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ANTIVIRALS FOR H1N1 INFECTION
Updated Interim Recommendations for the Use of Antiviral Medications in the Treatment and Prevention of Influenza for the 2009-2010 Season
September 22, 2009 2:00 PM ET
have been updated to provide additional guidance for clinicians in prescribing
antiviral medications for treatment and prevention of influenza during
the 2009-2010 season. In general, the priority use of antiviral medications
during this season continues to be in people who are hospitalized with
influenza and those at increased risk of influenza-related complications
as outlined in the recommendations first posted on May 6, 2009 and updated
on September 8, 2009. This document has been updated to:
To provide updated recommendations on the use of antiviral agents for treatment and chemoprophylaxis of influenza including 2009 H1N1 influenza infection and seasonal influenza, and assist clinicians in prioritizing use of antiviral medications for treatment or chemoprophylaxis for patients at higher risk for influenza-related complications. The health care provider's assessment of a patient's clinical presentation as well as underlying risk factors is always an essential part of decisions about the need for further medical evaluation or treatment.
These recommendations can be adapted according to local epidemiologic data, antiviral susceptibility patterns, and antiviral supply considerations. Additional revisions should be expected as the epidemiology and clinical presentation of 2009 H1N1 influenza is better understood. Additional information about these recommendations can be found in Questions and Answers: Revised Recommendations for the Use of Influenza Antiviral Drugs.
As of September 12, 2009, 99% of circulating influenza viruses in the United States were 2009 H1N1 influenza (previously referred to as novel influenza A (H1N1)). Among people who become infected with 2009 H1N1, certain groups appear to be at increased risk of complications and may benefit most from early treatment with antiviral medications. Approximately 70% of persons hospitalized with 2009 H1N1 influenza have had a recognized high risk condition. These groups are similar to those who are at increased risk for seasonal influenza-related complications:
Among children, rates of influenza-associated hospitalization from 2009 H1N1 have varied by age group. The risk of influenza-associated hospitalizations in healthy children younger than 2 years old is equal to or greater than the risk of other high-risk groups. During April to August 2009 hospitalization rates for laboratory-confirmed 2009 H1N1 influenza among children younger than 2 years old were 2.5 times higher than rates for children 2 year to 4 years old. Children 2 years to 4 years old had slightly (20%) higher rates of hospitalization compared with children 5 years to 17 years old. In studies of seasonal influenza, the risk for hospitalization is also highest for infants, with the risk decreasing as age increases. Given this increased risk for hospitalization, children younger than 2 years old are generally recommended for antiviral treatment. Children ages 2 through 4 years old without high risk conditions (see above) and who are not severely ill do not necessarily require antiviral treatment. Health care providers should use clinical judgment to guide treatment decisions. Children of any age presenting with suspected influenza and symptoms of lower respiratory tract illness or clinical deterioration should receive prompt empiric antiviral therapy in addition to other indicated treatment (e.g. antibiotics if bacterial co-infection is suspected). Updated information on hospitalization rates by age group can be found at www.cdc.gov/flu/weekly.
Persons 65 years and older are less likely to become ill with 2009 H1N1 influenza compared to younger persons. However, when persons aged 65 years or older acquire influenza, they are at higher risk for severe influenza-related complications.
Preliminary studies suggest that people who are morbidly obese (body mass index equal to or greater than 40) and perhaps people who are obese (body mass index 30 to 39) may be at increased risk of hospitalization and death due to 2009 H1N1 influenza infection. Additional studies to determine the risk of morbid obesity and /or obesity for these complications of 2009 H1N1 virus infection are underway. Patients with morbid obesity, and perhaps obesity, often have underlying conditions that put them at increased risk for complications due to 2009 H1N1 influenza infection, such as diabetes, asthma, chronic respiratory illness or liver disease. Patients with obesity or morbid obesity should be carefully evaluated for the presence of underlying medical conditions that are known to increase the risk for influenza complications, and receive empiric treatment when these conditions are present, or if signs of lower respiratory tract infection are present
Transmission of 2009 H1N1 influenza is being studied as part of the ongoing epidemiologic investigation, but data available indicate that this virus appears to be transmitted in ways similar to other influenza viruses. All respiratory secretions and bodily fluids (including diarrheal stool) of 2009 H1N1 cases should be considered potentially infectious.
