FormalPara Key Points

We studied trends in the percentage of oseltamivir prescriptions and ADR reports in pediatric outpatients.

The package insert for oseltamivir was revised because of ADRs described as “abnormal behavior.”

The number of prescriptions increased after the revision of the oseltamivir package insert, but not the number of reports of abnormal behavior.

1 Introduction

Oseltamivir phosphate (oseltamivir) is one of the drugs with a high frequency of adverse drug reactions (ADRs) in pediatric patients [1]. In November 2005, abnormal behavior after oseltamivir use was widely reported in the media, raising public concerns [2]. In March 2007, the Ministry of Health, Labour, and Welfare of Japan issued an “Emergency Safety Communication” regarding abnormal behavior after oseltamivir use [3], and the package insert for oseltamivir was revised, stating that, in principle, the drug should not be used in minors over 10 years of age [4]. In 2018, the age limitation on oseltamivir use was removed because the causal relationship between oseltamivir and abnormal behavior was unclear [5].

According to a survey of annual trends in ADR reporting, the highest number of reports pertained to "oseltamivir and abnormal behavior" in 2007 and "zanamivir hydrate (zanamivir) and abnormal behavior" in 2009 among pediatric patients [1]. These findings suggest that the safety information released and the revised package inserts by the Ministry of Health, Labour, and Welfare may affect the number of prescriptions and ADR reports. Pharmacovigilance involves the concurrent monitoring of trends in drug prescription and ADR reporting. Therefore, the aim of this study was to determine the trends in the prescription of anti-influenza drugs and ADR reports in pediatric outpatients after the revision of the oseltamivir package insert in Japan that occurred in 2018.

2 Methods

Prescriptions of anti-influenza drugs for pediatric outpatients aged 0–19 years with influenza included in the databases of acute Diagnosis Procedure Combination (DPC) hospitals from 1 April 2016 to 31 March 2020 were downloaded using the MDV analyzer® (Medical Data Vision Co., Ltd., Tokyo, Japan), a web analysis tool. This analyzer has the highest number of registered patients among commercial medical data analysis tools in Japan [6]. Patients were identified as having the influenza virus according to the International Statistical Classification of Diseases, 10th Revision codes J09, J101, J110, J111, and J118. Patients with influenza who were prescribed anti-influenza drugs within the same month on which one or more International Statistical Classification of Diseases, 10th Revision codes were assigned were defined as patients with influenza who were prescribed anti-influenza drugs. The five anti-influenza drugs recommended in the "Influenza Treatment Guidelines for the 2018/2019 Season" were as follows: oseltamivir, zanamivir, and laninamivir, as well as baloxavir, a new anti-influenza drug approved for manufacture and sale in February 2018. The proportion of prescriptions for anti-influenza drugs was calculated by age group and the drug. As raw patient data could not be retrieved from the MDV analyzer®, the proportion of each prescription was calculated using the available data as follows:

Proportion of anti-influenza drug (each anti-influenza drug) prescriptions =

$$\frac{\mathrm{Number\, of\, pediatric \,outpatients \,prescribed \,an \,anti-influenza\, drug }\times 100}{\mathrm{Number\, of \,pediatric\, outpatients\, with \,influenza}}.$$

The proportion of prescriptions was calculated for every quarter (April–June/July–September/October–December/January–March), taking into account the influenza epidemic season. The annual proportion of each prescription was calculated from 2016/2017 to 2019/2020. The values were stratified according to age (0–9 and 10–19 years). The study was performed in accordance with the tenets of the Declaration of Helsinki and was approved by the Institutional Review Board of Tohoku Medical and Pharmaceutical University Hospital (Approval Number: 2019-2-066).

ADR reports on the use of oseltamivir or similar drugs (zanamivir, amantadine, laninamivir, and baloxavir) among patients aged 0–19 years included in the Japanese Adverse Drug Event Report (JADER) database from 1 April 2004 to 31 May 2020 were downloaded from the Pharmaceuticals and Medical Devices Agency website. The JADER database comprises four tables: (1) patient demographic information, (2) drug information, (3) adverse events, and (4) primary diseases. The adverse reactions and underlying disease fields in the database are described using preferred terms (PTs) in the Japanese version of the Medical Dictionary for Regulatory Activities (version 23.1; International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, Geneva, Switzerland) in this study. The information collected included patient details (age and sex), reporting year and quarter, suspected drug, and ADR coded according to the PTs. As altered state of consciousness, abnormal behavior, delirium, hallucinations, delusions, and seizures were added to the revised package insert for oseltamivir in May 2004, these symptoms were termed abnormal behavior. Therefore, we extracted these terms, that is, altered state of consciousness, abnormal behavior, delirium, hallucinations, delusions, and seizures, from the JADER database and defined them as “abnormal behavior” for the purpose of this analysis. The reports were tabulated and analyzed after stratification according to patient age (0–9 and 10–19 years) and ADR (abnormal behavior and other ADRs). The Institutional Review Board of Tohoku University School of Medicine approved this survey (approval number: 2017-1-506). This survey was performed in accordance with the tenets of the Declaration of Helsinki. We examined the trends in these data and evaluated them as an ecological study.

