Antiviral Treatment Options, including Intravenous Peramivir, for Treatment of Influenza in Hospitalized Patients for the 2009-2010 Season

October 26, 2009 5:00 PM ET

Summary

• Empiric antiviral treatment with oral oseltamivir or orally inhaled zanamivir should be administered as soon as possible for all persons with suspected or confirmed influenza requiring hospitalization. Initiation of antiviral treatment should not be delayed pending laboratory confirmation of influenza.
• The FDA has issued an Emergency Use Authorization (EUA) to allow the use of intravenous peramivir to treat certain hospitalized adult and pediatric patients with suspected or laboratory confirmed 2009 H1N1 virus infection or infection due to nonsubtypable influenza A virus suspected to be 2009 H1N1 based on community epidemiology.
• Peramivir may be appropriate for certain hospitalized and critically ill patients with suspected or confirmed 2009 H1N1 influenza, such as patients not responding to either an oral or inhaled antiviral therapy and patients without a dependable oral or inhaled route of drug delivery (e.g. patients unable or unlikely to absorb oseltamivir due to ileus or high nasogastric tube output).
• Clinicians considering peramivir under the EUA must read and understand the content of the FDA-issued Emergency Use Authorization of Peramivir IV: Fact Sheet For Health Care Providers prior to initiating a request and must agree to comply with terms and conditions of authorized use of Peramivir per the FDA-issued EUA.
• The following materials are also available for clinicians considering peramivir treatment for eligible patients under their care: Peramivir IV Questions and Answers for Health Care Providers and FDA Questions and Answers for Health Care Providers: Renal Dosing and Administration Recommendations for Peramivir IV.
• To request Peramivir IV (licensed clinicians with prescribing privileges ONLY), CLICK HERE. For any questions, call 1-800-CDC-INFO (1-800-232-4636).

Objective

The US Food and Drug Administration (FDA) has authorized the use of peramivir under an Emergency Use Authorization (EUA). Peramivir is a neuraminidase inhibitor (NAI) that is administered intravenously to treat certain patients with suspected or confirmed 2009 H1N1 influenza virus infection. The healthcare provider fact sheet on peramivir reviews the limited available safety and efficacy data on peramivir.  This document provides additional recommendations on the use of antiviral agents, including peramivir, for treatment of hospitalized patients with influenza to provide context for the use of peramivir. These recommendations may be further revised if changes in the clinical presentation or antiviral susceptibility of 2009 H1N1 influenza virus are observed.

Hospitalized patients with 2009 H1N1 influenza virus infection

Since the emergence of 2009 H1N1 influenza virus, a wide spectrum of clinical complications in patients with 2009 H1N1 influenza virus infection requiring hospitalization have been reported. In contrast to seasonal influenza, most hospitalized 2009 H1N1 influenza patients have been children and non-elderly adults. A high proportion of hospitalized patients have had high risk conditions for influenza-related complications, including pregnancy.  Worldwide, approximately 6-25% of hospitalized patients with 2009 H1N1 influenza have required admission to an intensive care unit (ICU)^1-3.  Broadly, 3 categories of ICU patients have been described: 1) primary viral pneumonia with severe gas exchange abnormalities; 2) invasive bacterial co-infection (Staphylococcus aureus – including MRSA, Streptococcus pneumoniae, and Group A Streptococcus) causing pneumonia or sepsis, and 3) worsening organ dysfunction in patients with poor cardiopulmonary reserve due to underlying comorbidities. Severe complications have occurred among persons with underlying medical conditions, including pregnancy, and in previously healthy persons.

Antiviral Treatment for Hospitalized Patients with 2009 H1N1 Influenza

Recently published data suggest that early neuraminidase inhibitor treatment was associated with survival in hospitalized¹ U.S. patients, and neuraminidase inhibitor treatment was associated with survival compared to no treatment in critically ill² Mexican patients with 2009 H1N1 influenza virus infection.

Neuraminidase Inhibitors (NAIs):  Currently, two FDA-approved NAI antiviral medications, oseltamivir and zanamivir, are recommended by CDC for the treatment of hospitalized patients with 2009 H1N1 influenza virus infection4. Although FDA-approved for treatment of uncomplicated influenza in the outpatient setting, both oseltamivir and zanamivir are authorized under an emergency use authorization (EUA) for treatment of hospitalized patients with suspected or confirmed 2009 H1N1 influenza. Currently there are no FDA-approved IV antiviral products for the treatment of hospitalized patients with influenza. Peramivir is the first IV NAI antiviral medication to become available by EUA. IV zanamivir is available for compassionate use from its manufacturer via an emergency Investigational New Drug (IND) application to the FDA. Clinicians interested in enrolling patients in clinical trials of IV antiviral agents for influenza should contact the investigators of pertinent clinical trials.

