Updated Interim Recommendations for the Use of Antiviral Medications in the Treatment and Prevention of Influenza for the 2009-2010 Season

Updated Interim Recommendations for the Use of Antiviral Medications in the Treatment and Prevention of Influenza for the 2009-2010 Season
December 07-10, 2009 5:00 PM ET

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Objective
Introduction
Treatment of confirmed or suspected influenza
Antiviral Chemoprophylaxis of exposed individuals
Antiviral drug use for control of influenza outbreaks in institutions
Specific regimens for treatment and chemoprophylaxis of influenza
Antiviral prescription and dispensing considerations
Adverse events and contraindications
Further information
These recommendations contain the following updates:


Information regarding use of intravenous peramivir under an emergency use authorization
Information on availability of renal dosing for peramivir
Updated oseltamivir dosing instructions for children younger than 1 year of age based on weight
Antiviral treatment and chemoprophylaxis considerations for patients vaccinated with 2009 H1N1 and seasonal influenza vaccines
Guidance on early empiric antiviral treatment for patients with progressive or severe influenza-like illness, regardless of underlying medical conditions
Guidance on early empiric antiviral treatment patients with underlying medical conditions placing them at risk for complications
Clarification of treatment considerations for patients with illness longer than 48 hours
These recommendations focus on the use of antiviral medications for the treatment and chemoprophylaxis of influenza. As of December 4, 2009, influenza A (H1N1) virus (2009 H1N1), is the strain responsible for >99% of influenza in the U.S. during the 2009-2010 influenza season. For information about other influenza viruses refer to www.cdc.gov/flu. These recommendations were last updated on December 4, 2009, and will be updated periodically as new information becomes available.

Objective
To provide updated recommendations on the use of antiviral agents for treatment and prophylaxis of influenza during the 2009-2010 influenza season.

Introduction
Through November, 2009, ~99% of typed influenza viruses have been 2009 H1N1. The vast majority of 2009 H1N1 viruses tested for drug resistance have been susceptible to oseltamivir and zanamivir but resistant to the adamantanes (amantadine, rimantadine). Surveillance data, updated weekly, are available at www.cdc.gov/flu/weekly. These recommendations will be revised as needed to adapt to new information on risk factors, antiviral availability and resistance, or the circulation of other influenza viruses.

In general, treatment with an antiviral agent, when indicated, should begin as soon as possible after the onset of typical influenza-like symptoms. Influenza illness can present in a range of symptomatology: from a mild upper respiratory infection to an acute, life-threatening illness.

Mild or uncomplicated illness is characterized by typical symptoms like fever (although not everyone with influenza will have a fever), cough, sore throat, rhinorrhea, muscle pain, headache, chills, malaise, sometimes diarrhea and vomiting, but no shortness of breath and little change in chronic health conditions.
Progressive illness is characterized by typical symptoms plus signs or symptoms suggesting more than mild illness: chest pain, poor oxygenation (e.g. tachypnea, hypoxia, labored breathing in children), cardiopulmonary insufficiency (e.g. low blood pressure), CNS impairment (e.g. confusion, altered mental status), severe dehydration, or exacerbations of chronic conditions (e.g. asthma, chronic obstructive pulmonary disease, chronic renal failure, diabetes or other cardiovascular conditions).
Severe or complicated illness is characterized by signs of lower respiratory tract disease (e.g., hypoxia requiring supplemental oxygen, abnormal chest radiograph, mechanical ventilation), CNS findings (encephalitis, encephalopathy), complications of low blood pressure (shock, organ failure), myocarditis or rhabdomyolisis, or invasive secondary bacterial infection based on laboratory testing or clinical signs (e.g. persistent high fever and other symptoms beyond three days).
Influenza viruses are transmitted from person to person primarily through contact with infected respiratory secretions, especially airborne droplets generated by coughing and sneezing. Viral replication and shedding are key considerations in the timing of treatment, infection control, and chemoprophylaxis. In general, the incubation period for influenza is estimated to range from 1 to 4 days with an average of 2 days. Influenza virus shedding (the time during which a person might be infectious to another person) begins the day before illness onset and can persist for 5 to 7 days, although some persons may shed virus for longer periods, particularly young children and severely immunocompromised persons. The amount of virus shed is greatest in the first 2-3 days of illness and appears to correlate with fever, with higher amounts of virus shed when temperatures are highest. For these recommendations, however, the infectious period for influenza is defined as one day before fever begins until 24 hours after fever ends.

Treatment of Confirmed or Suspected Influenza
Who to treat

Prompt empiric treatment is recommended for persons with suspected or confirmed influenza and:

Illness requiring hospitalization
Progressive, severe, or complicated illness, regardless of previous health status, and/or
Patients at risk for severe disease (see below for groups at high risk)
How to treat

Antiviral drugs: oseltamivir (oral), zanamivir (inhaled)
For detailed dosing guidelines, see table 1 below
Initiate treatment as early as possible after onset of symptoms
Treat empirically before diagnostic test results are reported
When definitive diagnosis is indicated, request definitive diagnostic tests (rRT-PCR*, viral culture) rather than rapid tests (RIDT*, DFA*)
* rRT-PCR: real-time reverse transcriptase polymerase chain reaction; RIDT: rapid influenza diagnostic test, DFA: direct immunofluorescence assay

Antiviral Drugs for Treatment of Influenza
The neuraminidase inhibitors are the drugs of choice for treatment of 2009 H1N1 influenza and influenza-like illness in both children and adults in the U.S. at this time.

