Recommendations for Use of Antiviral Medications for the Management of Influenza in Children and Adolescent for the 2009-2010 Season -- Pediatric Supplement for Health Care Providers

December 24, 2009 1:30 PM ET

Contents

• Objective
• Background
• Spectrum of illness in infants, children, and adolescents
• Considerations for antiviral therapy
• Pediatric patients with progressive, severe, complicated illness or or who are hospitalized
• Groups at risk for severe illness
• Clinical assessment
• Antivirals after influenza vaccination
• Ensuring early treatment
• Testing considerations
• Pharmaceutical considerations
• Antiviral dosage
• Alternatives to commercially produced Tamiflu® oral suspension for pediatric patients
• Compounding as an alternative to commercially-produced suspension
• Use of antivirals for infants and children
• Supportive care
• Antiviral resistance
• Bacterial co-infections
• Considerations for post-exposure chemoprophylaxis
• Infectious period
• Close contact, defined by possible modes of transmission
• Chemoprophylaxis may be considered for:
• Chemoprophylaxis is NOT recommended for:
• Early treatment as an alternative to chemoprophylaxis
• Information about prophylaxis
• Specific Regimens for Treatment and Chemoprophylaxis of 2009 H1N1 Influenza
• Adverse events and contraindications
• Appendix A: Information on the Emergency Use Authorization (EUA) for Oseltamivir Treatment in Children younger than 1 year old

Objective

To provide supplemental recommendations for health care providers of infants, children and adolescents on the spectrum of illness, the use of antiviral medications  and the treatment and chemoprophylaxis of 2009 H1N1 influenza and seasonal influenza, particularly the use of antiviral medications for hospitalized children and adolescents and those at higher risk for influenza-related complications.
These recommendations:

1. Provide guidance on early empiric antiviral treatment of infants, children, and adolescents with progressive or severe influenza-like illness, or with symptoms of lower respiratory tract involvement regardless of underlying medical conditions.
2. Provide guidance on early empiric antiviral treatment of infants, children, and adolescents with underlying medical conditions placing them at risk for complications.
3. Provide updated oseltamivir dosing instructions for children younger than 1 year of age based on weight.
4. Clarify antiviral treatment and chemoprophylaxis considerations for infants, children, and adolescents vaccinated with 2009 H1N1 and seasonal influenza vaccines.
5. Provide information regarding use of intravenous peramivir under an emergency use authorization.

This document should be considered interim, and will be updated as needed.

Although the focus of this document is on treatment and chemoprophylaxis, vaccination and infection control measures remain the best way to prevent seasonal or 2009 H1N1 influenza. Information on the prevention of influenza virus infection can be found in other guidance documents mentioned at the end of this document.

These recommendations highlight issues specific to infants, children, and adolescents and are based on current recommendations for antiviral use and influenza diagnostic testing recommendations. These recommendations can be adapted according to local epidemiologic data, antiviral susceptibility patterns, and antiviral supply considerations. These recommendations may be further revised if changes in the clinical presentation or antiviral susceptibility of 2009 H1N1 or seasonal influenza are observed. Additional information about antiviral treatment can be found in Questions and Answers: Revised Recommendations for the Use of Influenza Antiviral Drugs.

Background

As of November 18th, the 2009 H1N1 influenza viruses continued to be the predominant circulating influenza viruses this season. However, circulation of seasonal influenza A and B viruses during the 2009-10 season also is likely. Health care providers should consult their hospital or local, state, or national surveillance data regularly to determine the current pattern of circulating influenza viruses as well as co-circulation of other respiratory viruses, such as respiratory syncytial virus, that can cause symptoms similar to influenza. Information on influenza activity and surveillance can be found at Weekly Flu View. These considerations, in addition to the ones below, should guide clinical decision-making and therapy.

Spectrum of illness in infants, children, and adolescents

Influenza illness in infants and children may present similarly to other respiratory viruses, and symptoms and presentation may be different than presentation in adults.  For example, sore throat or myalgia may not be reported by young children, and fever may not be present, particularly in young infants. In addition, infants and young children may experience diarrhea more frequently than older children and adults.

A wide spectrum of potential influenza-related complications is possible among children.  These range from mild-to-moderate complications such as otitis media, sinusitis, myositis, and febrile seizures to more severe manifestations such as myocarditis or encephalitis.  Severe complications may frequently include pneumonia, invasive bacterial co-infection, and exacerbation of underlying medical conditions (1-6). Patients who present initially with uncomplicated influenza may progress to more severe illness. Progression can be rapid (i.e., within 24 hours).