Close contact, for the purposes of this document, is defined as having cared for or lived with a person who is a confirmed, probable, or suspected case of influenza, or having been in a setting where there was a high likelihood of contact with respiratory droplets and/or body fluids of such a person. Examples of close contact include sharing eating or drinking utensils, physical examination, or any other contact between persons likely to result in exposure to respiratory droplets. Close contact typically does not include activities such as walking by an infected person or sitting across from a symptomatic patient in a waiting room or office.
Special Considerations for Children
Aspirin or aspirin-containing products (e.g. bismuth subsalicylate â€“ Pepto Bismol) should not be administered to any confirmed or suspected ill case of influenza aged 18 years old and younger due to the risk of Reye syndrome. For relief of fever, other anti-pyretic medications such as acetaminophen or non-steroidal anti-inflammatory drugs are recommended.
Children younger than 4 years of age should not be given over-the-counter cold medications without first speaking with a health care provider.
Recommendations for use of antiviral medications may change as data on antiviral effectiveness, clinical spectrum of illness, adverse events from antiviral use, or resistance among circulating viruses become available. As of September 12, 2009, 99% of circulating influenza viruses were 2009 H1N1 viruses susceptible to both oseltamivir and zanamivir. These treatment guidelines therefore focus on use of antiviral medications effective against 2009 H1N1 viruses. For antiviral treatment of 2009 H1N1 virus infection, either oseltamivir or zanamivir are recommended (Table 1).
Clinical judgment is an important factor in treatment decisions. Most patients who have had 2009 H1N1 virus infection have had a self-limited respiratory illness similar to typical seasonal influenza. Most healthy persons who develop suspected or confirmed 2009 H1N1 influenza or seasonal influenza who present with an uncomplicated febrile illness generally do not require antiviral treatment. In addition, persons who appear to be recovering from influenza generally do not require antiviral treatment. However, some groups appear to be at increased risk of influenza-related complications. Local public health authorities might provide additional guidance about prioritizing treatment within groups at higher risk for severe infection.
These recommendations should be used together with clinical judgment in making treatment decisions for both patients who are at higher risk for influenza-related complications and patients who are not at higher risk. When evaluating previously healthy children with possible influenza, clinicians should be aware that, similar to seasonal influenza, the risk for developing severe disease is likely to be highest among infants and younger children. Once the decision to administer antiviral treatment is made by the health care provider, treatment with zanamivir or oseltamivir should be initiated as soon as possible after the onset of symptoms.
Evidence for benefits from antiviral treatment in studies of uncomplicated seasonal influenza is strongest when treatment is started within 48 hours of illness onset. Initiating treatment as soon as possible after illness onset is also thought likely to reduce the risk of severe outcomes including severe illness or death. However, some studies of hospitalized patients with seasonal influenza treated with oseltamivir have suggested benefit, including reductions in mortality or duration of hospitalization, even for patients whose treatment was started more than 48 hours after illness onset. The recommended duration of treatment is five days. Hospitalized patients with severe infections (such as those with prolonged infection or who require intensive unit care admission) might require longer treatment courses. Antiviral doses recommended for treatment of 2009 H1N1 influenza virus infection 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 increased (doubled) doses of oseltamivir for some severely ill patients, although there are no published data demonstrating that higher doses are more effective. Oseltamivir use for children younger than 1 year old was recently authorized by the U.S. Food and Drug Administration (FDA) under an Emergency Use Authorization (EUA). These EUA provisions apply only when the product is provided in accordance with the local public health authority's response plans. Dosing for children younger than 1 year old is age-based in the EUA guidance. However, some experts who are currently conducting studies on oseltamivir use in this age group prefer weight based dosing for this age group, particularly for premature or underweight infants. (Table 2) (See Emergency Use Authorization of Tamiflu (oseltamivir) ).