Oseltamivir - The neuraminidase inhibitor oseltamivir formulated as capsules or oral suspension (Tamiflu®) is FDA-approved for the treatment of uncomplicated acute influenza in patients 1 year and older who have been symptomatic for no more than 2 days. The FDA has issued an Emergency Use Authorization (EUA) authorizing treatment with oseltamivir of patients less than 1 year old with 2009 H1N1 influenza. In addition, the EUA authorizes treatment of patients symptomatic with 2009 H1N1 influenza for more than 2 days and patients sick enough to require hospitalization (see www.cdc.gov/h1n1flu/eua/tamiflu.htm).

Zanamivir - The neuraminidase inhibitor zanamivir formulated for oral inhalation (Relenza®) is FDA-approved for the treatment of influenza in patients 7 years of age and older who, similar to approved uses for oseltamivir, have uncomplicated illness and have been symptomatic for no more than 2 days. As with oseltamivir, the FDA has issued an EUA authorizing treatment with zanamivir of patients with 2009 H1N1 influenza who have been symptomatic for more than 2 days and patients sick enough to require hospitalization (see www.cdc.gov/h1n1flu/eua/relenza.htm ).

Peramivir - A third neuraminidase inhibitor peramivir formulated for intravenous (IV) administration is an investigational product currently being evaluated in clinical trials. As of October, 2009, safety and/or efficacy data from 1,891 patients with acute uncomplicated seasonal influenza A has been submitted to the FDA. Efficacy and safety have not been evaluated in hospitalized patients. Even though the data are insufficient to allow FDA approval, the FDA issued an EUA for treatment with peramivir of hospitalized patients with 2009 H1N1 influenza who have potentially life-threatening suspected or laboratory confirmed infection. Peramivir IV is available through the CDC upon request of a licensed physician: http://www.cdc.gov/h1n1flu/eua/peramivir.htm. Under the EUA, treatment of adult patients with IV peramivir is approved only if: (1) the patient has not responded to either oral or inhaled antiviral therapy; (2) drug delivery by a route other than IV is not expected to be dependable or is not feasible; or (3) the clinician judges IV therapy is appropriate due to other circumstances. Treatment of pediatric patients is approved if either of the first two criteria apply (see www.cdc.gov/h1n1flu/eua/peramivir.htm).

Patients who have severe, complicated, or progressive illness or who are hospitalized

Treatment is recommended for patients with confirmed or suspected 2009 H1N1 influenza who have severe, complicated, or progressive illness or who are hospitalized. The recommended duration of treatment is 5 days. Hospitalized patients with severe infections (such as those with prolonged infection or who require intensive care unit admission) might require longer treatment courses. Even though treatment is most effective when started in the first 48 hours of illness, limited data from observational studies of hospitalized patients suggests treatment of persons with prolonged or severe illness reduces mortality or duration of hospitalization even when treatment is started more than 48 hours after onset of illness. Antiviral doses recommended for treatment of 2009 H1N1 influenza in adults or children 1 year of age or older are the same as those recommended for seasonal influenza (Table 1). Some experts have advocated use of doubled doses of oseltamivir for some severely ill patients, although there are no published data demonstrating that higher doses are more effective. For patients unable to take oral medication or in whom oral medication appears to be ineffective, peramivir for intravenous administration is available from the CDC under an FDA EUA, although studies of efficacy and safety are limited. For further information on treatment of hospitalized patients see, "Antiviral Treatment Options, including Intravenous Peramivir, for Treatment of Influenza in Hospitalized Patients for the 2009-2010 Season" (http://www.cdc.gov/h1n1flu/EUA/peramivir_recommendations.htm) and "Updated Recommendations for Health Care Providers of Children and Adolescents on the Use of Antiviral Medications for the Management of 2009 H1N1 and Seasonal Influenza for the 2009-2010 Season".