In a recent case series of hospitalized patients with 2009 H1N1 in the U.S., almost half of the hospitalizations involved persons less than 18 years of age.  Among patients who were less than 5 years of age, 44% had radiographic evidence of pneumonia and 16% required intensive care (1). In another study of 2009 H1N1 influenza cases in California, 32% (344 of the 1088) of persons hospitalized or died were less than 18 years. The overall rate of hospitalization and/or fatality per 100,000 was 11.9 in infants less than 1 year. Among  infants less than 1 year, the highest hospitalization rates per 100,000 were in infants 1 month old (35.8) and 2 months old (21.1)(2). As of November 28, 2009, a total of 210 influenza-associated deaths in children have been reported in the U.S. since April 2009 (7).

Mild illness is characterized by fever, cough, sore throat, rhinorrhea, headache, muscle pain, chills, malaise, diarrhea and vomiting, but no shortness of breath, dehydration, change in mental status, or change in chronic health conditions. Not all children with influenza will have a fever.

Progressive illness is characterized by signs and symptoms suggesting pneumonia (e.g., chest pain, rales), poor oxygenation (e.g. increased work of breathing, tachypnea, hypoxia), cardiac insufficiency (e.g., low blood pressure), CNS impairment (e.g., confusion, difficulty in arousal, drowsiness, convulsions), dehydration, or exacerbations of chronic conditions (e.g., asthma, hematologic conditions, neurologic conditions, diabetes, cardiovascular conditions and other chronic health conditions).

Severe or complicated illness is characterized by signs of lower respiratory tract disease (e.g. respiratory distress syndrome), CNS findings (encephalitis, encephalopathy), complications of low blood pressure (shock, organ failure), myocarditis or rhabdomyolysis, or invasive secondary bacterial infection based on laboratory testing or clinical signs (e.g. persistent high fever and other symptoms).
(Adapted from: WHO, Clinical management of human infection with pandemic influenza (H1N1) 2009: Revised guidance.November2009)

This document emphasizes early treatment for infants, children, or adolescents with progressive, severe or complicated illness and children with influenza-like illness who also have certain chronic medical conditions for management of influenza.

Considerations for antiviral therapy

Prompt empiric antiviral therapy is recommended for infants, children, and adolescents of any age presenting with suspected or confirmed influenza and.

• Illness requiring hospitalization, and/or
• Progressive, severe, or complicated illness, regardless of previous health, and/or
• Risk factors (see below in Box 1) for severe illness.

Influenza antiviral medications have the potential to reduce the severity and duration of influenza illness and the risk of influenza-related complications, including severe illness and death.  Although antiviral medications work best when initiated within the first 2 days of illness, they have also been shown to reduce the risk of respiratory failure and death among hospitalized persons even when started more than 2 days after illness onset.

If 2009 H1N1 seasonal or influenza infection is suspected, initiation of antiviral treatment should not wait for laboratory confirmation. Patients with a negative rapid influenza diagnostic test should be considered for treatment if clinically indicated because a negative result does not rule out influenza virus infection. The sensitivity of rapid influenza diagnostic tests to detect 2009 H1N1 virus in respiratory specimens ranges from 10% to 70%, and therefore false negative results occur frequently. Similarly, false negative results can also occur with immunofluorescence assays.

Treatment, when indicated, should be initiated as early as possible. Antiviral treatment is most effective when started within 2 days after symptom onset. However, studies of hospitalized patients with seasonal influenza or 2009 H1N1 influenza have shown benefit of oseltamivir treatment even when treatment was started more than 48 hours after illness onset.