Oseltamivir is an oral NAI for treatment of influenza.  Early treatment with oseltamivir has been associated with survival in hospitalized¹ and critically ill² patients with 2009 H1N1 influenza virus infection. Although rare, sporadic cases of 2009 H1N1 influenza with resistance to oseltamivir have been reported⁵, there is no evidence of ongoing community-wide transmission of oseltamivir-resistant 2009 H1N1 influenza virus worldwide.

Zanamivir is an orally inhaled NAI and to date there have been no reports of zanamivir-resistant 2009 H1N1 influenza virus infection. Inhaled zanamivir is contraindicated in persons with chronic pulmonary disease, and is not approved for treatment of influenza in persons aged <7 years. The commercial zanamivir formulation (Relenza® Inhalation Powder delivered via Diskhaler) is a mixture of zanamivir active drug substance and lactose drug carrier. This formulation is not designed or intended to be used in any nebulizer or mechanical ventilator as there is a risk that lactose can obstruct proper functioning of mechanical ventilator equipment ("Relenza (zanamivir) Inhalation Powder"). There are no controlled data regarding the effectiveness and tolerability of inhaled zanamivir delivered by the commercial Diskhaler device in hospitalized patients.

Peramivir: Peramivir is an investigational NAI available in IV formulation, whose efficacy and safety have not yet been established. The FDA has issued an EUA to allow the use of peramivir to treat certain adult and pediatric patients with suspected or laboratory confirmed 2009 H1N1 influenza. Clinicians considering the use of peramivir under EUA must read and understand the content of the FDA-issued EUA of Peramivir: Fact Sheet for Health Care Providers and the terms and conditions on this EUA prior to initiating a request for this product. This fact sheet also includes safety and efficacy data. Peramivir dosing information, including the recommended dose with renal insufficiency is also available in the Fact Sheet for Health Care Providers.

Specifically, peramivir is authorized for the following patients who are admitted to a hospital: 

• Adult patients for whom therapy with an IV agent is clinically appropriate, based upon one or more of the following reasons:
  • patient not responding to either oral or inhaled antiviral therapy, or
  • drug delivery by a route other than IV (e.g. enteral oseltamivir or inhaled zanamivir) is not expected to be dependable or is not    feasible, or
  • the clinician judges IV therapy is appropriate due to other circumstances.
• Pediatric patients for whom an IV agent is clinically appropriate because:
  • patient not responding to either oral or inhaled antiviral therapy, or
  • drug delivery by a route other than IV (e.g. enteral oseltamivir or inhaled zanamivir) is not expected to be dependable or is not feasible

There are currently no available data from clinical trials to guide the use of any antiviral medication, including peramivir, for treatment of critically ill patients with suspected or confirmed influenza.  One study comparing five days of IV peramivir to oral oseltamivir in non-critically ill hospitalized adults found no important differences in recovery⁶.  Early treatment with a single IV dose of peramivir was comparable to 5 days of oral oseltamivir treatment in adult outpatients with uncomplicated seasonal influenza⁷. Clinical judgment is an important factor in determining which hospitalized or critically ill patients would benefit from IV peramivir. If peramivir is ordered, hospitalized patients should continue to receive therapy with an available NAI (oseltamivir or zanamivir) until after the first dose of peramivir has been administered.  Combined therapy with oseltamivir or zanamivir and peramivir is not recommended, because of their overlapping mechanism of action.  The decision to administer peramivir treatment longer than 5 days should be based upon clinical judgment and virological data (rRT-PCR or viral culture), if available.  To request IV Peramivir (licensed clinicians with prescribing privileges ONLY), call 1-800-CDC-INFO (1-800-232-4636).

Antiviral Treatment Considerations in Hospitalized Patients

Empiric therapy: Antiviral therapy should be initiated empiricallyas early as possible with a NAI in any hospitalized patient with suspected influenza, even if 2009 H1N1 influenza virus infection has not been confirmed. (see Antiviral recommendations for dosing information, including for pediatric patients) The benefits of antiviral treatment are greatest when started within the first 2 days of illness or as soon after illness onset as possible. Initiation of antiviral treatment should not be delayed pending laboratory confirmation of influenza. Clinicians should be aware that the sensitivities of rapid influenza diagnostic tests (RIDTs) and direct immunofluorescence assays (DFAs) are lower than real-time reverse transcriptase polymerase chain reaction (rRT-PCR) tests and viral culture. Therefore, a negative RIDT or DFA result does not rule out influenza virus infection and NAI antiviral treatment should not be withheld based on a negative RIDT or DFA result. Information on influenza diagnostic testing can be found at "Interim Recommendations for Clinical Use of Influenza Diagnostic Tests During the 2009-10 Influenza Season".