Patients at Increased Risk for Complications

Prompt empiric antiviral drug treatment is recommended for persons with confirmed or suspected influenza who are at increased risk for serious morbidity and mortality. Based on currently available data, approximately 70% of persons hospitalized with 2009 H1N1 are in one or more of the following groups:

Children (see below) younger than 2 years old
Adults 65 years of age or older
Pregnant women and women up to 2 weeks postpartum (regardless of how the pregnancy ended [live birth, pregnancy termination, preterm birth, miscarriage, fetal death])
Persons with certain medical conditions, described below.
Children: Children younger than 2 years of age are at higher risk for influenza-related complications and have a higher rate of hospitalization compared to older children. Children aged 2 to 4 years are more likely to require hospitalization or urgent medical evaluation for influenza compared with older children and adults, although the risk is much lower than for children younger than 2 years old. From April through September 2009 hospitalization rates for laboratory-confirmed 2009 H1N1 influenza were 4.5-fold higher among children < 2 years of age, 2-fold higher among children 2-4 years of age, and 1.6-fold higher among children 5-17 years of age than among adults (see www.cdc.gov/flu/weekly ). In April, 2009, the FDA authorized oseltamivir use in children younger than 1 year under an Emergency Use Authorization (EUA) in response to the current public health emergency involving 2009 H1N1 influenza. Use of oseltamivir in children younger than 1 year is subject to the terms and conditions of the EUA. Retrospective safety data on oseltamivir treatment of seasonal influenza in children younger than 1 year old are limited and suggest that severe adverse events are rare. Prospective data continue to be collected on safety and efficacy of oseltamivir in this age group. Dosing for children younger than 1 year is based on the EUA guidance. Details are provided in Table 1, below. (See also: Emergency Use Authorization of Tamiflu (oseltamivir) available at http://www.cdc.gov/h1n1flu/eua/). Children and adolescents under 19 years of age who are receiving long-term aspirin therapy are also at increased risk. For more detailed information, see "Updated Recommendations for Health Care Providers of Children and Adolescents on the Use of Antiviral Medications for the Management of 2009 H1N1 and Seasonal Influenza for the 2009-2010 Season".

Adults aged 65 years and older: Even though persons aged 65 years and older are less likely to become ill with 2009 H1N1 influenza compared to younger persons, when they do acquire influenza, they are at higher risk for severe influenza-related complications.

Pregnant women: Pregnancy increases the risk of complications, hospitalization, and severe disease. One study estimated the risk of hospitalization for 2009 H1N1 to be four times higher for pregnant women than for the general population (Jamieson DJ, et al. Lancet. 2009;374:451-458). While oseltamivir and zanamivir are "Pregnancy Category C" medications, meaning no clinical studies have been conducted to assess the safety of these medications for pregnant women, available data suggest pregnant women with suspected or confirmed influenza should receive prompt antiviral therapy, and pregnancy should not be considered a contraindication to treatment with oseltamivir or zanamivir. Oseltamivir is preferred for treatment of pregnant women because of its systemic activity. Anecdotal reports suggest postpartum women, similar to pregnant women, might be at increased risk for severe complications and death from 2009 H1N1 influenza. The transition to normal immune, cardiac, and respiratory function occurs quickly, but not immediately after delivery. Therefore, the increased risk associated with pregnancy should be considered to extend for 2 weeks postpartum regardless of the outcome of the pregnancy (including live birth, premature birth, termination of pregnancy, miscarriage, fetal death). Prompt empiric antiviral treatment is indicated for suspected or confirmed 2009 H1N1 influenza in women who are up to 2 weeks postpartum regardless of how the pregnancy ended.

Medical conditions : The following medical conditions have been associated with increased risk of complications from influenza:

Asthma
Neurological and neuro-developmental conditions [including disorders of the brain, spinal cord, peripheral nerve, and muscle such as cerebral palsy, epilepsy (seizure disorders), stroke, intellectual disability (mental retardation), moderate to severe developmental delay, muscular dystrophy, or spinal cord injury].
Chronic lung disease (such as chronic obstructive pulmonary disease [COPD] and cystic fibrosis)
Heart disease (such as congenital heart disease, congestive heart failure and coronary artery disease)
Blood disorders (such as sickle cell disease)
Endocrine disorders (such as diabetes mellitus)
Kidney disorders
Liver disorders
Metabolic disorders (such as inherited metabolic disorders and mitochondrial disorders)
Weakened immune system due to disease or medication (such as people with HIV or AIDS, or cancer, or those on chronic steroids)
People younger than 19 years of age who are receiving long-term aspirin therapy
Local public health authorities might provide additional guidance about prioritizing treatment within groups at higher risk for severe infection.

Clinical Assessment

While most persons who have had confirmed or suspected 2009 H1N1 influenza have had a mild, uncomplicated self-limited respiratory illness similar to typical seasonal influenza and while persons not considered to be at increased risk of developing severe or complicated illness may not require treatment, they can be considered for antiviral treatment. Benefits of treating such patients might include a reduced duration of illness. However, based on experience with seasonal influenza treatment, patients not considered to be at increased risk of developing severe or complicated illness and who have mild, uncomplicated illness are not likely to benefit from treatment if initiated more than 48 hours after illness onset. Clinical judgment is always an essential part of treatment decisions.

People who are already recovering from influenza do not need antiviral medications for treatment. Options for close follow-up should be carefully considered. Clinicians who prefer not to treat empirically should discuss signs and symptoms of worsening illness with such patients and arrange for follow up at least by telephone.

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Updated Interim Recommendations for the Use of Antiviral Medications in the Treatment and Prevention of Influenza for the 2009-2010 Season