Pediatric patients with progressive, severe, complicated illness or who are hospitalized

• Treatment is recommended for all hospitalized patients with confirmed or suspected 2009 H1N1 or seasonal influenza;
• Oral oseltamivir should be started as soon as possible if the patient is able to take medication orally, or inhaled zanamivir can be used if the patient is aged 7 years or older and has no underlying airway disease that would contraindicate its use.
  • The FDA has issued an Emergency Use Authorization (EUA) that authorizes treatment with oseltamivir for,2:
• Infants less than 1 year old with 2009 H1N1 influenza
• The FDA has issued an EUA that authorizes treatment with oseltamivir or zanamivir for2:
• Patients who have been symptomatic with 2009 H1N1 influenza for more than 2 days
• Patients sick enough to require hospitalization.
• Intravenous peramivir is an option if the child is unable to take liquids or use zanamivir. The FDA has issued an EUA authorizing treatment with peramivir of hospitalized patients with 2009 H1N1 influenza who have potentially life-threatening suspected or laboratory confirmed infection
• Peramivir IV is an unlicensed drug available through the Centers for Disease Control and Prevention under an EUA. Treatment of pediatric patients with IV peramivir is approved only if:
• the patient has not responded to either oral or inhaled antiviral therapy;
• drug delivery by a route other than IV is not expected to be dependable or is not feasible.
• Peramivir dosing needs adjustment in patients with renal insufficiency based on their creatinine clearance.
• Clinicians are reminded to consider bacterial co-infections that can occur during or after influenza. Treatment of pneumonia may include oseltamivir plus antibiotics when influenza is circulating in the community and the clinician believes that influenza may be causing or coinciding with the pneumonia.

Groups at increased risk for severe illness

• Early outpatient empiric treatment with oseltamivir (for all ages) or zanamivir3  (for ages 7 and older) is recommended for people with suspected or confirmed influenza who are at increased risk for complications including:

Box 1

• Children younger than 5 years of age, particularly those less than 2 years of age
• Adults 65 years of age and older
• Pregnant women
• People who have medical conditions including:
• Asthma
• o Neurological and neurodevelopmental 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].
• o 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)
• Deficiencies in immune function 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

The American Academy of Pediatrics has developed a document that describes in detail children who are at higher risk for mortality.

• Assessment of an infant’s, child’s or adolescent’s clinical presentation and underlying risk factors for influenza-related complications and death should guide medical decisions regarding evaluation, follow-up, or treatment.
• While most infants, children and adolescents who have had confirmed or suspected 2009 H1N1 virus infection have had a mild, uncomplicated self-limited respiratory illness similar to typical seasonal influenza and while those children 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.

Antivirals after influenza vaccination

In October 2009, inactivated and live attenuated 2009 H1N1 monovalent influenza vaccines became available in the United States. These vaccines are prepared using the same methods used for manufacture of seasonal influenza vaccines and are licensed for persons > 6 months old. Although these vaccines are expected to be highly effective, no vaccine is 100% efficacious. Further, influenza vaccines are not effective immediately after administration; time must pass for the immune response to the vaccine to develop. Therefore, a history of receipt of 2009 H1N1 or seasonal influenza vaccine does not rule out influenza virus infection. Early empiric treatment should be initiated for vaccinated persons with suspected influenza illness when indicated (e.g., persons requiring hospitalization, with severe infection, or at higher risk for influenza-related complications). Vaccination with 2009 H1N1 influenza vaccine is not expected to provide protection against infection with seasonal influenza A or B viruses. Similarly, vaccination with seasonal influenza vaccine is not expected to prevent infection with 2009 H1N1 influenza virus.

If a person has received the live, intranasal spray influenza vaccine in the 2 weeks prior to being treated with antivirals, the vaccine dose should be repeated.  However, vaccination does not need to be repeated if a person received the inactivated influenza vaccine (the flu shot) before being treated with influenza antiviral medications.

Ensuring early treatment

• Because rapid access to antiviral medications is essential, health care providers who care for infants, children, and adolescents at higher risk for influenza complications (Box 1) should develop methods to ensure that antiviral treatment can be started quickly after symptom onset. Actions that should be taken to reduce delays in treatment initiation include:

Informing caretakers of infants, children, and adolescents at higher risk for influenza complications (see Box 1) of influenza signs and symptoms (see “Spectrum of illness in infants, children, and adolescents” section above) and the need for early treatment after onset of symptoms.

• Ensuring rapid access to telephone consultation and clinical evaluation for infants, children, and adolescents at higher risk for influenza complications or who report severe illness.
• Based on telephone consultation, health care providers can recommend appropriate follow-up (e.g., immediate medical care or outpatient follow-up).

