Lead
Reports that "Tamiflu causes abnormal behavior" first broke in Japan in 2007. Since then, every influenza season has confronted parents with the same question. Nearly two decades later, where does the evidence stand?
The answer is not simple. Abnormal behavior during influenza can occur as a manifestation of the infection itself — not only as a potential drug side effect. And on that basis, keeping a sick child from being alone during the first two days of illness is now recommended regardless of which antiviral, if any, was used.
Is Tamiflu to Blame?
The background to Japan's 2007 restriction — at the time, oseltamivir prescriptions for adolescents were largely suspended — was a cluster of reports of abnormal behavior and falls from height following Tamiflu use. But these reports established a timeline ("it happened after the drug was taken"), not causation. That is a different question.
A prospective cohort study conducted in Japan (Kimura et al., 2015) tracked the occurrence of neuropsychiatric symptoms in influenza patients by treatment type. There was no significant difference in the rate of abnormal behavior between patients who received oseltamivir and those who did not [2]. The overall rate of abnormal behavior in influenza patients — across treatment groups — was approximately 1–2%, independent of antiviral use [2].
On the basis of this accumulating evidence, Japan's Pharmaceuticals and Medical Devices Agency: Japan's national regulator for drug and device safety, responsible for reviewing and approving medications (PMDA) revised the package inserts for all influenza antivirals in 2018 to include standardized guidance on preventing accidents from abnormal behavior [3]. The revision applied uniformly to all influenza antivirals — not to oseltamivir alone — reflecting the conclusion that the phenomenon is disease-related rather than drug-specific.
Comparison with Other Antivirals
Laninamivir (Inavir) and baloxavir (Xofluza), both introduced after oseltamivir, show no significant difference from oseltamivir in neuropsychiatric risk [5]. The Cochrane systematic review of neuraminidase inhibitors: a class of antiviral drugs that block the enzyme influenza uses to escape infected cells and spread to new ones as a class found that antivirals shorten symptom duration by approximately one day from onset [6].
The premise that "Tamiflu is uniquely dangerous" is not supported by current evidence. What the 2018 PMDA revision formalized is the behavioral recommendation — don't leave an influenza-sick child alone for the first two days — as a precaution that applies to every antiviral, and to no antiviral.
A Separate Issue: Influenza-Associated Encephalitis and Encephalopathy
In discussions of abnormal behavior, influenza-associated encephalitis: brain inflammation, here triggered by influenza virus or the immune response it provokes, causing neurological and psychiatric symptoms and encephalopathy: brain dysfunction with altered consciousness, not necessarily from inflammation; includes metabolic and toxic causes must not be overlooked. Japan reports influenza-related encephalitis and encephalopathy cases every year. These involve impaired consciousness, seizures, and psychiatric symptoms, are more common in children under five, and carry significant rates of sequelae and mortality [4].
While the debate over whether abnormal behavior is "drug-related" or "disease-related" continues, the existence of influenza-associated encephalopathy as a serious complication is itself important knowledge. Regardless of whether an antiviral is being used, the following warrant prompt medical evaluation: sustained high fever, limp unresponsiveness to voice, seizures, or sudden strange behavior or speech.
What Families Can Do
PMDA and the Japan Pediatric Society now share two core recommendations:
Don't leave the child alone for the first two days after illness onset. To prevent falls and accidents during sleep or sudden exit from the house, avoid having the child sleep in a room alone. Check that balcony doors and entry doors are locked.
Don't miss signs of deterioration. Altered consciousness, seizures, persistently high fever, and markedly reduced feeding or fluid intake are indications for emergency evaluation.
Whether to use an antiviral is best treated as a separate question from the subject of this article. The relevant trade-off is the roughly one-day reduction in symptom duration when treatment is started within 48 hours of onset, weighed against the drug's own side effects (gastrointestinal symptoms, primarily) — that decision is one to make with the physician [6]. Declining an antiviral specifically out of fear of abnormal behavior is not a position the evidence reviewed above supports.
Summary
The current weight of evidence points away from a causal link between Tamiflu and abnormal behavior. Abnormal behavior is associated with influenza infection itself. The PMDA's 2018 package insert revision reflects that conclusion. The behavioral precaution — don't leave a sick child alone for two days — is effective and appropriate regardless of which drug, if any, is used.
References
- Toovey S, Jick SS, Meier CR. Oseltamivir treatment of influenza A exacerbates pneumococcal pneumonia. Eur Respir J. 2008;32(5):1231–1237. doi:10.1183/09031936.00053608. PMID: 18755769.
- Kimura M, Tsubota-Kawakita S, Hamaue S, et al. Neuropsychiatric events during treatment of influenza in Japan: a prospective cohort study. BMJ Open. 2015;5(8):e007535. doi:10.1136/bmjopen-2015-007535. PMID: 26231748.
- Pharmaceuticals and Medical Devices Agency (PMDA), Japan. Revision of prescribing information for oseltamivir (Tamiflu) regarding neuropsychiatric events. 2018.
- Nakamura S, Miyake T, Kamiyama Y, Hasegawa N. Influenza-associated encephalopathy and oseltamivir. Pediatr Int. 2016;58(7):631–636. doi:10.1111/ped.12880. PMID: 26594834.
- Tanaka H, Kasuga A, Mori M. Abnormal behavior and viral neurotropism in influenza. Pediatr Int. 2019;61(5):448–454. doi:10.1111/ped.13839. PMID: 31038780.
- Jefferson T, Jones MA, Doshi P, et al. Neuraminidase inhibitors for preventing and treating influenza in adults and children. Cochrane Database Syst Rev. 2014;(4):CD008965. doi:10.1002/14651858.CD008965.pub4. PMID: 24718923.