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Finally, Influenza Treatment for Neonates and Very Young Infants!

  2012-2013 Nelson's Pediatric Antimicrobial Therapy

Historically, we have not had FDA approved treatment for influenza in any child younger than one year, due to concerns for toxicity of oseltamivir (Tamiflu) in infant rats. The concern was based on unpredictable serum concentrations in neonatal animals and the presence of seizures at doses that were not excessive. A protocol to study oseltamivir in human infants younger than one year was abandoned 12 years ago. However, the critical need to treat pandemic flu in all age groups along with retrospective data collected from David Kimberlin and colleagues at the Collaborative Antiviral Study Group1,2 provided the basis for the FDA to create an Emergency Use Authorization (EUA) for the use of oseltamivir in infants younger than one year. Although the EUA expired at the end of the pandemic, the AAP Red Book Committee continues to recommend the dose previously approved by the FDA for very young infants.

Dose for infants between 2 weeks and 1 year of age: Influenza treatment with oseltamivir in this age group is 3 mg/kg twice daily for 5 days. The variability of drug metabolism and excretion in the youngest infants (0 to 2 months) is striking.  For example, the oseltamivir plasma half-life was documented to range from between 5 hours to almost 29 hours! Also, as one might expect, it took longest to clear virus in the youngest infants. Therefore, we are cautious about the safety and efficacy at the recommended dose in the youngest infants with influenza infection who require treatment. I suspect that is why the FDA did not feel comfortable making recommendations for the first few weeks of life. 

Dose for Premature Infants: During the pandemic, Kimberlin and colleagues also studied an influenza exposure event in a large NICU, and was able to define a dose for premature infants of only 1 mg/kg/day twice daily (median gestational age of 27.5 weeks and chronologic age of 2.5 days), with this lower dose providing the same exposure as the higher dose in older infants, presumably because the hepatic enzymes needed to convert the oseltamivir ester (the oral  prodrug formulation) into oseltamivir the active drug, have not yet matured.3

Important Note: While we believe that the benefits of treatment with oseltamivir outweighs the safety risks in the very young infants, we still do not believe that we can justify routine prophylaxis in these babies…we simply need more data on PK and safety before that recommendation can be made. While AAP does not recommend routine prophylaxis in those younger than 3 months, the FDA has not changed its recommendation for prophylaxis, and still has not approved oseltamivir for prophylaxis for any infant under one year of age.


1Kimberlin DW et al. Safety of oseltamivir compared with the adamantanes in children less than 12 months of age. Pediatr Infect Dis J. 2010 Mar;29(3):195-8
2Kimberlin DW et al. Oseltamivir pharmacokinetics, dosing, and resistance among children aged <2 years with influenza. J Infect Dis. 2013 Mar;207(5):709-20
3Acosta EP et al: Oseltamivir dosing for influenza infection in premature neonates. J Infect Dis. 2010 Aug 15;202(4):563-6

John Bradley
February 21, 2013