Fighting Influenza from Behind the Counter: A Treatment Review

Influenza, more commonly called the flu, is a virus so ubiquitous that its true impact is not easily quantified; not all who feel sick from the flu seek medical care or are even tested for influenza. Each week, the CDC uses a mathematical model to calculate a lower and upper estimate of illnesses, medical visits, hospitalizations, and deaths from the flu. From October 1, 2024, through December 7, 2024, the estimated number of flu illnesses was anywhere from 1.2 to 2.1 million people, with 530,000 to 930,000 medical visits due to the flu; in the same time frame, an estimated 15,000 to 33,000 flu-related hospitalizations and 630 to 3,200 deaths occurred.¹

Although most people can recover from uncomplicated influenza, complications can result in serious illness and possibly death, particularly among very young children, older adults, immunocompromised patients, pregnant and postpartum women within 2 weeks of delivery, and those with certain chronic pulmonary, cardiac, and metabolic diseases. Given these statistics from the CDC, the importance of appropriately testing and treating the flu cannot be overestimated.

Older woman with the flu | Image credit: © Vasiliy | stock.adobe.com

Treatment Guidelines

The current treatment guidelines for influenza come from the Infectious Diseases Society of America (IDSA) and were most recently released in 2018.² Those with confirmed influenza, regardless of influenza vaccination history, should be started on antiviral treatment as long as they meet 1 or more of the following criteria: those hospitalized with influenza regardless of illness duration prior to hospitalization, outpatients with severe or progressive illness regardless of illness duration, outpatients at a high risk of complications from influenza, children younger than 2 years of age, adults 65 years of age and older, and pregnant and postpartum women within 2 weeks of delivery. Essentially, anyone at a higher risk of complications that could cause severe illness or death should be given treatment with antivirals.²

The grey area exists more with those who are not at increased risk of developing complications from influenza. Considerations for treatment should be made for outpatients with illness onset within 48 hours of presentation, symptomatic outpatients who are household contacts of people with higher risk of developing complications from the flu, and symptomatic health care providers who routinely care for people with higher risk of developing complications from the flu. As pharmacists, the outpatient setting is where our assistance can be most useful by helping patients decide whether they should be referred to a prescriber for an antiviral prescription or whether supportive care with fluids, rest, decongestants, cough suppressants, and/or antipyretics is the best option.

If a patient requires an antiviral medication, the choice is slightly more straightforward, at least per the guidelines. For those requiring treatment, using a neuraminidase inhibitor (NAI) is recommended. The neuraminidase enzyme cleaves the new viruses from their cellular envelopes just prior to release, helping to prevent new viruses from spreading. In the outpatient setting, for uncomplicated influenza in otherwise healthy patients, treatment includes oral oseltamivir or inhaled zanamivir for 5 days or a single dose of intravenous peramivir; most commonly, the medication used is oseltamivir (Tamiflu; Genentech). A longer duration of antiviral treatment can be considered for immunocompromised patients or for those requiring hospitalization for severe lower respiratory tract disease. Oseltamivir is dosed based on age, weight, and renal function, whereas peramivir is dosed based on age and weight; zanamivir is the same treatment dose for all. Oseltamivir can be given to patients of any age with influenza, including premature infants (though data is limited in this population), whereas zanamivir has a minimum age limit of 7 years old and peramivir has a minimum age limit of 2 years old.

The IDSA guidelines also recommend antiviral prophylaxis with a neuraminidase inhibitor (only oseltamivir or zanamivir) but only in certain situations because routine use can lead to the development of resistance. Both preexposure and post-exposure prophylaxis are recommended only in those 3 months of age and older at a high risk of developing complications from influenza and if vaccination is contraindicated, unavailable, or expected to be ineffective (such as in those with immunocompromising conditions). The dosing frequency of neuraminidase inhibitors are reduced in these situations from twice daily to once daily dosing, and post-exposure prophylaxis is recommended for 7 days.²

The efficacy of oseltamivir has been previously questioned. A systematic review in 2014 studying the potential benefits and harms of oseltamivir found a reduction in symptom duration for treatment but no significant effect on asymptomatic influenza or reduction in transmission. In prophylaxis trials, oseltamivir did have a significant reduction in proportion of symptomatic influenza. Among these studies, notable adverse effects included nausea, vomiting, headaches, and dose-related neuropsychiatric events.³