Persons at higher risk for complications from influenza or who have already developed severe illness should be treated as quickly as possible after signs or symptoms develop. To reduce delays in starting treatment, health care providers should:
Patients receiving treatment should be advised that they remain potentially infectious to others while on treatment. Despite treatment with antiviral agents, including treatment with the neuraminidase inhibitors, patients may continue to shed influenza virus for up to four or more days after beginning therapy. Therefore, patients should continue good hand washing and respiratory hygiene practices during the entire period on therapy to prevent the transmission of virus to close contacts. View information about homecare of ill persons for providers and patients is available at: Taking Care of a Sick Person in Your Home and Physician Directions to Patient/Parent.
Treatment of influenza when oseltamivir-resistant viruses are circulating
Oseltamivir resistance is common among seasonal influenza A (H1N1) viruses. These viruses typically remain susceptible to rimantadine and amantadine. However, since April 2009, very few seasonal H1N1 viruses have circulated in the United States. Therefore, treatment, when indicated, with either oseltamivir or zanamivir is appropriate. However, if viral surveillance data indicate that oseltamivir-resistant seasonal H1N1 viruses have become more common or are associated with identified community outbreaks, zanamivir or a combination of oseltamivir and rimantadine or amantadine should be considered for use as empiric treatment for patients who might have oseltamivir-resistant seasonal human influenza A (H1N1) virus infection. National surveillance data on influenza viruses circulating in the United States is available and is updated weekly. State and local health departments are also a source of viral surveillance data in some areas. Guidance on empiric treatment recommendations when multiple influenza strains are circulating is available at http://www2a.cdc.gov/HAN/ArchiveSys/ViewMsgV.asp?AlertNum=00279.
The infectious period for persons infected with the 2009 H1N1 virus appears to be similar to that observed in studies of seasonal influenza. Infected persons may shed influenza virus, and potentially be infectious to others, beginning one day before they develop symptoms to up to 7 days after they become ill. Children, especially younger children, and persons who are immune compromised can shed influenza virus for longer periods. However, the amount of virus shed generally correlates with magnitude of fever and for these recommendations, the infectious period for influenza is defined as one day before until 24 hours after fever ends.
Patients given post-exposure chemoprophylaxis should be informed that the chemoprophylaxis lowers but does not eliminate the risk of influenza and that protection stops when the medication course is stopped. Patients receiving chemoprophylaxis should be encouraged to seek medical evaluation as soon as they develop a febrile respiratory illness that might indicate influenza. For antiviral chemoprophylaxis of 2009 H1N1 influenza virus infection, either oseltamivir or zanamivir is recommended (Table 1). Duration of post-exposure chemoprophylaxis is 10 days after the last known exposure to 2009 H1N1 influenza.
Oseltamivir was authorized for use for chemoprophylaxis under the EUA for children younger than 1 year of age, subject to the terms and conditions of the EUA. (See Treatment and Chemoprophylaxis for Children Younger than 1 Year of Age, below.) Age-based dosing recommendations are provided in the fact sheetsincluded with the EUA letter of authorization, however weight-based dosing is an alternative preferred by some experts who are currently conducting studies of oseltamivir use in this age group.
An emphasis on early treatment is an alternative to chemoprophylaxis after a suspected exposure. Persons with risk factors for influenza complications who are household or close contacts of confirmed or suspected cases, and health care personnel who have occupational exposures, can be counseled about the early signs and symptoms of influenza, and advised to immediately contact their health care provider for evaluation and possible early treatment if clinical signs or symptoms develop. Health care providers should use clinical judgment regarding situations where early recognition of illness and treatment might be an appropriate alternative to chemoprophylaxis.
