William Simonson, PharmD, BCGP, FASCP
Oregon State University, USA
If an individual has the misfortune of contracting the ﬂu either because they were not vaccinated, or they contracted a ﬂu strain that is resistant to the vaccine they received, an active case of the ﬂu can be treated with one of a number of antiviral medications although it is important to point out that the availability of these medications should not detract from the importance of being vaccinated against the ﬂu. Antivirals should be used as a second line should previously administered vaccination be ineffective.
Antiviral treatment is recommended as early as possible for any patient with confirmed or suspected inﬂuenza who is hospitalized; has severe, complicated or progressive illness; or is at higher risk for inﬂuenza complications regardless of whether they have previously been vaccinated. High-risk patients include individuals over age 65 and residents of nursing homes and long-term care facilities.2
Antiviral ﬂu treatment also can be considered for any previously healthy, symptomatic outpatient not at high risk for inﬂuenza complications, who is diagnosed with confirmed or suspected inﬂuenza, on the basis of clinical judgment, if treatment can be initiated within 48 h of illness onset.2
Two antivirals, amantadine and rimantadine are not recommended to treat the ﬂu due to high levels of antiviral resistance among circulating inﬂuenza A viruses.2 Currently, four inﬂuenza anti-viral medications approved by the FDA are recommended for use in the United States during the 2018-19 ﬂu season. Three of these newer anti-inﬂuenza drugs are chemically-related neuraminidase inhibitors. Oseltamivir (Tamiﬂu®), is taken by mouth and zanamivir (Relenza®) is administered by oral inhalation. It should be noted that some patients may have difficulty using the zanamivir inhaler device.
Each of these products are administered twice daily for ﬁve days after the onset of ﬂu symptoms. A third agent, peramivir (Rapivab®)is administered intravenously in one dose infused over 15 to 30 min. Oral oseltamivir is the recommended antiviral for patients with severe, complicated, or progressive illness who are not hospitalized, and for hospitalized inﬂuenza patients.2
It is recommended that antiviral therapy be started within two days of the start of ﬂu symptoms. These antiviral drugs won’t result in an immediate cure but they can lessen symptoms and shorten the time patients feel sick by about one day.3 Rapid diagnosis is important so antiviral therapy can be started. The most commonly used test is called a rapid inﬂuenza diagnostics test, which looks for sub-stances (antigens) on a swab sample from the back of the nose or throat. These tests can provide results in about 15 min. However, results vary greatly and are not always accurate. Other more reliable tests are available but treatment can begin based on the presence of ﬂu symptoms.3
In October, 2018 the U.S. Food and Drug Administration approved a new antiviral drug indicated for the treatment of acute uncomplicated inﬂuenza. Baloxavir marboxil (trade name 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 h. Unlike the other antivirals for ﬂu, Xoﬂuza® interferes with viral RNA transcription and blocks virus replication.2 US Food and Drug Administration commissioner Scott Gottlieb, MD stated “This is the ﬁrst new antiviral ﬂu treatment with a novel mechanism of action approved by the FDA in nearly 20 years. With thousands of people getting the ﬂu every year, and many people becoming seriously ill, having safe and effective treatment alternatives is critical. This novel drug provides an important, additional treatment option.4”
Xoﬂuza® was approved by the FDA based on two randomized con-trolled clinical trials involving almost 2000 patients. These trials were designed to study both safety and efficacy of the drug. Study participants were assigned to receive either Xoﬂuza®, a placebo, or another antiviral inﬂuenza drug within 48 h of ﬁrst experiencing ﬂu symptoms. It is of interest that none of the subjects in these two pivotal clinical trials were age 65 or older. However, other published and ongoing studies include subjects over the age of 65.
In both pivotal trials patients’ ﬂu symptoms were alleviated more quickly in those treated with Xoﬂuza® compared to placebo. How-ever, in one of the trials there was no difference in the time it took to alleviate ﬂu symptoms in the subjects who received Xoﬂuza and those who received the other ﬂu treatment. The most common adverse reactions in patients taking Xoﬂuza® included diarrhea and bronchitis.
Xoﬂuza® was granted priority review by the FDA which is reserved for products that would significantly improve the safety or effectiveness of treating, diagnosing or preventing a serious condition. A significant difference between Xoﬂuza® and Tamiﬂu®, the other oral inﬂuenza antiviral drug, is that the entire Xoﬂuza® treatment is administered in a single oral dose.