Oseltamivir Dosing: In patients with pneumonia or severe lower respiratory tract disease, some experts recommend a higher oseltamivir dose (e.g. twice standard dosing or 150 mg twice daily in adults)⁸ and longer duration of treatment (10 days versus 5 days) because of the potential for decreased enteral absorption among critically ill patients, and high and prolonged viral replication in the lower respiratory tract. Intubated patients can be administered oral oseltamivir via nasogastric or orogastric tube. Limited data indicate that 150 mg twice daily of oseltamivir can be well absorbed in mechanically ventilated patients who are critically ill from influenza virus infection⁹. Unpublished data from Canada indicate that the standard dose of oseltamivir (75mg twice daily) given by nasogastric tube in critically ill adults with 2009 H1N1 influenza virus infection is adequately absorbed. Clinical trials evaluating the efficacy of higher dose and longer duration of oseltamivir therapy for critically ill influenza patients are not yet completed. The higher dose of oral oseltamivir (e.g. 150 mg po BID) was not associated with increased adverse effects in clinical trials among adult outpatients^10. Dose-adjustment of NAIs may be needed in critically ill patients with impaired renal function, and for patients who develop renal failure as a complication of 2009 H1N1 influenza virus infection.

Oseltamivir Resistance:  Because determination of NAI treatment failure is difficult based on clinical criteria alone, virological testing (rRT-PCR or viral culture) to confirm on-going viral replication may help inform antiviral treatment decisions in critically ill patients. Symptomatic patients with highly suspected or documented oseltamivir resistance, should not be treated with peramivir because clinical isolates expressing the oseltamivir resistance-associated substitution H275Y in neuraminidase have demonstrated reduced in-vitro susceptibility to peramivir, although the clinical significance of this is currently unknown. Patients with oseltamivir-resistant influenza virus infection should be treated with an antiviral agent to which the virus is known or suspected to be susceptible (e.g., zanamivir). Limited quantities of IV zanamivir are available from its manufacturer for compassionate use via an emergency Investigational New Drug (IND) application to the FDA. Despite treatment with IV antiviral agents, hospitalized patients may continue to shed influenza virus during therapy, so appropriate infection control measures should be maintained until illness has resolved or there is evidence of cessation of viral shedding.

References

1. Jain S et al. Hospitalized Patients with 2009 H1N1 Influenza in the United States, April-June 2009. N Engl J Med. 2009 Oct 8. [Epub ahead of print]

2. Dominguez-Cherit G et al. Critically Ill Patients with 2009 Influenza A(H1N1) in Mexico.  JAMA. 2009 Oct 12.  [Epub ahead of print]

3. Baker MG et al. Pandemic influenza A(H1N1)v in New Zealand: the experience from April to August 2009. Euro Surveill. 2009;14(34)

4. 2009 H1N1 influenza virus is resistant to the adamantane class of antiviral medications (amantadine and rimantadine), and the use of these drugs is not recommended.  

5. Centers for Disease Control and Prevention. Oseltamivir-Resistant Novel Influenza A (H1N1) Virus Infection in Two Immunosuppressed Patients — Seattle, Washington, 2009.  MMWR Morb Mortal Wkly Rep 2009; 58: 893-896. 

6. Ison MG et al. Safety and Efficacy of Multiple-Day Treatment with Intravenous Peramivir or Oral Oseltamivir in Hospitalized Adults with Acute Influenza. XI International Symposium on Respiratory Viral Infections. 2009.  Oral abstract

7. Kohno S et al. Single-intravenous Peramivir vs. Oral Oseltamivir to Treat Acute, Uncomplicated Influenza in the Outpatient Setting:A Phase III Randomized, Double-blind Trial. Abstract V-537a. 49th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA September 12-15, 2009.

8. WHO.  WHO Guidelines for Pharmacological Management of Pandemic (H1N1) 2009 Influenza and other Influenza Viruses. August 2009.

9. Taylor WRJ et al. Oseltamivir Is Adequately Absorbed Following Nasogastric Administration to Adult Patients with Severe H5N1 Influenza. PLoS One. 2008: 3 (10): e3410 [Epub ahead of print]

10. Treanor JJ, et al. Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized controlled trial. JAMA 2000; 283:1016–24