Managing and Preventing Influenza with Antivirals: Information That May Not Be Familiar

MARCH 12, 2018

With this year’s strain of influenza gaining so much attention due to its severity, it is important to understand and choose the best treatment option for each patient. The CDC currently recommends treating the flu with a neuriminidase inhibitor (NAI), such as oral oseltamivir (Tamiflu), inhaled zanamivir (Relenza), or IV peramivir (Rapivab).1 They recommend against the use of adamantanes, such as amantadine and rimantidine, due to their high level of resistance in the past few years.1 The NAIs work by preventing NA formation, which leads to a reduction in viral replication by inhibition of release of the virus from infected cells.2

While it is ideal to treat the infection within 48 hours of symptoms, even treatment with an antiretroviral after 4 to 5 days of onset has shown to reduce severe outcomes in both inpatient and outpatient settings.3 A study published in Clinical Infectious Diseases compared patients with influenza who were treated versus those untreated, and found all patients treated with an NAI, even if it was initiated up to 5 days after symptom onset, were more likely to survive (p<0.05 for each day through day 5 of treatment, with 58% of patients surviving in the untreated group, 89% survival if the patient was treated on day 1 after onset of symptoms, 84% on day 2, 76% on day 3 , 73% on day 4, and 72% survivial on day 5).3 In a retrospective cohort study conducted in critically ill children diagnosed with influenza, ages 1-21, those treated with oseltamivir had an approximately 18% shorter duration of hospital stay than those not given oseltamivir (p=0.02).4

Another member of the NAI family, zanamivir, is often forgotten, but it is a strong alternative to oseltamivir treatment. In a head to head study in outpatient-treated influenza patients, the difference in efficacy and adverse events between patients using zanamivir vs oseltamivir was not significant, showing that either one could be appropriately used in treating influenza patients on an outpatient basis.5 However, due to lack of data in severely ill hospitalized patients, only oseltamivir is currently recommended for these patients.1 Comparing these two therapies’ cost, it is important to note the significant difference between them. Zanamivir costs about $65 without insurance for a full course of treatment, while oseltamivir costs roughly $130 for a full course.6 This difference in price is significant, and should be considered in areas where zanamivir is readily accessible.

Since oseltamivir is such a popular choice for treatment, it is important to recognize ways to handle its common adverse event. Oral oseltamivir is known to cause GI upset. It is important to inform patients that symptoms such as nausea and vomiting have shown to be lessened when taken with food.2 If patients, especially children, have difficulty swallowing this medication due to taste or swallowing considerations, it is appropriate to mix the contents of a capsule or the dose of the liquid with about a spoonful of thick, sweetened syrup, such as chocolate syrup.7 Mix directly before administration, draw it up in a syringe, and administer the full dose.7

With so many patients using oseltamivir, there has been concern for resistance. Current CDC data for the week ending February 24, 2018 shows a 1% resistance rate with oseltamivir and peramivir for influenza A strain H1N1 pdm09, but a zero percent resistance rate for these drugs with another strand of influenza A.8 There is no resistance reported thus far for zanamivir, and no resistance for any drug regarding influenza B.8 One trial that studied resistance patterns for oseltamivir showed that resistance was much more frequent in ages 1-5 as compared with the combined older age groups, when treated within 48 hours of onset.9

There is also data showing antiviral utility for influenza prophylaxis. The decision on whether to administer antivirals for prophylaxis should depend on the exposed person’s risks for influenza complications, type and duration of exposure, recommendations from local or public health authorities, and, perhaps most importantly, clinical judgement.1

Jackson RJ et al. found in a systematic review that oseltamivir is an effective influenza prophylactic agent when used in healthy adults and at-risk elderly patients, and zanamivir was effective in the same populations as well as post-exposure prophylaxis in elderly patients. The amantadines had very limited data supporting their use for influenza prophylaxis.10  Types of exposure will primarily refer to a variety of different degrees of close contact, which include droplet exposure via coughing or sneezing, contact with an infectious patient, or small particle aerosols in close proximity to the infectious patient. In general, prophylaxis with antivirals following exposure should be used only if they can can be started within 48 hours of that exposure. Local public health authorities should also be able to provide additional information with regard to use of prophylaxis in times of antiviral medication shortage or whether efforts should be focused on treatment versus prophylaxis.

Preexposure prophylaxis with antivirals has also shown to be effective, but should be reserved for patients who are at very high risk for influenza-related complications who cannot otherwise be protected during times of a high risk of exposure.1 Residents of nursing homes or long-term facilities are at a high risk of developing influenza related complications and may experience severe and fatal illness during an influenza outbreak. It is recommended by the CDC that all nursing home residents and healthcare personnel be vaccinated as soon as the influenza vaccine becomes available for that season, and, during an influenza outbreak, all eligible residents in the entire long-term care facility should receive prophylaxis. It is also recommended that prophylaxis within the long-term care facility should be given for at least two weeks and continuing for at least seven days after the last known case was identified. The drugs of choice for prophylaxis in this patient population is oseltamivir or zanamivir, and zanamivir should be used if a oseltamivir-resistant strain in suspected.11 However, researchers showed that amantadine chemoprophylaxis initiated five or more days following an influenza outbreak resulted in longer duration of outbreaks, greater incidence of outbreaks, and higher case-fatality rates in long-term care facilities. This study showed that prophylaxis within the nursing homes or long-term care facilities can be critical for the health and safety of the residents.12 Ease of administration should be considered when making prophylaxis decisions, especially in this population.