Persons at ongoing occupational risk for exposure (e.g., health care personnel, public health workers, or first responders who are working in communities with influenza outbreaks) should carefully follow guidelines for appropriate personal protective equipment. Efforts to reduce the risk of exposure or infection for healthcare personnel should include appropriate administrative controls (e.g. having health care personnel stay home from work when ill, and triaging for identification of potentially infectious patients), cough and hand hygiene, personal protective equipment, and vaccination when available.
2009 H1N1 influenza viruses are susceptible to the neuraminidase inhibitor antiviral medications, oseltamivir and zanamivir, but are resistant to the adamantane antiviral medications, amantadine and rimantadine. This susceptibility pattern is the same as that observed among seasonal influenza A (H3N2) and B viruses in recent years. Oseltamivir resistance appears to be rare at this time. However, oseltamivir-resistant 2009 H1N1 viruses have been identified, typically among persons who develop illness while receiving oseltamivir for chemoprophylaxis or immunocompromised patients with influenza who are being treated.These findings underscore the importance of careful and limited use of antiviral medications for chemoprophylaxis and the need for persons taking antiviral medications to continue to follow recommendations for hand and respiratory hygiene to prevent the spread of antiviral resistant viruses. Additional information on oseltamivir resistance among 2009 H1N1 viruses is available at http://www.cdc.gov/h1n1flu/HAN/070909.htm. Monitoring for antiviral resistance is ongoing and clinicians and state health departments should continue to follow state and national guidance for submission and testing of clinical specimens from persons with suspected 2009 H1N1 virus infection, particularly from those who develop influenza while taking chemoprophylaxis or who have prolonged viral shedding while on treatment.
Antiviral Use for Control of 2009 H1N1 Influenza Outbreaks
Use of antiviral drugs for treatment and chemoprophylaxis of influenza has been a cornerstone for the control of seasonal influenza outbreaks in nursing homes and other long-term care facilities that house large numbers of patients at higher risk for influenza complications. (See MMWR: Prevention and Control of Influenza: Recommendations of the Advisory Committee on Immunization Practices (ACIP), 2008). At this time, no outbreaks of 2009 H1N1 have been reported in such settings. This may be the result of some level of immunity among persons 65 years and older and/or possibly fewer exposures of such persons to 2009 H1N1 thus far. However, if such outbreaks were to occur, it is recommended that ill patients be treated with oseltamivir or zanamivir and that chemoprophylaxis with either oseltamivir or zanamivir be started as early as possible to reduce the spread of the virus as is recommended for seasonal influenza outbreaks in such settings. Additional guidance for infection control measures in long-term care facilities can be found at: Using Antiviral Medications to Control Influenza Outbreaks in Institutions.
In addition to use in nursing homes, antiviral chemoprophylaxis also can be considered for controlling influenza outbreaks in other closed or semi-closed settings (e.g., correctional facilities, or other settings in which persons live in close proximity) where large numbers of persons at higher risk for influenza complications are housed. For more information about influenza outbreaks in facilities see:
Outbreaks in schools, camps, workplaces and other group settings should not be managed by providing chemoprophylaxis to all persons potentially exposed to influenza viruses. The healthy populations typically present in these settings should be educated about the signs and symptoms of influenza, and urged to consult their health care provider if severe illness develops. Post-exposure chemoprophylaxis can be considered for those who meet the above criteria for exposure and who have a medical condition or are of an age that confers a higher risk for influenza complications. An emphasis on early evaluation and treatment, as described above, is an alternative. Persons in these settings also should be educated about hygiene and infection control measures that can reduce transmission of influenza viruses.