Testing considerations

Definitive testing for 2009 H1N1 influenza infection requires real-time reverse transcriptase-polymerase chain reaction (rRT-PCR) or viral culture. These tests should be prioritized for persons with suspected or confirmed influenza requiring hospitalization and based on guidelines from local and state health departments. Updated influenza diagnostic testing recommendations are available.  However, for infants, children, and adolescents with suspected influenza illness and who have an indication for influenza treatment, treatment should not be delayed pending influenza diagnostic testing.  Rather, treatment should be started empirically as early as possible.

Pharmaceutical considerations

• Antiviral dosage can be determined by age and weight (Table 1); for treatment of uncomplicated influenza, the duration of antiviral treatment is 5 days. Hospitalized patients with severe illness (such as those with severe lower respiratory tract disease who require intensive unit care admission and patients with evidence of prolonged viral replication and shedding) might require longer treatment courses.

Alternatives to commercially produced Tamiflu® oral suspension for pediatric patients

• While commercially-manufactured Tamiflu® Oral Suspension (12 mg/mL) is the preferred product for patients who have difficulty swallowing capsules or where lower doses are needed, this product may not be available locally.

  For patients who are less than one year old, there is one alternative:

  • a suspension compounded by a pharmacy (see links below)

  For children who are at least one year old, there are two alternatives:

  • a suspension compounded by a pharmacy (see links below)
  • 30 mg, 45 mg, or 75 mg capsules, which may be mixed into a sweetened liquid by a caregiver if the child cannot swallow capsules (see links below).

Compounding as an alternative to commercially-produced suspension

• When commercially manufactured oseltamivir (Tamiflu®) oral suspension is not available, oseltamivir (Tamiflu®) 75 mg capsules can be compounded at most retail pharmacies into a suspension. Health care providers can suggest this compounding alternative when writing prescriptions for Tamiflu® oral suspension. Tamiflu® oral suspension concentration is 12 mg/mL; the compounded suspension concentration is 15 mg/mL.
• Health care providers and pharmacists should be aware that the oral dosing dispenser packaged with the Tamiflu® oral suspension is in milligram (mg) graduations rather than in milliliters (mL) or teaspoons (tsp). If the units of measure on the prescription dosing instructions (mL, tsp) do not match the units on the dosing device (mg), there is potential for confusion and dosing errors. For more information, see FDA Drug Safety Information: Emergency Compounding of an Oral Suspension from Tamiflu 75 mg Capsules (Final Concentration 15 mg/mL); opening and Mixing Tamiflu Capsules with Liquids if Child Cannot Swallow Capsules.

Use of antivirals for infants and children

• The U.S. Food and Drug Administration has issued EUAs to make Tamiflu® (oseltamivir), Relenza® (zanamivir), and peramivir available to treat 2009 H1N1 influenza infection under certain circumstances.
• General EUA information. 
• For additional fact sheets for health care providers for these products please see
  • Tamiflu
  • Relenza
  • Peramivir
    

• Aspirin, other salicylates, or any salicylate-containing products (e.g., bismuth subsalicylate – Pepto Bismol) should not be administered to patients aged 18 years old and younger with suspected or confirmed influenza due to the risk of Reye’s 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 old should not be given over-the-counter cold medications without first speaking with a health care provider

Antiviral resistance

• As of November 2009, circulating 2009 H1N1 influenza viruses are susceptible to oseltamivir and zanamivir, but resistant to amantadine and rimantadine. Updated information on influenza antiviral resistance is available.

Bacterial coinfections

• Clinicians are also reminded to consider the possibility of bacterial coinfections that can occur during or after an influenza illness.
• Treatment of community-acquired pneumonia may include oseltamivir and antibiotics when influenza viruses are circulating in the community and the clinician believes that influenza may be causing or coinciding with the community acquired pneumonia.

Considerations for post-exposure chemoprophylaxis

• 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. For these recommendations, the infectious period for influenza is defined as one day before until 24 hours after fever ends (without the use of fever reducing medications).

Close contact, defined by possible modes of transmission

• Droplet exposure of mucosal surfaces (e.g., nose, moth, and eyes) by respiratory secretions from coughing or sneezing
• Contact, usually of hands, with an infectious patient or fomite (a surface that is contaminated with secretions) followed by self-inoculation of virus onto mucosal surfaces such as those of the nose, mouth, and eyes; and
• Small particle aerosols in the vicinity of the infectious individual.

