**Criteria for Use of Antiviral Agents for Influenza**

**VHA Pharmacy Benefits Management Service and the Medical Advisory
Panel**

*The following recommendations are based on current medical evidence.
The content of the document is dynamic and will be revised as new
clinical data become available. The purpose of this document is to
assist practitioners in clinical decision making, to standardize and
improve the quality of patient care, and to promote cost-effective drug
prescribing. The clinician, however, must make the ultimate judgment
regarding the propriety of any course of treatment in light on
individual patient situations*

Four licensed influenza antiviral agents are available in the United
States (U.S.): amantadine, rimantadine, and oseltamivir, and zanamivir.
Historically, amantadine and rimantadine have been 70-90% effective in
preventing illness from influenza A infection (not active against
influenza B). However, recent reports have shown increasing resistance
to adamantanes, and for the 2005-06 influenza season, 91% of the
influenza A (H3N2) isolates tested by the CDC demonstrate resistance to
amantadine and rimantadine. The CDC does not recommend amantadine or
rimantadine to be used for the treatment or chemoprophylaxis of
influenza in the United States.

**Chemoprophylaxis for seasonal influenza**

The CDC (and the VA) recommends that oseltamivir be used for
chemoprophylaxis and that neither amantadine nor rimantadine be used for
chemoprophylaxis.

**Table 1: Criteria for chemoprophylaxis with oseltamivir**

+-----------------------------------------------------------------------+
| Either criterion A. or B. must be satisfied                           |
|                                                                       |
| > A. Patient falls into a high risk group\* for serious complications |
| > from influenza [AND]{.underline} there is **[seasonal               |
| > influenza]{.underline}** in the community or an institutional       |
| > outbreak                                                            |
|                                                                       |
| **AND [\>]{.underline} 1 of the following:**                          |
|                                                                       |
| -   Resident of a nursing home, hospital, etc. where there has been   |
|     an **[institutional outbreak]{.underline}** of influenza (provide |
|     chemoprophylaxis for the duration of the outbreak regardless of   |
|     prior vaccination)                                                |
|                                                                       |
| -   Patient has not had time to mount an immune response to the       |
|     vaccine (provide chemoprophylaxis for a period of 2 weeks after   |
|     vaccination)                                                      |
|                                                                       |
| -   Patient does not receive, cannot receive or does not respond to   |
|     vaccine (i.e., immunocompromised patients) (provide               |
|     chemoprophylaxis for duration of outbreak, i.e., 6 -- 8 weeks)    |
|                                                                       |
| > **[OR]{.underline}**                                                |
| >                                                                     |
| > B. Patient is a healthcare worker\*\* [AND]{.underline} there is    |
| > **[seasonal influenza]{.underline}** in the community               |
| >                                                                     |
| > **AND [\>]{.underline} 1 of the following:**                        |
|                                                                       |
| -   Regardless of prior vaccination: works in an institution (nursing |
|     home, hospitals, etc.) where there has been an **[outbreak of     |
|     influenza]{.underline}** and the outbreak is caused by a strain   |
|     of influenza virus that is not well-matched by the vaccine (e.g., |
|     multiple documented breakthrough influenza-virus infections among |
|     vaccinated persons or circulation in the surrounding community of |
|     suspected index case(s) of strains not contained in the vaccine). |
|     (provide chemoprophylaxis for the duration of the outbreak).      |
|                                                                       |
| -   Has direct patient care responsibilities and is not able to       |
|     obtain influenza vaccine. (provide chemoprophylaxis for duration  |
|     of seasonal influenza in the community, i.e., 6 -- 8 weeks)       |
+-----------------------------------------------------------------------+

\*High-risk patients include: \> 65years old, nursing home patient or
resident of VA long term care facility, chronic diseases (e.g. heart
disease, lung disease, diabetes, blood diseases, end-stage renal
disease), cancer or cancer treatment, HIV/AIDS, steroid therapy, persons
who are or intend to become pregnant during the influenza season.
Persons who are or intend to become pregnant should consult their
primary healthcare providers. Because of the unknown effects of
influenza antiviral drugs on pregnant women and their fetuses, these
drugs should be used during pregnancy only if the potential benefit
justifies the potential risk to the embryo or fetus.

