Tamiflu and Abnormal Behavior — What Japan's Regulator Concluded, and Why "Don't Leave Them Alone for Two Days" Applies to Every Drug

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 for at least two days after fever onset 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.

Since the 2006/07 season, a Ministry of Health, Labour and Welfare (MHLW) research group has asked medical institutions nationwide to report severe abnormal behavior — suddenly running off, trying to jump from a height, and other unpredictable actions that could be fatal if no one intervened. An analysis of 858 cases collected over seven seasons (the first season retrospectively, the rest prospectively) found that the incidence of abnormal behavior followed the same curve as the influenza epidemic, and no specific association with the type of medication used was clearly observed [1]. An analysis using national medical-claims data as the denominator likewise found severe abnormal behavior reported with every antiviral and in patients given no antiviral at all [2]. A later analysis of the data through the 2021/22 season concluded that oseltamivir alone does not raise the risk of abnormal behavior [3].

At the same time, the 2018 report of Japan's national drug-safety committee noted that most studies argued against a link between Tamiflu and abnormal behavior, yet judged that confounding and bias made it "difficult to reach a clear conclusion" on causation [4]. What can be said with confidence is that abnormal behavior occurs with influenza itself, whether or not a drug is taken [4].

On that basis, in August 2018 the MHLW instructed that the warning restricting oseltamivir use in teenagers be deleted and that the abnormal-behavior precaution appear in the package inserts of all influenza antivirals (published by the Pharmaceuticals and Medical Devices Agency, PMDA) [5]. 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

Severe abnormal behavior has also been reported in patients given laninamivir (Inavir) and other drugs introduced after oseltamivir, with no pattern of oseltamivir standing out as higher-risk [2][3]. Baloxavir (Xofluza), introduced in 2018, was included in the same revision's abnormal-behavior precaution [5]. The Cochrane systematic review of neuraminidase inhibitors assessed both benefits and harms: oseltamivir shortened the time to first symptom relief by about 17 hours in adults and about 29 hours in otherwise healthy (non-asthmatic) children [6]. The same review also reported a small increase in psychiatric adverse events with oseltamivir in adult prevention trials [6].

The premise that "Tamiflu is uniquely dangerous" is not supported by current evidence. What the 2018 revision formalized is the behavioral recommendation — don't leave an influenza-sick child alone for at least two days after fever onset — 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 and encephalopathy must not be overlooked. Japan reports influenza-related encephalitis and encephalopathy cases every year. These involve impaired consciousness, seizures, and psychiatric symptoms, and in a nationwide survey of the 1998–99 season developed mainly in children under five, with high mortality (about 32%) and disability (about 28%) [7].

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

Two things are worth holding on to at home:

Don't leave the child alone for at least two days after fever onset. This is what the MHLW notice and the package inserts ask for, whether or not a drug is used [4][5]. To prevent falls and accidents during sleep or sudden exit from the house, avoid having the child sleep in a room alone. Check that the front door and windows are locked, and have the child sleep in a room that does not open onto a balcony.

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 reduction in symptom duration of roughly half a day to a day 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 the idea that Tamiflu specifically raises the risk of abnormal behavior, although no definitive conclusion on causation has been reached. Abnormal behavior is associated with influenza infection itself. The 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

1. Nakamura Y, Sugawara T, Ohkusa Y, et al. Abnormal behavior during influenza in Japan during the last seven seasons: 2006-2007 to 2012-2013. J Infect Chemother. 2014;20(12):789–793. doi:10.1016/j.jiac.2014.08.016. PMID: 25284815.
2. Nakamura Y, Sugawara T, Ohkusa Y, et al. Severe abnormal behavior incidence after administration of neuraminidase inhibitors using the national database of medical claims. J Infect Chemother. 2018;24(3):177–181. doi:10.1016/j.jiac.2017.10.001. PMID: 29273435.
3. Sugawara T, Ohkusa Y, Taniguchi K, et al. Association of severe abnormal behavior of influenza patients and administered anti-influenza virus drugs: 2006-2022. Int J Infect Dis. 2026;166:108553. doi:10.1016/j.ijid.2026.108553. PMID: 41862079.
4. Pharmaceutical Affairs and Food Sanitation Council, Committee on Drug Safety (Japan). Report on the relationship between Tamiflu and abnormal behavior [タミフルと異常行動等の関連に係る報告書]. 2018. https://www.mhlw.go.jp/content/11121000/000341848.pdf
5. Ministry of Health, Labour and Welfare (Japan), Pharmaceutical Safety Division. Revision of precautions for anti-influenza antiviral drugs [抗インフルエンザウイルス薬の「使用上の注意」の改訂について]. Notice PSEHB/PSD 0821-1, August 21, 2018.
6. 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.
7. Morishima T, Togashi T, Yokota S, et al. Encephalitis and encephalopathy associated with an influenza epidemic in Japan. Clin Infect Dis. 2002;35(5):512–517. doi:10.1086/341407. PMID: 12173123.