Post-exposure antiviral chemoprophylaxis can be considered for:

• Infants, children and adolescents at higher risk for complications from influenza (see Box 1) who have had close contact with someone likely to have been infectious with influenza if contact occurred during the ill person’s infectious period and it has been less than 48 hours since the last contact with the infectious person.

Chemoprophylaxis is NOT recommended for:

• Prevention of illness among healthy infants, children, and adolescents after exposures in community, school, camp, or other settings. When mass chemoprophylaxis has been used in healthy infants, children, and adolescents in these settings, sporadic cases of oseltamivir resistant 2009 H1N1 influenza viruses have developed.
• Healthy vaccinated infants, children, and adolescents. Early evaluation and antiviral treatment is preferred to chemoprophylaxis after a suspected exposure.

Early treatment as an alternative to chemoprophylaxis

• Early evaluation and treatment of infants, children, and adolescents at increased risk for complications from influenza is emphasized as an alternative to chemoprophylaxis after a suspected exposure Caregivers of infants, children, or adolescents who are at higher risk for complications from influenza and who are household or close contacts of suspected or confirmed cases can be counseled about the early signs and symptoms of influenza, and advised to immediately contact the health care provider for evaluation and possible early treatment if clinical signs or symptoms develop in these infants, children, or adolescents.

Information about prophylaxis

• Caregivers of infants, children, or adolescents should be informed that post-exposure chemoprophylaxis lowers but does not eliminate the risk of influenza and that protection stops when the medication course is stopped.
• The duration of antiviral chemoprophylaxis post-exposure is 10 days after the last known exposure. See Table 1 for dosing information; note that zanamivir chemoprophylaxis can be used for children 5 years or older.
• Oseltamivir chemoprophylaxis for influenza virus infection in children younger than 1 year old is age-based; however, chemoprophylaxis for asymptomatic infants younger than 3 months old is not recommended due to lack of safety data.
• If early signs and symptoms of influenza occur in infants, children, or adolescents receiving post-exposure chemoprophylaxis, the person should be clinically evaluated to determine if the dosage of antiviral chemoprophylaxis might need to be increased to the therapeutic dose and if evaluation for other respiratory pathogens is indicated.

Specific Regimens for Treatment and Chemoprophylaxis of 2009 H1N1 Influenza

Table 1. Antiviral medication dosing recommendations for treatment or chemoprophylaxis of 2009 H1N1 infection for infants and children.  (Table extracted from product information for Tamiflu® and Relenza® and EUA for Tamiflu and Relenza).

1. Weight-based dosing is preferred, however, if weight is not known, dosing by age for treatment (give dose twice daily) or prophylaxis (give dose once daily) of influenza in full-term infants younger than 1 year of age may be necessary (3-5 months = 20 mg (1.6 mL of commercial suspension), 6-11 months = 25 mg (2 mL of commercial suspension).

2. Oseltamivir is administered orally without regard to meals, although administration with meals may improve gastrointestinal tolerability. Oseltamivir is available as Tamiflu® in 30 mg, 45 mg, and 75 mg capsules; and as a powder for oral suspension that is reconstituted to provide a final concentration 12 mg/mL. If the commercially-manufactured oral suspension is not available, the capsules may be opened and the contents mixed with a sweetened liquid to mask the bitter taste or a suspension can be compounded by most retail pharmacies (final concentration: 15 mg/mL). In patients with renal insufficiency the dose should be adjusted based on creatinine clearance.

3. Current weight-based dosing recommendations are not intended for premature infants. Premature infants may have slower clearance of Tamiflu due to immature renal function, and doses recommended for full term infants may lead to very high drug concentrations in this age group. Very limited data from a cohort of premature infants receiving an average dose of 1.7 mg/kg twice daily demonstrated drug concentrations higher than those observed with the recommended treatment dose in term infants (3 mg/kg twice daily). Observed drug concentrations were highly variable among premature infants. These data are insufficient to recommend a specific dose of Tamiflu for premature infants.

4. Zanamivir is administered by inhalation using a proprietary “Diskhaler” device distributed together with the medication. Zanamivir is a dry powder, not an aerosol, and should not be administered using nebulizers, ventilators, or other devices typically used for administering medications in aerosolized solutions. Zanamivir is not recommended for persons with chronic respiratory diseases such as asthma or chronic obstructive pulmonary disease that increase the risk of bronchospasm.