The concern for neuropsychiatric events is controversial; the neuropsychiatric events listed in the manufacturer’s package insert come from post-marketing surveillance reports of severe abnormal behavior in adolescents with influenza after starting oseltamivir.⁴ However, a 2015 study examined the incidence of neuropsychiatric events in between 1.6 and 2.2 million patients aged 10 to 19 years who received NAIs in Japan through an adverse events reports database and found no significant difference among incidence rates of severe abnormal behavior by neuraminidase inhibitors (p=0.75).⁵ Additional studies in 2018 and 2020 (in the United States and South Korea, respectively) looking at insurance claims for oseltamivir to study the rates of neuropsychiatric events similarly found no difference in overall risk.^6,7

Baloxavir Marboxil

A newer agent, baloxavir marboxil (Xofluza; Genentech), was approved in 2018 just after the IDSA guidelines were finalized and therefore does not have recommendations in the guidelines. Baloxavir marboxil is an oral prodrug that is converted to baloxavir, a first-in-class cap-dependent endonuclease inhibitor. Viral endonuclease in required for polymerase activity and viral gene transcription, and its inhibition prevents viral replication. Currently, it is approved for the treatment of acute uncomplicated influenza in individuals 5 years of age and older who have been symptomatic for 48 hours at most, whether healthy or at high risk for developing complications, and for post-exposure prophylaxis in patients 5 years of age and older.⁸

The first phase 3 trial for baloxavir, CAPSTONE-1 (NCT02954354), compared it with oseltamivir and placebo for use in otherwise healthy adults and adolescents aged 12 through 64 years of age with uncomplicated influenza and symptoms for no more than 48 hours.⁹ The study authors found a significantly shortened median time to alleviation of symptoms by 26.5 hours with baloxavir compared with placebo (p<0.001), but no difference in clinical benefit between a single dose of baloxavir compared with standard dose oseltamivir. The median duration of infectious virus detection in upper respiratory tract specimens was significantly shorter for baloxavir compared with oseltamivir (24 vs. 72 hours, respectively; p<0.001). However, 10% of the baloxavir recipients had emergence of mutation leading to reduced drug susceptibility and most of these patients had infectious virus detected 5 days after treatment and longer duration of symptoms than in baloxavir recipients without these mutations.⁹

The second phase 3 trial for baloxavir, CAPSTONE-2 (NCT02949011), compared baloxavir with placebo and oseltamivir for uncomplicated influenza with symptoms for no more than 48 hours in the same age group (12-64 years of age) but for patients with at least 1 high-risk medical condition.¹⁰ A single dose of baloxavir reduced the median time to improvement of symptoms by 29.1 hours compared with placebo (p<0.001), but was not significantly different than standard dose oseltamivir. In patients with influenza B, baloxavir significantly reduced the median time to improvement of symptoms by 26 hours compared to placebo (p<0.0138) and 27 hours compared with oseltamivir (p<0.0251).¹⁰

The third phase 3 trial for baloxavir, miniSTONE-2 (NCT03629184), compared baloxavir with standard dose oseltamivir for uncomplicated influenza in otherwise healthy children aged 1 to less than 12 years old. Children were enrolled in parallel to 2 cohorts of ages 1 to less than 5 years old and 5 to less than 12 years old.¹¹ The study authors found similar rates of adverse events between groups though with less vomiting (6.1% vs 15.5%), suggesting tolerability of baloxavir in children. Additionally, time to alleviation of influenza signs and symptoms was similar between groups; a post hoc analysis studying safety and efficacy of the 5- to less than 12-year-old cohort confirmed these results, and allowed for its approval in this population.¹²

Finally, another phase 3 trial compared baloxavir to placebo for people aged 5 years and older for the post-exposure prophylaxis of influenza. This trial found a statistically significant reduction in the proportion of household contacts with confirmed clinical influenza (1.9% in the baloxavir group vs 13.6% in the placebo group, p<0.001).¹³ The incidence of adverse events was similar between the 2 groups (22.2% with baloxavir and 20.5% with placebo), and viral mutations were similar between groups as well (2.7% with baloxavir and 1.3% with placebo).¹³

Given these trials, baloxavir is a promising option for treating influenza and will likely be incorporated into any future influenza guideline updates. Considering its efficacy is similar to that of oseltamivir, the main selling point of baloxavir is that it is a single dose, and as such, greatly improves adherence for both post-exposure prophylaxis and treatment; in a patient who is likely to have or has documented adherence issues, baloxavir may be a better option to recommend over oseltamivir.

Considerations for Treatment Decisions

Although peramivir is also a single-dose medication, it is only available intravenously and can result in injection-related complications such as infections; additionally, it is only available through a single manufacturer. Tolerability of baloxavir is similar to that of oseltamivir, though with less vomiting and less of a concern for neuropsychiatric events (although, again, this claim is disputed). The main problem with the use of baloxavir, at least for the time being, is that it is a brand name-only medication, so cost can be prohibitive, especially if a patient’s insurance does not cover it. As it is only 6 years past its approval, baloxavir still has some time before generic medication manufacturing companies can acquire the rights to manufacture a generic version, and so this cost-prohibitive nature may be an issue for a few more years.