Health care providers and pharmacists should be aware that an oral dosing dispenser with 30 mg, 45 mg, and 60 mg graduations is provided with TAMIFLU® for Oral Suspension, rather than graduations in milliliters (mL) or teaspoons (tsp). There have been cases where the units of measure on the prescription instructions (mL, tsp) do not match the units on the dosing device (mg), which has lead to patient or caregiver confusion and dosing errors. When dispensing commercially manufactured TAMIFLU® for Oral Suspension, pharmacists should ensure the units of measure on the prescription instructions match the dosing device. If prescription instructions specify administration using millilters (mL) or teaspoons (tsp), then the device included in the Tamiflu® product package should be removed and replaced with an appropriate measuring device, such as an oral syringe if the prescribed dose is in milliliters (mL).
Treatment and Chemoprophylaxis for Children younger than 1 Year of Age
Children younger than 1 year of age are at higher risk for influenza-related complications and have a higher rate of hospitalization compared to older children. Oseltamivir is not approved for use in children younger than 1 year of age. However, limited safety data on oseltamivir treatment of seasonal influenza in children younger than 1 year of age suggest that severe adverse events are rare. Oseltamivir is authorized for emergency use in children younger than 1 year of age under an EUA issued by FDA, subject to the terms and conditions of the EUA.
Because infants experience high rates of morbidity and mortality from influenza, infants with 2009 H1N1 influenza virus infections may benefit from treatment using oseltamivir. (Table 2 and Emergency Use Authorization of Tamiflu (oseltamivir)).
When dispensing TAMIFLU® for Oral Suspension for children younger than 1 year of age, the oral dosing dispenser that is included in the Tamiflu package should always be removed. Pharmacists and health care providers should provide an oral syringe that is capable of accurately measuring the prescribed milliliter (mL) dose, and counsel the caregiver how to administer the prescribed dose.
Some experts prefer weight-based dosing for children aged younger than 1 year, particularly for very young or premature infants based on preliminary data from a National Institutes of Health-funded Collaborative Antiviral Study Group (CASG). When using weight-based dosing for infants aged younger than 1 year for treatment, those 9 months or older should receive 3.5 mg/kg/dose BID, and those aged younger than 9 months should receive 3.0 mg/kg/dose BID. When using weight-based dosing for infants aged younger than 1 year for chemoprophylaxis, those 9 months or older should receive 3.5 mg/kg/dose QD, and those aged younger than 9 months should receive 3.0 mg/kg/dose QD (Source: D Kimberlin et al. Oseltamivir (OST) and OST Carboxylate (CBX) Pharmacokinetics (PK) in Infants: Interim Results from a Multicenter Trial. Abstract accepted to Infectious Diseases Society of America meeting, October 2009). Health care providers should be aware of the lack of data on safety and dosing when considering oseltamivir use in a seriously ill young infant with confirmed 2009 H1N1 influenza virus infection or who has been exposed to a confirmed 2009 H1N1 influenza case, and carefully monitor infants for adverse events when oseltamivir is used. Additional information on oseltamivir for this age group can be found at: http://www.fda.gov/downloads/Drugs/DrugSafety/InformationbyDrugClass/UCM153547.pdf
Pregnant women are known to be at higher risk for complications from infection with seasonal influenza viruses, and severe disease among pregnant women was reported during past pandemics. Hospitalizations and deaths have been reported among pregnant women with 2009 H1N1 influenza virus infection, and one study estimated that the risk for hospitalization for 2009 H1N1 influenza was four times higher for pregnant women than for the general population. While oseltamivir and zanamivir are "Pregnancy Category C" medications, indicating that no clinical studies have been conducted to assess the safety of these medications for pregnant women, the available risk-benefit data indicate pregnant women with suspected or confirmed influenza should receive prompt antiviral therapy. Pregnancy should not be considered a contraindication to oseltamivir or zanamivir use. Because of its systemic activity, oseltamivir is preferred for treatment of pregnant women. The drug of choice for chemoprophylaxis is less clear. Zanamivir may be preferable because of its limited systemic absorption; however, respiratory complications that may be associated with zanamivir because of its inhaled route of administration need to be considered, especially in women at risk for respiratory problems.