For 20 years, oseltamivir (Tamiflu) has carried a black-box warning suggesting that use in pediatric patients may be linked to neuropsychiatric events, including confusion, delirium, and abnormal behavior.
But a new study in JAMA Neurology debunks this association and suggests that influenza itself, not Tamiflu use, increases a child’s risk of experiencing neuropsychiatric events when ill.
The study comes from researchers at Monroe Carell Jr. Children’s Hospital at Vanderbilt University who used data from 692,295 children ages 5 to 17 enrolled in Tennessee Medicaid between July 1, 2016, and June 30, 2020.
Follow-up began on the first day of the influenza season and continued through the earliest occurrence of an outcome event, loss of enrollment, death, age 18 years, or end of the season or study, the authors said.
The median age of children included in the study was 11 years, and children enrolled in the study experienced a total of 1,230 serious neuropsychiatric events (898 neurologic and 332 psychiatric). Overall, the most common neuropsychiatric events seen during the study period were mood disorders (36.3%) and suicidal or self-harm behaviors (34.2%).
Among the 151,401 influenza episodes, 66.7% (95% confidence interval [CI], 66.5% to 67.0%) were dispensed oseltamivir. Of those, 60.1% were at high risk for influenza complications.
Tamiflu tied to 50% lower risk of events
Compared with untreated influenza, event rates were lower during oseltamivir-treated influenza periods (incidence rate ratios [IRR], 0.53; 95% CI, 0.33 to 0.88) and posttreatment periods (IRR, 0.42; 95% CI, 0.24 to 0.74).
“Risk of serious neuropsychiatric events increased during periods of influenza infection,” the authors wrote. “During these periods, treatment with oseltamivir was associated with an approximately 50% reduction in the incidence of serious neuropsychiatric events compared with influenza periods without oseltamivir treatment.”
Moreover, children treated with oseltamivir prophylactically had the same rate of events as the baseline group with no influenza.
The authors said the current black-box warning on Tamiflu originated in case reports, not clinical studies of the antiviral. Randomized trials have not shown an association, but evidence from prophylactic trials has shown neuropsychiatric events among adults only.
Our findings demonstrated what many pediatricians have long suspected, that the flu, not the flu treatment, is associated with neuropsychiatric events.
"Our findings demonstrated what many pediatricians have long suspected, that the flu, not the flu treatment, is associated with neuropsychiatric events,” said principal investigator James Antoon, MD, PhD, MPH, assistant professor of pediatrics at Monroe Carell, in a press release. “In fact, oseltamivir treatment seems to prevent neuropsychiatric events rather than cause them.”
