Oseltamivir Not Linked to Increase Risk for Neuropsychiatric Events

No difference was seen in the risk for serious neuropsychiatric events in patients who received oseltamivir in the 30 days after influenza diagnosis compared with those who did not. Further, the risk for moderate to severe neuropsychiatric events was significantly lower among those prescribed oseltamivir, according to a study published in Clinical Infectious Diseases. Although these results were slightly different in children and adolescents, the differences did not reach statistical significance.

Oseltamivir is a potent inhibitor of influenza viral neuraminidases, and usually well tolerated; the most common side effects are gastrointestinal in nature. However, in Japan and Korea reports of suicide attempts, delirium, and other psychiatric events, particularly in children and adolescents, have raised concerns about the safety of oseltamivir. Though some explanations for a possible association between the use of oseltamivir and neuropsychiatric events have been hypothesized—most centering on drug penetration into the central nervous system—none have been supported.

Therefore, researchers conducted this population-based retrospective cohort study to evaluate whether an association exists between the use of oseltamivir and neuropsychiatric events. The study analyzed data on a random 50% sample of patients aged >8 years in the Korean National Health Insurance Service database who had an influenza diagnosis between 2009 and 2017. Oseltamivir prescription at the time of diagnosis was the primary exposure, and the primary outcome was neuropsychiatric events diagnosis within 30 days. Analyses included information extracted on oseltamivir prescription, neuropsychiatric event diagnoses, comorbidities, prescriptions during the year before influenza diagnosis, demographics, and healthcare utilization.

Of the 3,352,015 individuals included in the analysis, oseltamivir was prescribed to 1,266,780 participants (37.8%). Neuropsychiatric events were observed in 10,913 (0.86%) of participants in the oseltamivir group compared with 24,286 (1.16%) of controls. For participants in the oseltamivir group compared with the control group, the hazard ratio (HR) for neuropsychiatric events was 0.74 (95% CI, 0.73-0.75; P <.001). A total of 51 oseltamivir participants (0.004%) experienced a severe neuropsychiatric event (suicide or suicide attempt) compared with 137 (0.007%) of control group participants (HR, 0.61; 95% CI, 0.29-0.93; P =.003).

In the oseltamivir group, 0.28% of participants experienced a moderate to severe neuropsychiatric event, compared with 0.44% in the control group (HR, 0.64; 95% CI, 0.60-0.68; P <.001). The adjusted analysis showed no significant difference in overall neuropsychiatric events risk between the oseltamivir and control groups (HR, 0.98; 95% CI, 0.96-1.01; P =.16) or severe neuropsychiatric event risk (HR, 0.82; 95% CI, 0.50-1.14; P =.23), but a significantly lower risk for a moderate to severe event was seen in the oseltamivir group (HR, 0.92; 95% CI, 0.88-0.96; P <.001).

Although the crude neuropsychiatric events incidence in patients aged 8 to 18 years was significantly lower in the oseltamivir group (HR, 0.88; 95% CI, 0.85-0.91; P <.001), the adjusted model showed no difference in neuropsychiatric event risk between the 2 groups (HR, 1.04; 95% CI, 1.00-1.09; P =.08), and moderate to severe neuropsychiatric event incidence followed a similar pattern.

However, the risk for suicide or attempted suicide in children and adolescents was higher among participants prescribed oseltamivir, both in the crude analysis (HR, 2.16; 95% CI, 1.41-2.91; P =.04), and in the adjusted analysis (HR, 2.01; 95% CI, 1.25-2.77; P =.07). Of note, the differences were below the preset significance threshold.

In addition, no significant difference was seen in neuropsychiatric event risk among participants with chronic kidney disease, in either the crude (HR, 0.83; 95% CI, 0.70-1.02; P =.10), or the adjusted analyses (HR, 0.93; 95% CI, 0.70-1.16; P =.51).

Despite limitations, including using International Statistical Classification of Diseases and Related Health Problems, 10^th Revision codes rather than microbiologic diagnoses to identify patients with influenza, as well as identifying oseltamivir by prescription reimbursement when some patients may have taken the medication without qualifying for reimbursement, investigators conclude, “we observed a protective effect of oseltamivir against [neuropsychiatric events] using national, population-based claims data. The results were consistent across analytic models that adjusted for comorbidities and concomitant medications. We did not find an association between oseltamivir use and [neuropsychiatric events] among individuals with chronic kidney diseases, a group with greater susceptibility to potential adverse effects of oseltamivir due to impaired renal clearance. Oseltamivir prescription was associated with a small increase in the incidence of suicide attempts among children and adolescents, but the difference was extremely small. Our findings suggest that oseltamivir use is not associated with an increased risk [for neuropsychiatric events].”

Reference

Huh K, Kang M, Shin DH, Hong J, Jung J. Oseltamivir and the risk of neuropsychiatric events: a national, population-based study [published online January 30, 2020]. Clin Infect Dis. doi: 10.1093/cid/ciaa055