\*\*Chemoprophylaxis of healthcare works should be prescribed in
consultation with occupational health

Table 2: Dosing for influenza prophylaxis

+-------+----------+-----------+-----------+-------------------------+
|       |          | **13-64   | **[\>]{.u | **Hepatic or renal      |
|       |          | years     | nderline} | dysfunction**           |
|       |          | old**     | 65 years  |                         |
|       |          |           | old**     |                         |
+-------+----------+-----------+-----------+-------------------------+
| O     | I        | 75mg once | 75mg once | CrCl 10 - 30 ml/min:    |
| selta | nfluenza | daily     | daily     |                         |
| mivir | A or B   |           |           | 75 mg every other day   |
|       |          |           |           | or 30mg once daily      |
+-------+----------+-----------+-----------+-------------------------+

**Treatment for Seasonal Influenza**

Oseltamivir is indicated for treatment of Influenza A and B based on the
following criteria.\*\* The CDC also recommends the use of zanamavir
(which is not currently on the VA National Formulary) for treatment of
influenza.

> **Table 3: Criteria for treatment with oseltamivir for seasonal
> influenza**

+-----------------------------------------------------------------------+
| > Patients who already have serious cases of influenza (e.g.,         |
| > warranting hospitalization)                                         |
|                                                                       |
| **[OR]{.underline}**                                                  |
|                                                                       |
| > Onset of symptoms is within 48 hours [AND]{.underline} Patient is   |
| > at risk for a potentially life-threatening influenza-related        |
| > illness\*                                                           |
+-----------------------------------------------------------------------+

\*High-risk patients include: \> 65years old, nursing home patient,
chronic diseases (e.g. heart disease, lung disease, diabetes, blood
diseases, end-stage renal disease), cancer or cancer treatment,
HIV/AIDS, steroid therapy

\*\* The most reliable way to diagnose influenza is by the use of
specific laboratory tests
(<http://www.cdc.gov/flu/professionals/diagnosis/>). If rapid testing is
not available, clinicians need to rely upon epidemiological data and
clinical findings. However, while clinical criteria, i.e., the presence
of fever and cough has been reported to have an accuracy as high as 80
-- 90% in otherwise health young adults^1-3^, the predictive value of
such symptom complex is significantly less in older adults^4^,
children^5^ and nursing home residents^6,7^.

**Table 4:** Dosing for treatment of influenza

+-------+----------+-----------+-----------+-------------------------+
|       |          | **13-64   | **[\>]{.u | **Hepatic or renal      |
|       |          | years     | nderline} | dysfunction**           |
|       |          | old**     | 65 years  |                         |
|       |          |           | old**     |                         |
+-------+----------+-----------+-----------+-------------------------+
| O     | I        | 75mg      | 75mg      | CrCl 10-30ml/min 75mg   |
| selta | nfluenza | twice     | twice     | once daily for 5 days.  |
| mivir | A or B   | daily for | daily for | No recommendations are  |
|       |          | 5 days    | 5 days    | available for patients  |
|       |          |           |           | undergoing hemodialysis |
|       |          |           |           | or continuous           |
|       |          |           |           | peritoneal dialysis.    |
|       |          |           |           |                         |
|       |          |           |           | Oseltamivir has not     |
|       |          |           |           | been studied in         |
|       |          |           |           | patients with liver     |
|       |          |           |           | disease.                |
+-------+----------+-----------+-----------+-------------------------+
| Zanam | I        | 10mg      | 10mg      | No dosage reduction is  |
| ivir¶ | nfluenza |           | twice     | recommended for         |
|       | A or B   | (2        | daily     | patients with           |
|       |          | inh       |           | mild-moderate renal     |
|       |          | alations) |           | impairment              |
|       |          | twice     |           |                         |
|       |          | daily     |           | Zanamivir has not been  |
|       |          |           |           | studied in patients     |
|       |          |           |           | with liver disease.     |
+-------+----------+-----------+-----------+-------------------------+

¶Zanamivir is available as a dry powder inhaler that is orally inhaled.
Doses are packaged in a blister pack and must be loaded into the
Rotadisk. Each blister contains 5mg of drug.

