Marilyn Bulloch, PharmD, BCPS

With the United States having experienced its 

most severe flu season since the 2009 influenza A (H1N1) pandemic

, prompting the Centers for Disease Control (CDC)’s Acting Director, Anne Schuchat, MD, RADM, USPHS, to call the season a 

, it is important for health care providers to understand and choose the best treatment option for each patient that they see.

The CDC currently recommends treating the flu with a neuriminidase inhibitor (NAI), such as oral oseltamivir (Tamiflu), inhaled zanamivir (Relenza), or IV peramivir (Rapivab).

They recommend against the use of adamantanes, such as amantadine and rimantidine, due to their high level of resistance in the past few years.

The NAIs work by preventing NA formation, which leads to a reduction in viral replication by inhibition of releasing the virus from infected cells.

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. In a study published in 

, researchers compared patients with influenza who were treated versus those who were not, and found that all patients who were treated with an NAI—even if it was initiated up to 5 days after symptom onset&mdash;were more likely to survive (p<0.05 for each day through day 5 of treatment; 58% of patients survived in the untreated group, while there was 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% survival on day 5).

In a retrospective cohort study conducted in critically ill children diagnosed with influenza, between the ages of 1 and 21, those treated with oseltamivir had an approximately 18% shorter duration of hospital stay than those who were not given oseltamivir (p=0.02).

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. However, due to lack of data in severely ill hospitalized patients, only oseltamivir is currently recommended for these patients.

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. 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. 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. Mix directly before administration, draw it up in a syringe, and administer the full dose.

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. Thus far, there is no resistance reported for zanamivir, and no resistance for any drug regarding influenza B. One trial that studied resistance patterns for oseltamivir showed that resistance was much more frequent in ages 1 to 5 as compared with the combined older age groups, when treated within 48 hours of onset.

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.

A recent 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.

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 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.

Pre-exposure 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. 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 an oseltamivir-resistant strain in suspected.

 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. 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.

 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 lifesaving this year in many different venues of use.

A previous version of this article was posted on 

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Taking into account the severity of this flu season, it is important that health care providers understand and choose the best treatment option for each patient.

Fighting Flu: Managing and Preventing Influenza with Antivirals

As flu continues to beat down on the United States, different headlines have been boasting several remedies that allegedly offer quick and natural restorative powers to those who have fallen ill with the virus.

Oscillococcinum, which markets itself like a natural oseltamivir, is one such product that has been gaining a lot of attention lately. The product has been around for decades and has enjoyed its share of both popularity and criticism. Social media buzz is active with individuals attesting to its efficacy.

However, the manufacturer of the product landed in hot water with the US Food and Drug Administration as well as the Federal Trade Commission in 2009/10 over purported claims of being able to cure the H1N1 influenza strain.

Anas barbariae hepatis et cordis extractum 

200CK, which is made from the heart and liver of wild duck and is diluted repeatedly until essentially no molecules of duck heart or liver are found in the actual pill. Since wildfowl are a natural reservoir for influenza, and since nucleic and phosphoric compounds in the pill resemble influenza, it is thought that the combination contributes to antiviral activity. However, the exact mechanism of action is not well described.

The product's website cites 2 clinical studies indicating that it decreases the severity and duration of influenza-related symptoms. Both were placebo-controlled studies whose primary outcome included resolution of fever and other symptoms by or at 48 hours of treatment; each study showed a statistical advantage over placebo. Other studies, including multiple Cochrane systemic reviews (most recently in 2015), have been published.

The 2015 Cochrane review evaluated 6 studies; 2 using Oscillosoccinum for influenza prophylaxis and 4 for the treatment of influenza. The review specifically commented on notable flaws and bias within the studies' methods; it concluded that there was no significant benefit of the product in preventing influenza, and, based on 2 low-quality rated studies, that there was an absolute risk reduction of 7.7% in flu-like symptoms compared with placebo after 2 days of Oscillococcinum use (

=0.001), but that a significant difference was no longer seen by day 4 of treatment (

=0.1). The authors ultimately concluded that Oscillococcinum may work, but the evidence was not strong or sufficient enough reach a definitive conclusion, particularly given the poor quality of the studies available.

Another review by Marrari et al. published in 2012 looked at 3 studies, all published between 1988 and 1998.

 Two of the 3 studies were the sources cited on the product's webpage for proof of clinical efficacy. The authors' conclusion was in direct support of Oscillococcinum's efficacy. However, the conflict of interest section at the very end of the article indicates that all of the authors were employees of the product's maker; therefore, there is a strong potential for a potential biased conclusion and recommendation. Interestingly, studies looking at the active ingredient, 

, outside of Oscillococcinum, are not readily retrievable.

Overall, Oscillococcinum is relatively safe. The inactive ingredients include sucrose and the most common side-effects seen in published studies were a headache, rash, itching, and myalgia. Each dose is approximately $1.10, which is cheaper than the approximate $5-7 per dose of the now generic oseltamivir, but still not inexpensive. It is interesting that given the potential Oscillococcinum showed in early studies, that subsequent large, well-designed studies were never conducted to definitively determine its efficacy.

The product is still being marketed based off of 2 older studies. Such studies would provide valuable answers to the role Oscillococcinum has in influenza management, but like with so many homeopathic products, it seems questions regarding that role will remain unanswered for the foreseeable future.

In the age of evidence-based medicine, what recommendation should be made when the evidence is inconclusive? The old adage "it probably won't help, but it won't hurt either" seems applicable.

 An earlier version of this article stated that the manufacturer received a warning letter from the FDA about off-label claims. The statement referred to a warning letter sent to 1 internet marketer who made off-label claims for many products during the influenza pandemic. The manufacturer requested the marketer to cease and desist making such claims, and ultimately stopped sales to this retailer.  

Boiron. Oscillococcinum. Newtown Square, PA.

Mathie RT, Frye J, Fisher P. Homeopathic Oscillococciunum for preventing and treating influenza and influenza-like illness. 

. 2015;1:CD001957.doi: 10.1002/14651858.CD001957.pub6.

Ulbricht C, Chao W, Clark A, et al. Oscillococcinum (

200CK HPUS): an evidence-based systematic review by the Natural Standard Research Collaboration. 

Papp R, Schuback G, Beck E, et al. Oscillococcinum in patients with influenza-like syndromes: a placebo-controlled, double-blind evaluation. 

Marrari LA, Terzan L, Chauferrin G. Oscillococcinum for influenza treatment. 

A pharmacist cuts through the noise surrounding Oscillococcinum and its alleged role in flu management.

Marilyn Bulloch, PharmD, BCPS

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