Zanamivir can be an effective agent for prophylaxis, but researchers found that 20% of long-term care facility residents found difficulties with the inhalation product and only about 3% of each dose was absorbed in patients who were not able to adequately use the inhaled product. Nausea and vomiting is still associated with oseltamivir in this setting, but it was found to be less common in older patients compared to younger adults.13 Both oseltamivir and zanamivir can be effective agents when used prophylactically, but it is imperative that all patient factors be considered when making treatment decisions.

Overall, antivirals have many uses during the influenza season and beyond. Not only are there a variety of products available to treat the flu, there are also options to use these agents as prophylaxis to prevent an outbreak in various populations. In addition, these agents have been shown to decrease the severity of flu symptoms and hospital stays, even if the virus is caught late and treatment is initiated outside of the ideal window. There are three agents available to combat the flu, and they have proved to be life saving this year in many different venues of use.
  
References
  1. Influenza Antiviral Medications: Summary for Clinicians. Centers for Disease Control and Prevention, National Center for Immunization and Respiratory Diseases (NCIRD): January 9, 2018. https://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm. Accessed March 12, 2018.
  2. Njoku, JC. Influenza. Pharmacotherapy: A Pathophysiologic Approach, 10e Eds. Joseph T. DiPiro, et al. New York, NY: McGraw-Hill, , http://accesspharmacy.mhmedical.com/content.aspx?bookid=1861§ionid=146071550. Accessed March 12, 2018.
  3. Louie JK, Yang S, Acosta M, Yen C, Samuel MC, et al. (2012) Treatment With Neuraminidase Inhibitors for Critically Ill Patients With Influenza A (H1N1)pdm09, Clinical Infectious Diseases, 55(9):1198–1204, https://doi.org/10.1093/cid/cis636. Accessed March 12, 2018.
  4. Coffin SE ,Leckerman K, Keren R, et. al. (2011). Oseltamivir Shortens Hospital Stays of Critically Ill Children Hospitalized with Seasonal Influenza: A Retrospective Cohort Study. The Pediatric Infectious Disease Journal, 30(11):962–966. http://doi.org/10.1097/INF.0b013e318232ede9. Accessed March 12, 2018.
  5. Tuna N, Karabay O, YahyaoÄŸlu, M (2012). Comparison of efficacy and safety of oseltamivir and zanamivir in pandemic influenza treatment. Indian Journal of Pharmacology, 44(6):780–783. http://doi.org/10.4103/0253-7613.103301 Accessed March 12, 2018.
  6. Oseltamivir. Relenza. GoodRx. https://www.goodrx.com/tamiflu?drug-name=tamiflu Accessed March 12, 2018.
  7. Opening and mixing tamiflu capsules with liquids. US Department of health and human services: centers for disease control and prevention. https://www.cdc.gov/h1n1flu/antivirals/09_208940-A_JILES_Tamiflu_InstrSHEET5_WEB.pdf Accessed March 12, 2018.
  8. Weekly U.S. Influenza Surveillance Report. Centers for Disease Control and Prevention, National Center for Immunization and Respiratory Diseases (NCIRD): February 9, 2018. https://www.cdc.gov/flu/weekly/index.htm Accessed March 12, 2018.
  9. Lina B, Boucher C, Osterhaus A, et. al. (2018). Five years of monitoring for the emergence of oseltamivir resistance in patients with influenza A infections in the Influenza Resistance Information Study. Influenza Other Respi Viruses, 12(2):1–12. https://www.ncbi.nlm.nih.gov/pubmed/29265727 Accessed March 12, 2018.
  10. Jackson RJ, Cooper KL, Tappenden P, et al. Oseltamivir, zanamivir, and amantadine in the prevention of influenza: A systematic review. Journal of Infection. Jan 2011;62(1):14-25.
  11. Interim Guidance for Influenza Outbreak Management in Long-Term Care Facilities. Centers for Disease Control and Prevention, National Center for Immunization and Respiratory Diseases (NCIRD): March 28, 2017. https://www.cdc.gov/flu/professionals/infectioncontrol/ltc-facility-guidance.htm Accessed March 12, 2018.
  12.  Rubin MS, Nivin B, Ackelsberg J. Effect of timing of amantadine chemoprophylaxis on severity of outbreaks of influenza a in adultlong-term care facilities. Clin Infect Dis. 2008 Jul 1;47(1):47-52.
  13. McGeer A, Sitar DS, Tamblyn SE, et al. Use of antiviral prophylaxis in influenza outbreaks in long term care facilities. Can J Infect Dis. Jul 2000;11(4):187-192.


Marilyn Bulloch, PharmD, BCPS, FCCM
Marilyn Bulloch, PharmD, BCPS, FCCM
Marilyn Novell Bulloch, PharmD BCPS, is an Associate Clinical Professor of Pharmacy Practice at the Auburn University School of Pharmacy and an Adjunct Associate Professor at the University of Alabama-Birmingham School of Medicine and the University of Alabama College of Community Health Sciences . She completed a post-graduate pharmacy practice residency at the University of Alabama-Birmingham Hospital and a post-graduate specialty residency in critical care pharmacy at Charleston Area Medical Center in Charleston, West Virginia. Dr. Bulloch also completed a Faculty Scholars Program in geriatrics through the University of Alabama-Birmingham Geriatric Education Center in 2011. She serves on multiple committees and in leadership positions for many local, state, and national pharmacy and interdisciplinary medical organizations.
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