Oseltamivir, on the other hand, has been available longer, with more data for its use, and a well-documented adverse effect profile. That adverse effect profile, however, can be problematic for a patient. For someone who may already be having gastrointestinal effects from the flu, the nausea and vomiting caused by oseltamivir may not be easily tolerated; even for someone who is not having nausea and vomiting from the flu itself, the addition of nausea and vomiting from a medication standpoint may not be welcome. Additionally, the potential for neuropsychiatric events, although questionable, may be a concern for some patients with comorbid psychiatric conditions such as anxiety or depression. Unlike baloxavir, however, oseltamivir is available as a generic medication and may be available at a cost that is much easier to swallow compared to the price for a single brand-name Xofluza tablet. Additionally, given its generic status, insurances may cover oseltamivir more frequently and with less of a copay for the patient, thus reducing the price even further.

Ultimately, pharmacists should prioritize the needs of the patient in front of them and determine what matters most in each specific situation. Each situation involving influenza is different, as some patients may not need treatment or are not recommended to be treated. Of those that require treatment, it is important to take all factors into consideration when selecting an appropriate agent, including efficacy, adherence, adverse effects, and cost, in order to maximize benefit for the patient.

REFERENCES

1. Preliminary Estimated Flu Disease Burden 2024-2025 Flu Season. CDC. January 3, 2025. Accessed January 9, 2025. https://www.cdc.gov/flu-burden/php/data-vis/2024-2025.html

2. Uyeki Tm, Bernstein HH, Bradley JS, et al. Clinical practice guidelines by the Infectious Diseases Society of America: 2018 update on diagnosis, treatment, chemoprophylaxis, and institutional outbreak management of seasonal influenza. Clin Infect Dis. 2019;68(6):e1-e47. doi:10.1093/cid.ciy866

3. Jefferson T, Jones M, Doshi P, Spencer EA, Onakpoya I, Heneghan CJ. Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments. BMJ. 2014:348:g2545. doi:10.1136/bmj.g2545

4. Oseltamivir phosphate [prescribing information]. Genentech; updated August 2019. Accessed January 9, 2025. https://www.gene.com/download/pdf/tamiflu_prescribing.pdf

5. Nakamura Y, Sugawara T, Ohkusa Y, et al. Life-threatening abnormal behavior incidence in 10-19 year old patients administered neuraminidase inhibitors. PLoS One. 2015;10(7):e0129712. doi:10.1371/journal.pone.0129712

6. Harrington R, Adimadhyam S, Lee TA, Schumock GT, Antoon JW. The relationship between oseltamivir and suicide in pediatric patients. Ann Fam Med. 2018;16(2):145-148. doi:10.1370/afm.2183

7. Huh K, Kang M, Shin DH, Hong J, Jung J. Oseltamivir and the risk of neuropsychiatric events: a national, population-based study. Clin Infect Dis. 2020;71(9):e409-e414. doi:10.1093/cid/ciaa055

8. Baloxavir marboxil [prescribing information]. Genentech; updated March 2024. Accessed January 9, 2025. https://www.gene.com/download/pdf/xofluza_prescribing.pdf

9. Hayden FG, Sugaya N, Hirotsu N, et al. Baloxavir marboxil for uncomplicated influenza in adults and adolescents. N Engl J Med. 2018;379(10):913-923. doi:10.1056/NEJMoa1716197

10. Ison MG, Portsmouth S, Yoshida Y, et al. Early treatment with baloxavir marboxil in high-risk adolescent and adult outpatients with uncomplicated influenza (CAPSTONE-2): a randomized, placebo-controlled, phase 3 trial. Lancet Infect Dis. 2020;20(10):1204-1214. doi:10.1016/S1473-3099(20)30004-9

11. Baker J, Block SL, Matharu B, et al. Baloxavir marboxil single-dose treatment in influenza-infected children: a randomized, double-blind, active controlled phase 3 safety and efficacy trial (miniSTONE-2). Pediatr Infect Dis J. 2020;39(8):700-705. doi:10.1097/INF.0000000000002747

12. Baker JB, Block SL, Cagas SE, et al. Safety and efficacy of baloxavir marboxil in influenza-infected children 5-11 years of age: a post hoc analysis of a phase 3 study. Pediatr Infect Dis J. 2023;42(11):983-989. doi:10.1097/INF.0000000000004062

13. Baloxavir marboxil for prophylaxis against influenza in household contacts. N Engl J Med. 2020;383(4):309-320. doi:10.1056/NEJMoa1915341