**Adverse events of Neuraminidase inhibitors**

[]{.mark}

*[Neuropsychiatric Events]{.underline}*: Transient neuropsychiatric
events (i.e., hallucinations, delirium and abnormal behavior leading to
self-injury including ones with fatal outcomes) have been reported in
patients receiving neuraminidase inhibitors in postmarketing experience.
These reports are mostly from Japan among pediatric patients. Although
causality has not been established, the prescribing information
recommends that patients with influenza should be closely monitored for
signs of abnormal behavior throughout the treatment period. An
assessment of risk versus benefit should be conducted if a patient
experiences neuropsychiatric symptoms while receiving oseltamivir or
zanamivir.

**Oseltamivir:** Nausea and vomiting were reported more frequently among
adults receiving oseltamivir for treatment (nausea without vomiting,
approximately 10%; vomiting, approximately 9%) than among persons
receiving placebo (nausea without vomiting, approximately 6%; vomiting,
approximately 3%). In postmarking experience, rare cases of anaphylaxis
and serious skin reactions including toxic epidermal necrolysis,
Stevens-Johnson Syndrome, and erythema multiforme have been reported.

**Zanamivir:** 13% of patients receiving zanamivir and 14% of patients
who received placebo (inhaled powdered lactose vehicle) experienced a
\>20% decline in forced expiratory volume in 1 second (FEV1) after
treatment.  Because of the risk for serious adverse events and because
the efficacy has not been demonstrated among this population, zanamivir
is not generally recommended for treatment for patients with underlying
airway disease.  However, if benefits outweigh the risk, and zanamivir
is used in patients with asthma or COPD, a fast-acting bronchodilator
should be available when inhaling zanamivir. In postmarking experience,
rare cases of allergic-like reactions including oropharyngeal edema,
serious skin rashes, and anaphylaxis have been reported.

References

1.  Boivin G, Hardy I, Tellier G, Maziade J. Predicting influenza
    infections during epidemics with use of a clinical case definition.
    Clin Infect Dis. 2000;31:1166-1169.

2.  Monto AS, Gravenstein S, Elliott M, et al. Clinical signs and
    symptoms predicting influenza infection. Arch Intern Med.
    2000;160:3243-3247.

3.  Zambon M, Hays J, Webster A, et al. Diagnosis of influenza in the
    community: Relationship of clinical diagnosis to confirmed
    virological, serologic, or molecular detection of influenza. Arch
    Intern Med. 2001;161:2116-2122.

4.  Walsh EE, Cox C, Falsey AR. Clinical features of influenza A virus
    infection in older hospitalized persons. J Am Geriatr Soc.
    2002;50:1498-1503.

5.  Ruest A, Michaud S, Deslandes S, Frost EH. Comparison of the
    Directigen Flu A+B test, the QuickVue influenza test, and clinical
    case definition to viral culture and reverse transcription-PCR for
    rapid diagnosis of influenza virus infection. J Clin Microbiol.
    2003;41:3487-3493.

6.  Falsey AR. Noninfluenza respiratory virus infection in long-term
    care facilities. Infect Control Hosp Epidemiol. 1991;12:602-608.

7.  Drinka PJ, Gravenstein S, Krause P, et al. Non-influenza respiratory
    viruses may overlap and obscure influenza activity. J Am Geriatr
    Soc. 1999;47:1087-1093.

8.  Fiogre AE, Shaw DK, Haber P, et al. Prevention and control of
    influenza. Recommendations of the Advisory Committee on
    Immuniqzation Practices (ACIP), 2007. MMWR. 2007; 56:1-54.

The PBM-MAP acknowledges Larry Mole, PharmD Director of VA Center for
Quality Management in Public Health and Pam Belperio, PharmD, BCPS
National Public Health Clinical Pharmacist, VA Center for Quality
Management in Public Health for their participation in the development
of the criteria.