Co-administration of polyvalent cation-containing products may decrease Xoﬂuza® absorption which could possibly decrease the pro-duct’s efficacy. Dairy products, calcium-fortiﬁed beverages, polyvalent cation-containing laxatives or antacids, or oral supplements (e.g., calcium, iron, magnesium, selenium, or zinc) should be avoided when taking Xoﬂuza®.
As with all new drugs, we won’t know how Xoﬂuza® will ﬁt into our armamentarium of therapeutic weapons against inﬂuenza until we gain experience with its use.
As noted above, recommended duration for ﬂu treatment is 5 days for oral oseltamivir or inhaled zanamivir. A longer duration of daily dosing can be considered for patients who remain severely ill after 5 days of treatment but this extended therapy is only for oseltamivir or zanamivir.2
Intravenous peramivir or oral baloxavir are given only as a single dose and are not approved for extended dosing.
This article was originally published in the middle of the 2018-19 US ﬂu season. Since it takes approximately two weeks for a ﬂu vaccination to stimulate ﬂu resistance it’s is not too late to vaccinate and get protection for the latter part of the 2018 – 2019 ﬂu season.1
It is possible that long-term care facilities and other communities of elderly will be faced with ﬂu outbreaks and epidemics. Preparation for such events is paramount and this is where these inﬂuenza antivirals can play a role in preventing individuals from contracting the ﬂu. This application is referred to as chemoprophylaxis.
Use of antiviral drugs for chemoprophylaxis of inﬂuenza is a key component of inﬂuenza outbreak control in institutions that houseresidents at higher risk of inﬂuenza complications. While highly effective, antiviral chemoprophylaxis is not 100% effective in preventing inﬂuenza illness. All eligible residents in the entire long-term care facility (not just currently impacted wards or areas) should receive antiviral chemoprophylaxis as soon as an inﬂuenza outbreak is deter-mined.
When at least 2 patients are ill within 72 h of each other and at least one resident has laboratory-conﬁrmed inﬂuenza, the facility should promptly initiate antiviral chemoprophylaxis to all non-ill residents, regardless of whether they have previously received inﬂuenza vaccination. Priority should be given to residents living in the same unit or ﬂoor as an ill resident. However, since staff and residents may spread inﬂuenza to residents on other units, ﬂoors, or buildings of the same facility, all non-ill residents are recommended to receive antiviral chemoprophylaxis to prevent transmission and control inﬂuenza outbreaks.5
CDC recommends antiviral chemoprophylaxis for a minimum of 2 weeks, and continuing for at least 7 days after the last known case is identified. There are no data for use of peramivir or baloxavir for chemoprophylaxis of inﬂuenza.
Preparation for a ﬂu outbreak is important including establishing systems for rapid diagnosis, ordering of antivirals and quick access to sufficient quantities of these products.
Use of these antivirals to prevent ﬂu outbreaks is an involved subject that cannot be dealt with in detail in the limited space available here but the reader is referred to the informative CDC publication cited in reference #5 below for a detailed description and discussion of chemoprophylaxis in long-term care facilities.
1. Sun LH. Flu broke records for deaths, illnesses in 2017-2018, new CDC numbers show. Washington Post; September 27, 2018. Available at: https://www.washingtonpost.com/national/health-science/last-years-ﬂu-broke-records-for-deaths-and-illnesses-new-cdc-numbers-show/2018/09/26/97cb43fc-c0ed-11e8-90c9-23f963eea204_story.html?noredirect=on&utm_term=.0dd3b84cc42b. Accessed 12 December 2018.
2. United States Centers for Disease Control. Inﬂuenza (ﬂu). Inﬂuenza antiviral medica-tions: summary for clinicians; November 28, 2018. Available at: https://www.cdc.gov/ﬂu/professionals/antivirals/summary-clinicians.htm#dosage. Accessed 12 December 2018.
3. Mayo Clinic. Patient care & health information. Inﬂuenza (ﬂu); September 20, 2018. Available at: https://www.mayoclinic.org/diseases-conditions/ﬂu/diagnosis-treat-ment/drc-20351725. Accessed 8 December 2018.
4. United States Food and Drug Administration. FDA News release. FDA approves new drug to treat inﬂuenza; October 24, 2018. Available at: https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm624226.htm. Accessed 12 December 2018.
5. United States Centers for Disease Control. Interim guidance for inﬂuenza outbreak management in long-term care facilities; October 30, 2018. Available at: https://www.cdc.gov/ﬂu/professionals/infectioncontrol/ltc-facility-guidance.htm. Accessed 12 December 2018.