Tamiflu® oral suspension concentration is 12 mg/mL; the compounded suspension concentration is 15 mg/mL. When prescribing Tamiflu® Oral Suspension, prescribers should specify the concentration if prescribing in mL or teaspoons, or prescribe the dose in milligrams (mg).

Note to Pharmacists: When dispensing commercially-manufactured Tamiflu® Oral Suspension:

• 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® package should be removed and replaced with an appropriate measuring device, such as an oral syringe if the prescribed dose is in milliliters (mL).
• For children younger than 1 year of age or whose dose is less than 30 mg,the oral dosing dispenser that is included in the Tamiflu® product package should always be removed. An oral syringe that is capable of accurately measuring the prescribed dose in milliliters (mL) should be provided, and the caregiver counseled on how to administer the prescribed dose accurately with the oral syringe provided.
• For additional information, please refer to FDA Public Health Alert: Potential Medication Errors with Tamiflu® for Oral Suspension

Adverse Events and Contraindications

Oseltamivir and zanamivir are generally well-tolerated among FDA-approved age groups. Among children treated with oseltamivir, 14% had vomiting, compared with 8.5% of placebo recipients. Oseltamivir suspension is formulated with sorbitol, which may be associated with diarrhea and abdominal pain in patients who are fructose-intolerant. Allergic reactions (rash, swelling of the face or tongue, anaphylaxis) have been reported in clinical practice with both oseltamivir and zanamivir.
Zanamivir, an inhaled medication, can induce bronchospasm and is not recommended for treatment for patients with an underlying increased risk of bronchospasm. Zanamivir should only be used as directed in the prescribing information by using the Diskhaler device provided with the drug product.  The commercial zanamivir formulation (Relenza® Inhalation Powder) 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 the lactose sugar can obstruct proper functioning of mechanical ventilator equipment.  Although there are published and unpublished reports of zanamivir being used via nebulizer and mask in clinical trials, the currently available commercial formulation is not designed or intended to be administered by nebulization.

Rarely, transient neuropsychiatric events (self-injury or delirium) have been reported in postmarketing surveillance among persons taking oseltamivir and zanamivir. The majority of reports were among infants, children, and adolescents living in Japan. Because influenza infection itself can be associated with a variety of neurologic and behavioral symptoms, including seizures, delirium, and hallucinations, whether the neuraminidase inhibitors are directly responsible for these neuropsychiatric effects is unclear. To date, retrospective analyses conducted by Roche, the manufacturer of oseltamivir, have not found evidence for an increased risk of neuropsychiatric events after oseltamivir use. Until additional data are available, FDA advises that persons receiving neuraminidase inhibitors be monitored for abnormal behavior. For additional information please refer to the FDA MedWatch Safety Alert: Tamiflu®.

Retrospective safety data on oseltamivir treatment of seasonal influenza in children younger than 1 year old is limited but suggests that severe adverse events are rare. Prospective data continue to be collected on safety and efficacy of oseltamivir in this age group.

Reporting Adverse Events

Health-care professionals should report all serious adverse events (SAE) after antiviral medication use promptly to MedWatch, the FDA’s adverse event reporting program for medications.

Links to CDC recommendations regarding 2009 H1N1 influenza on infants, children, and adolescents:

• Antiviral treatment: Updated Interim Recommendations for the Use of Antiviral Medications in the Treatment and Prevention of Influenza for the 2009-2010 Season
• Influenza Diagnostic Testing: Interim Recommendations for Clinical Use of Influenza Diagnostic Tests During the 2009-10 Influenza Season 
• Child Care settings
• K-12 Schools
• Colleges and Universities

