Meta-Analysis: Flu Drug Oseltamivir (TAMIFLU) Ineffective for Preventing Hospitalizations in Outpatients

Influenza (flu) is a contagious respiratory illness that is caused by influenza viruses (mainly type A or B) that infect the nose, throat and sometimes the lungs. Although usually self-limiting, severe cases require treatment in the hospital and some patients die.[1]

Stockpiled as part of the U.S. pandemic response,[2] oseltamivir (TAMIFLU and generics) is an oral antiviral prescription drug that the Food and Drug Administration (FDA) approved in 1999 for the treatment of uncomplicated acute illness due to influenza in adults with flu symptoms that have not lasted more than two days.[3] Subsequently, the agency expanded the approved treatment indication of oseltamivir to include people who are two weeks of age or older. The FDA has also approved the drug for short-term prophylaxis (prevention) of the flu in people who are one year of age or older.[4] Importantly, however, the FDA has not approved oseltamivir for the prevention of flu complications or to diminish the transmission of influenza viruses.

Clinical trials supporting the approval of oseltamivir showed modest benefits of oseltamivir compared with a placebo: an additional one-day reduction in the median time to improvement of symptoms in influenza-infected subjects (after taking the drug twice daily for five days) and an additional 4% reduction of the rate of new cases of laboratory-confirmed clinical influenza during a community outbreak among healthy unvaccinated adults (after taking the drug once daily for 42 days).

A recent meta-analysis (which analyzed combined data from multiple prior studies) demonstrated that oseltamivir was no better than placebo in reducing hospitalizations. Conducted independently of the drug industry by Canadian researchers, the meta-analysis was published in JAMA Internal Medicine in June 2023.

The new meta-analysis[5]

Researchers identified 15 randomized clinical trials that recorded the effect of oseltamivir on a first hospitalization due to any cause (hereafter referred to as hospitalization) among outpatient subjects aged 12 years or older who had a confirmed diagnosis of influenza. The researchers focused on all hospitalizations, rather than solely on those related to influenza, so that they could capture information about hospitalizations related to oseltamivir’s adverse effects.

The 15 trials enrolled 6,295 subjects with a mean age of 45 years: 54% were women. Each trial compared the use of oseltamivir at the recommended dosage (75 milligrams twice daily for five days) with the use of either a placebo or standard care.

Pooling data across all 15 trials, the meta-analysis showed that oseltamivir was not associated with a reduced risk of hospitalization during the follow-up period, which generally ranged from 21 to 28 days. The drug also was not associated with reduced rates of hospitalization in older subjects or in subjects considered at greater risk of hospitalization. Moreover, oseltamivir was strongly associated with an increased risk of nausea and vomiting.

The researchers noted that it was unlikely that the use of oseltamivir in a general outpatient population had a meaningful effect on serious influenza-related outcomes that lead to hospitalization. They concluded that “[f]or oseltamivir to continue to be part of a viable influenza response with respect to preventing severe complications, future studies should focus on identifying the groups of higher-risk participants, with laboratory confirmed influenza, who may derive benefit.”

Key prior evidence

The findings of the new meta-analysis are consistent with those from a 2014 meta-analysis conducted by the nonprofit Cochrane Collaboration.[6] The Cochrane researchers, who initially experienced difficulties in accessing oseltamivir’s data from its manufacturer,[7] concluded that, although the drug reduced the time to alleviation of symptoms in adults by 17 hours, it did not have an effect on hospitalizations. They also found a lack of credible evidence for an effect of the drug on serious flu complications. The researchers concluded that there was no evidence to support the use of oseltamivir to prevent serious outcomes during annual influenza outbreaks, and that there was minimal evidence that the drug was effective for prevention.

Importantly, oseltamivir’s minimal benefits must be weighed against its adverse effects. In addition to nausea and vomiting, these adverse effects include headache, pain, neuropsychiatric effects (such as agitation, confusion, hallucinations and seizures) in children especially, skin reactions (including skin blisters) and serious allergic reactions (including swelling of the face, eyes, lips or throat).[8]

Conclusions

The benefits of oseltamivir, which has been on the U.S. market for almost 25 years, are limited to a small reduction in flu symptoms. Evidence is lacking that the drug decreases hospitalizations or prevents complications (such as serious bacterial infections) that may occur during or after influenza infections. Moreover, there is no evidence from clinical trials demonstrating oseltamivir’s usefulness in treating influenza patients with severe medical conditions who are at greater risk of hospitalization.

Unless strong evidence becomes available demonstrating oseltamivir’s effectiveness, its benefits do not seem to outweigh its adverse effects, particularly for otherwise healthy individuals who are not in a hospital, nursing home or other institution. Therefore, Public Citizen’s Health Research Group has designated oseltamivir as a Limited Use[9] drug, keeping in mind that recommendations from the Centers for Disease Control and Prevention[10] and others indicate that the drug may be beneficial for institutionalized individuals and others at high risk of flu complications (who may not have been well-represented in the meta-analyses) when taken as soon as possible after symptoms develop.

What You Can Do

The best way to reduce your risk of catching the flu and developing related complications is by receiving the flu vaccine each year.[11]

If you are a healthy individual, you do not need to take oseltamivir for flu prevention or treatment. People who are hospitalized or at high risk of flu-related complications should consider consulting with their clinicians, and discussing the recent meta-analysis with them.
 

References

[1] Centers for Disease Control and Prevention. Abut flu. September 20, 2022. https://www.cdc.gov/flu/about/index.html. Accessed September 28, 2023.

[2] Department of Health and Human Services. HHS increases access to Tamiflu through the strategic national stockpile. December 21, 2022. https://www.hhs.gov/about/news/2022/12/21/hhs-increases-access-to-tamiflu-through-the-strategic-national-stockpile.html. Accessed September 28, 2023.

[3] Roche Laboratories Inc. Label: oseltamivir (TAMIFLU). October 1999. https://www.accessdata.fda.gov/drugsatfda_docs/label/1999/21087lbl.pdf. Accessed September 28, 2023.

[4] Roche Group. Label: oseltamivir (TAMIFLU). August 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021087s071,021246s054lbl.pdf. Accessed September 28, 2023.

[5] Hanula R, Bortolussi-Courval É, Mendel A, et al. Evaluation of oseltamivir used to prevent hospitalization in outpatients with influenza: A systematic review and meta-analysis [published online ahead of print June 12, 2023]. JAMA Intern Med. doi:10.1001/jamainternmed.2023.0699.

[6] Jefferson T, Jones MA, Doshi P, et al. Neuraminidase inhibitors for preventing and treating influenza in adults and children. Cochrane Database Syst Rev. 2014;2014(4):CD008965.

[7] Cohen D. Complications: Tracking down the data on oseltamivir. MBJ. 2009;339(December 8):b5387.

[8] Roche Group. Label: oseltamivir (TAMIFLU). August 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021087s071,021246s054lbl.pdf. Accessed September 28, 2023.

[9] Drug profile: oseltamivir (TAMIFLU). April 30, 2023. https://www.worstpills.org/monographs/view/311. Accessed September 28, 2023.

[10] Centers for Disease Control and Prevention. Influenza antiviral medications: Summary for clinicians. September 9, 2022. https://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm. Accessed September 28, 2023.

[11] Centers for Disease Control and Prevention. Abut flu. September 20, 2022. https://www.cdc.gov/flu/about/index.html. Accessed September 28, 2023.