses with polymerase acidic protein amino acid substitutions that may confer resistance to Xofluza™. Cross-resistance between Xofluza™ and neuraminidase inhibitors is not expected but this has not been studied yet.4
The Infectious Disease Society of America (IDSA) guidelines for influenza that were updated in Dec. 2018 did not include recommendations regarding Xofluza™. Overall, Xofluza™ looks like a well-tolerated treatment for influenza with the advantage of being a single-dose oral option and may have some use against neuraminidase-resistant influenza.
1. Centers for Disease Control and Prevention [Internet]. Atlanta (GA): CDC; Influenza; [updated 2019 Apr. 20; cited 2019 Apr 20];. Available from: https://www.cdc.gov/flu/index.htm
2. Baloxavir Marboxil. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, Ill. Available at: http://online.lexi.com. Accessed Apr. 3, 2019.
3. Xofluza™ (baloxavir marboxil) [prescribing information]. South San Francisco, Calif.: Genentech USA, Inc.: Oct. 2018.
4. Hayden FG, Sugaya N, Hirotsu N, Lee N, de Jong MD, Hurt AC, et al. Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents. N Engl J Med. 2018 Sept. 5;379(10):913–23.