References

1. Jain S, Kamimoto L, Bramley AM, Schmitz AM, Benoit SR, Louie J, Sugerman DE, Druckenmiller JK, Ritger KA, Chugh R, Jasuja S, Deutscher M, Chen S, Walker JD, Duchin JS, Lett S, Soliva S, Wells EV, Swerdlow D, Uyeki TM, Fiore AE, Olsen SJ, Fry AM, Bridges CB, Finelli L; the 2009 Pandemic Influenza A (H1N1) Virus Hospitalizations Investigation Team. Hospitalized Patients with 2009 H1N1 Influenza in the United States, April-June 2009. N Engl J Med. 2009, Epub Oct 8.
2. Louie JK, Acosta M, Winter K, Jean C, Gavali S, Schechter R, Vugia D, Harriman K, Matyas B, Glaser CA, Samuel MC, Rosenberg J, Talarico J, Hatch D; for the California Pandemic (H1N1) Working Group. Factors Associated With Death or Hospitalization Due to Pandemic 2009 Influenza A (H1N1) Infection in California. JAMA. 2009 Nov 4;302(17):1896-1902.
3. Hackett S, Hill L, Patel J, Ratnaraja N, Ifeyinwa A, Farooqi M, Nusgen U, Debenham P, Gandhi D, Makwana N, Smit E, Welch S. Clinical characteristics of paediatric H1N1 admissions in Birmingham, UK. Lancet. 2009 Aug 22;374(9690):605.
4. Lister P, Reynolds F, Parslow R, Chan A, Cooper M, Plunkett A, Riphagen S, Peters M. Swine-origin influenza virus H1N1, seasonal influenza virus, and critical illness in children. Lancet. 2009 Aug 22;374(9690):605-7.
5. Larcombe PJ,Moloney SE, Schmidt PA.  Pandemic (H1N1) 2009: A clinical spectrum in the general paediatric population [published online ahead of print November 10 2009].  Arch Dis Child.  2009. Accessed November 16, 2009.
6. O'Riordan S, Barton M, Yau Y, Read SE, Allen U, Tran D. Risk factors and outcomes among children admitted to hospital with pandemic H1N1 influenza. CMAJ. 2009 Nov 19. [Epub ahead of print]
7. CDC. Flu activity and surveillance. Atlanta, GA: US Department of Health and Human Services, CDC; 2009.

Appendix A

Information on the Emergency Use Authorization (EUA) for Oseltamivir Treatment in Children younger than 1 year old²:

• Infants with 2009 H1N1 influenza virus infections may benefit from treatment using oseltamivir. Children younger than 1 year old are at higher risk for influenza-related complications and have a higher rate of hospitalization compared to older children. Updated information on hospitalization rates by age group is available
• Oseltamivir is authorized by the FDA for the treatment of 2009 H1N1 influenza infections in children younger than 1 year old, under an EUA in response to the current public health emergency involving 2009 H1N1 influenza virus. The use of oseltamivir 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 is limited but suggests that severe adverse events are rare. Prospective data continue to be collected on safety and efficacy of oseltamivir in this age group.
• Oseltamivir dosing for influenza treatment in children younger than 1 year old is weight-based in the EUA guidance.
• Health care providers should be aware that there are limited data on safety and dosing when considering oseltamivir use in seriously ill, young infants with confirmed 2009 H1N1 influenza, or in one that has been exposed to a confirmed 2009 H1N1 influenza case. Infants should be carefully monitored for adverse events when oseltamivir is used.
• Among older children treated with oseltamivir, 14% had vomiting, compared with 8.5% of placebo recipients.
• Commercially-produced Tamiflu® is formulated with sorbital, which may be associated with diarrhea and abdominal pain in patients who are fructose-intolerant. Additional information on oseltamivir for this age group is available.

1. Subject to the terms and conditions of the EUA, see Appendix A.
2. Emergency Use Authorization (EUA) issued by the U.S. Food and Drug Administration (FDA), subject to the terms and conditions of the EUA.

Subject to the terms and conditions of the EUA, see Appendix A.

Emergency Use Authorization (EUA) issued by the U.S. Food and Drug Administration (FDA), subject to the terms and conditions of the EUA.

Additional Resources

• Resources for Pediatric and Child Health Care Providers
  
• 2009 H1N1 Influenza : Patient Management
  
• Pediatric Triage Algorithm for Healthcare Providers
• Messages for Pediatricians' Offices and Clinics Caring for Children  (English and Spanish)
  

Influenza vaccination

• 2009 H1N1 Influenza Vaccine
• The ACIP Recommendations for 2009 H1N1 Influenza Vaccine
• The ACIP Recommendations for Seasonal Influenza Vaccine
• Frequently Asked Questions on Use of 2009 H1N1 Influenza Vaccine
• Vaccine Co-administration

Pneumococcal vaccination

• ACIP Recommendations on Conjugate Vaccine
• Updated Provisional ACIP Recommendations on Polysaccharide Vaccine
• Guidance on Preventing Influenza-related Pneumococcal Infections

Infection control issues

• Infection Control in Health Care Settings
• Infection Control Considerations in Obstetrics Settings