3 Results

Table 1 and Figs. 1 and 2 show the prescription trends of anti-influenza drugs and reporting trends of ADRs related to anti-influenza drugs in every quarter during the 2016/2017 and 2019/2020 seasons. There was no difference in the oseltamivir prescription percentages in patients aged 0–9 years with influenza between the influenza epidemic seasons (January–March) of 2016/2017 (63.4%) and 2019/2020 (59.1%) (i.e., before and after the revision of the oseltamivir package insert, respectively), and the number of reports of abnormal behavior tended to decrease (15 and 1, respectively). Furthermore, oseltamivir prescriptions in patients aged 10–19 years with influenza during the influenza epidemic season (January–March) tripled in percentage after the revision of the oseltamivir package insert (29.2% and 9.3% during the 2019/2020 and 2016/2017 seasons, respectively). However, the number of reports of abnormal behavior did not increase (0 and 2 during the 2019/2020 and 2016/2017 seasons, respectively). Regardless of the age group, the number of ADR reports was low during the 2019/2020 season after the revision of the oseltamivir package insert, partially because the number of patients with influenza decreased. There were no changes in the prescription trends of anti-influenza drugs other than oseltamivir and the reporting trends of ADRs related to anti-influenza drugs other than oseltamivir between the periods before and after the revision of the oseltamivir package insert.

Table 1 Trends in anti-influenza drug prescription and related ADR reporting (A: 0–9 years, B: 10–19 years)
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Fig. 1
figure 1

Trends in anti-influenza drug prescription and related adverse drug reaction (ADR) reporting (0–9 years). a Prescription trends of different anti-influenza drugs. The horizontal, left vertical, and right vertical axes show the year, number of patients with influenza enrolled in the MDV analyzer, and proportion of each anti-influenza drug prescription (%), respectively. b ADR reporting related to different anti-influenza drugs. The horizontal and left vertical axes show the year and number of ADR reports included in the JADER database, respectively

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Fig. 2
figure 2

Trends in prescription of anti-influenza drugs and related adverse drug reaction (ADR) reporting (10–19 years). a Prescription trends of different anti-influenza drugs. The horizontal, left vertical, and right vertical axes show the year, number of patients with influenza enrolled in the MDV analyzer, and proportion of each anti-influenza drug prescription (%), respectively. b ADR reporting related to different anti-influenza drugs. The horizontal and left vertical axes show the year and number of ADR reports included in the JADER database, respectively

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4 Discussion

In this study, we assessed trends in the prescription of anti-influenza drugs and ADR reporting in pediatric outpatients after the revision of the oseltamivir package insert in Japan in 2018. The proportion of oseltamivir prescriptions after the revision of the oseltamivir package insert in 2018 did not change among children aged 0–9 years with influenza and increased among those aged 10–19 years in DPC hospitals. In August 2018, a research group from the Japan Agency for Medical Research and Development reported that abnormal behavior after influenza was not related to oseltamivir use [7]. Based on this report, the following statement was added to the adverse effects section of the package inserts of all anti-influenza drugs: “Although the causal relationship is unknown, abnormal behaviors (such as sudden running and wandering) that may lead to falls may occur in patients with influenza,” and the age limitation for oseltamivir prescription was lifted. Therefore, in the influenza treatment guidelines of the Japanese Pediatric Society, oseltamivir was recommended for all ages during the 2018/2019 season [8]. The results of this study are thus in accordance with these guidelines. We also found that the number of ADR reports related to oseltamivir use did not increase, although the proportion of oseltamivir prescriptions increased after the revision of the oseltamivir package insert. This finding may be attributed to the efforts of the medical professionals to appropriately prescribe drugs that decreased the frequency of reporting abnormal behavior as an ADR.

This study had several limitations. Many patients with influenza consult their general practitioners. However, we retrieved information from acute DPC hospitals using the MDV analyzer®, given that drugs are more likely to be prescribed to high-risk patients requiring urgent treatment or with potentially complicated conditions. The JADER database, a spontaneous reporting system of suspected cases with ADRs, has several limitations, such as a lack of user denominator [9] and under-reporting [10]. The unclear causal relationship between oseltamivir and abnormal behavior may have reduced the number of spontaneous reports. The proportion of oseltamivir prescriptions and the number of ADR reports were calculated using different databases. Therefore, factors other than the lifted age limitation may have accounted for these trends.

A previous study found that media reports on the abnormal behavior caused by anti-influenza drugs had a large impact on society and that both consumers and healthcare professionals focused their attention on the issue [2]. We concurrently evaluated trends in drug prescription and ADR reporting and found that after the revision of the oseltamivir package insert, the number of prescriptions, but not the number of reports of abnormal behavior, increased. As previous studies have also shown that new anti-influenza drugs and their dosage forms might have influenced prescription trends in recent years [11], we will continue to focus on future trends.

5 Conclusions

The results of our study confirmed that the number of ADR reports related to oseltamivir did not increase after the revision of the oseltamivir package insert regarding its use in minors over 10 years of age despite an increase in the proportion of oseltamivir prescriptions.