Influenza Antiviral Therapies

The Centers for Disease Control and Prevention (CDC) estimated that during the 2013-2014 influenza season, the influenza vaccination prevented approximately 7.2 million illnesses and 90,000 influenza-associated hospitalizations. Despite this preventive measure, the influenza virus remains an imperative health concern. Three neuraminidase inhibitors (NAIs) have been approved to treat influenza in the United States: oseltamivir (Tamiflu), peramivir (Rapivab), and zanamivir (Relenza).¹

PHARMACOLOGY^2-5

NAIs inhibit neuraminidase, which is the enzyme that releases viral particles from infected cells. Thus, NAIs disable the influenza virus by preventing infected cells from releasing viral progeny. Each NAI has the same end result yet different binding characteristics and chemical structures. Because of these differences, NAIs may have varying resistance patterns, as mutations in the neuraminidase active site are responsible for the development of resistance.

THERAPEUTIC USE^2-4,6

All 3 NAIs are indicated for the treatment of influenza; oseltamivir and zanamivir are also indicated for prophylaxis. For treatment, a patient should initiate therapy within 2 days of symptom onset, as NAIs have not been shown effective if initiated past that point. Oseltamivir may be used to treat patients at least 2 weeks of age and for prophylaxis in patients older than 1 year. Peramivir is indicated for influenza treatment in patients at least 18 years. For treatment and prophylaxis, zanamivir may be used in patients at least 7 years and 5 years, respectively.

DOSING AND ADMINISTRATION^2-4,6

Each NAI is available as a unique dosage form. Oseltamivir is formulated for oral administration as capsules and as a powder for suspension. Adult patients should be treated with 75 mg twice daily for 5 days. For prophylaxis, the dose should be 75 mg once daily for at least 10 days. Oseltamivir may be administered without regard to meals, but taking it with food can improve tolerance. Specific dosing guidelines are available for pediatric patients and those with a creatinine clearance less than 60 mL/min.

For uncomplicated illness in the outpatient setting, peramivir is administered as a single 600-mg intravenous (IV) infusion over 15 to 30 minutes. However, for the 2015-2016 influenza season, the CDC has recommended that hospitalized patients receive at least 5 days of IV treatment. Peramivir should be diluted to a maximum volume of 100 mL with 0.9% or 0.45% sodium chloride, 5% dextrose, or lactated Ringer’s solution.

Zanamivir is administered via oral inhalation. A Diskhaler device is included with individual blisters containing medication. For treatment, 10 mg (2 inhalations) should be administered twice daily for 5 days. For prophylaxis in the household setting, 10 mg should be used once daily for 10 days. If zanamivir is being used in response to a community outbreak, 10 mg should be continued for 28 days.

COMPARATIVE EFFICACY^2-4,7

Each NAI was approved on the basis of placebo-controlled studies. The primary outcome of these studies was time to improvement of symptoms (typically self-assessed by the patient). All studies initiated treatment within 48 hours of symptom onset. Oseltamivir, peramivir, and zanamivir trials reported similar results and reduced the time to improvement by 1.3 days, 21 hours, and 1 day, respectively. Thus, when initiated quickly after the onset of symptoms, NAIs may reduce influenza duration by approximately 1 day.

In addition, a multicenter observational study compared the efficacy of zanamivir and oseltamivir in treating influenza A and influenza B. The study enrolled 1113 patients and assessed the duration of fever in patients who received zanamivir, oseltamivir, or no anti-influenza treatment within 48 hours of symptom onset. Zanamivir and oseltamivir did not significantly differ in the duration of fever in patients with influenza A (49.7 + 21.7 hours and 52.5 + 25.6 hours, respectively), although they did vary significantly from the group that did not receive treatment (75.4 + 24.2 hours; P <.001 for both). However, zanamivir treatment of influenza B resulted in a significantly shorter duration of fever compared with oseltamivir treatment or no anti-influenza treatment (53.9 + 26.4 hours, 69.4 + 32.9 hours, 75.3 + 27.3 hours, respectively; P <.001 for both). Overall, zanamivir and oseltamivir are considered equally effective for the treatment of influenza A, but zanamivir is more effective (using fever reduction as a surrogate) than oseltamivir for treating influenza B.

ADVERSE EFFECTS^2-4,6

Although adverse effects (AEs) associated with NAIs are generally mild, there are a few rare and severe AEs. These agents may cause serious skin and/or hypersensitivity reactions. Also, it is important to note that influenza may be associated with neurologic and behavioral symptoms. Therefore, although these AEs are rare and the contribution of NAIs to them is unknown, patients should be monitored for abnormal behavior.

In addition, the use of zanamivir is not recommended in patients with underlying airway disease (eg, asthma, chronic obstructive pulmonary disease) because serious cases of bronchospasm have been reported. Less serious AEs associated with these agents include fatigue, nausea/vomiting, diarrhea, and headache.

DRUG INTERACTIONS^2-4,6

Minimal drug interactions are observed with NAIs. The main concern associated with these agents is the concomitant use of certain influenza vaccines. Inactivated influenza vaccines do not interact and can be administered at any time. However, antiviral drugs may inhibit the replication of a live vaccine virus, thus making live attenuated influenza vaccines less effective if administered 2 weeks before or 48 hours after these antiviral agents.

SAFETY ISSUES⁸

When patients are receiving the oral suspension of oseltamivir, an appropriate measuring device should be provided and patients should be instructed based on the milliliter unit. Additionally, because zanamivir is administered via inhalation, the technique and ability of the patient to selfadminister should be evaluated before prescribing.

Jennifer L. Cruz, PharmD, BCPS, is an assistant professor of clinical education at UNC Eshelman School of Pharmacy. Katherine Summers is a PharmD candidate at UNC Eshelman School of Pharmacy.

References

• Reed C, Kim IK, Singleton JA, et al; Centers for Disease Control and Prevention. Estimated influenza illnesses and hospitalizations averted by vaccination—United States, 2013-2014 influenza season. MMWR Morb Mortal Wkly Rep. 2014;63(49):1151-1154.
• Tamiflu [package insert]. South San Francisco, CA: Genentech, Inc; 2014.
• Rapivab [package insert]. Durham, NC: BioCryst Pharmaceuticals; 2014.
• Relenza [package insert]. Philadelphia, PA: GlaxoSmithKline; 2013.
• Spanakis N, Pitiriga V, Gennimata V, Tsakris A. A review of neuraminidase inhibitor susceptibility in influenza strains. Exert Rev Anti Infect Ther. 2014;12(11):1325-1336. doi: 10.1586/14787210.2014.966083.
• Facts & comparisons eAnswers. online.factsandcomparisons.com. Accessed November 6, 2015.
• Kawai N, Ikematsu H, Iwaki N, et al. A comparison of the effectiveness of zanamivir and oseltamivir for the treatment of influenza A and B. J Infect. 2008;56(1):51-57.
• Lexicomp [online database]. Hudson, OH: Wolters Kluwer Health; 2015.