This is the largest report to date of oseltamivir use in infants younger than 12 months of age. In our retrospective study, neurologic events were not more common during oseltamivir treatment than with either amantadine or rimantadine. A previous report of 103 Japanese infants who received oseltamivir also found no association between the use of oseltamivir and either mortality or encephalopathy.5
Subjects in that study had a mean age of 7.5 months, and received 4.0 mg/kg/d of oseltamivir for a mean of 3.9 days.
A complete understanding of neurotoxicity, if any, associated with oseltamivir use is important because of the juvenile rat data previously discussed,4
in addition to reports of rare neuropsychiatric events in adolescent patients receiving oseltamivir.6,7
The US Food and Drug Administration reviewed data on the latter events, and wording in the package inserts of oseltamivir, zanamivir, and the adamantanes has been modified to indicate that existing data suggest that neuropsychiatric adverse events can occur in patients with influenza infection, with or without antiviral therapy.3,8
These events do not appear to be associated solely with use of oseltamivir or the neuraminidase inhibitor class of antiviral medications.9
Oseltamivir pharmacokinetics and clinical efficacy have been studied in pediatric patients 12 months of age and older.2,10
Accordingly, oseltamivir is licensed for treatment and prophylaxis of influenza in children ≥1 year of age. The broad dosing ranges of oseltamivir used in infants younger than 12 months in the current study (1–7 mg/kg/dose) illustrate the need for pharmacokinetic data to provide dosing guidelines for this younger population. The NIAID CASG currently is conducting a prospective pharmacokinetic and safety study of oseltamivir among children less than 2 years of age, utilizing an age-deescalation trial design, which includes the neonatal age range.11
Infants and young children are at greater risk of mortality from epidemic influenza than are older children.12–16
with the highest mortality rates occurring in those less than 2 years of age.12
Furthermore, young age is a risk factor independent of any under-lying medical problems.13–16
An understanding of these risks has led the Centers for Disease Control and Prevention Advisory Committee for Immunization Practices to revise recommendations for influenza vaccination to include universal vaccination of all children ≥6 months of age.17
Influenza immunization of younger infants is not recommended because of insufficient data. Although the finding that only one infant in the current study died as a consequence of influenza is encouraging, the retrospective nature of the trial precludes any conclusions about antiviral efficacy. The lower incidence of head/eyes/ears/nose/throat abnormalities in the oseltamivir-treated patients may reflect the known benefit of this drug in preventing otitis media during influenza infection.2
Worldwide, influenza resistance to oseltamivir developed rapidly during 2008. By the 2007 to 2008 season, 11.3% of influenza A(H1N1) isolates in the United States were resistant to oseltamivir.18
Then, with the 2008 to 2009 influenza season, oseltamivir resistance among A(H1N1) isolates skyrocketed to essentially 100% in many parts of the world, including the United States19–21
; the overwhelming majority of A(H1N1) isolates remain susceptible to the adamantanes. On the other hand, the influenza A(H3N2) viruses continue to have near universal resistance to amantadine and rimantadine, but remain susceptible to oseltamivir and zanamivir. Influenza B viruses remain susceptible to oseltamivir and zanamivir as well. Knowledge of the appropriate dosing of each of these medications in infants under 12 months of age is lacking, further complicating the development of additional alternative treatment strategies for this vulnerable population.
These retrospective data provide some reassurance that neurologic events are not associated with oseltamivir administration at moderate or high frequencies in infants less than 12 months. However, rare neurologic events cannot be excluded by our analysis, because of the modest sample size of this study and the difficulty in discerning causality of observed events in retrospective trials, especially in the setting of an illness with known neurologic effects. The CASG’s ongoing prospective investigation of oseltamivir pharmacokinetics and safety in young children will provide additional data to assure safe use of this medication in young infants.