Analysis of Neuropsychiatric Adverse Events in Patients Treated with Oseltamivir in Spontaneous Adverse Event Reports

Abstract

There have been concerns that oseltamivir causes neuropsychiatric adverse events (NPAEs). We analyzed the association of age and gender with NPAEs in patients treated with oseltamivir using a logistic regression model. NPAE data were obtained from the U.S. Food and Drug Administration Adverse Event Reporting System (2004 to 2013). The lower limit of the reporting odds ratio (ROR) 95% confidence interval (CI) of “abnormal behavior” in Japan, Singapore, and Taiwan was ≥1. The effects of the interaction terms for oseltamivir in male patients aged 10–19 years were statistically significant. The adjusted ROR of “abnormal behavior” was 96.4 (95% CI, 77.5–119.9) in male patients aged 10–19 years treated with osletamivir. In female patients, the results of the likelihood ratio test for “abnormal behavior” were not statistically significant. The adjusted NPAE RORs were increased in male and female patients under the age of 20 years. Oseltamivir use could be associated with “abnormal behavior” in males aged 10–19 years. After considering the causality restraints of the current analysis, further epidemiological studies are recommended.

Oseltamivir (Tamiflu) is a neuraminidase inhibitor commonly used as an anti-viral in the treatment of influenza.¹⁾ Administrative authorities have issued warnings regarding the risk of neuropsychiatric adverse events (NPAEs) following oseltamivir use. In March 2007, the Japanese Ministry of Health, Labour and Welfare (MHLW) warned against the use of oseltamivir in children aged 10–19 years because it could cause abnormal behavior. The U.S. Food and Drug Administration (FDA) added a warning to the oseltamivir label in 2006 to draw attention to the risk of NPAEs. Recent reports suggest that NPAEs may occur after oseltamivir administration.^2–9)

In prophylaxis studies, oseltamivir increased the risk of psychiatric adverse events during the combined “on-treatment” and “off-treatment” periods (risk difference 1.06, 0.07 to 2.76%).²⁾ A cohort study indicated a slightly increased risk of delirium with oseltamivir use in patients under 18 years (hazard ratio: 1.51, 95% confidence interval (CI) 0.95–2.40, p=0.084).³⁾ Data from the FDA Adverse Event Reporting System (FAERS) indicates that certain NPAEs are disproportionally reported after oseltamivir use.⁴⁾ Several cases of oseltamivir-induced NPAEs have been reported, including mania in a Chinese patient⁵⁾ and depressive episodes in Korean patients.⁶⁾

However, a number of epidemiological studies, controlled studies, and commentaries indicate that there is no relationship between oseltamivir use and NPAEs.^10–13) Significant controversy exists regarding whether NPAEs result from oseltamivir use. Given this conflicting data, the optimal dosing for patients who require oseltamivir therapy is uncertain.

FAERS is a passive reporting system covering several million case reports on adverse events that is used for pharmacovigilance.¹⁴⁾

Data from the FAERS indicate that certain NPAEs are disproportionately reported after oseltamivir use, especially in Japan.⁴⁾ To our knowledge, reports from Asian countries other than Japan were not evaluated in the FAERS database. Furthermore, the effect of age and gender on the relationship between oseltamivir and NPAEs has not yet been evaluated using the FAERS database.

Owing to the risk of reporting bias, there are legitimate reasons to doubt the stated benefits and/or risks of FAERS data.¹⁴⁾ Despite the limitations inherent to spontaneous reporting, these databases are still the primary tool used for pharmacovigilance, because they reflect the realities of clinical practice.^15,16) The pharmacovigilance index, termed the reporting odds ratio (ROR), was developed to detect drug-associated adverse events in the spontaneous reporting database, and is not applicable for evaluating the comparative strength of causalities.¹⁷⁾ However, the ROR is applicable to a logistic regression model, which allows for the control of covariates.^15,17) We evaluated the possible relationship between oseltamivir use and NPAEs from data available in the FAERS databases using the ROR and logistic regression analysis.

MATERIALS AND METHODS

Adverse events recorded from January 2004 to March 2013 in the FAERS database were obtained from the FDA website (www.fda.gov). The FAERS structure complies with the International Conference on Harmonization and the international safety reporting guidelines, ICH E2B. The adverse events are coded according to the terminology preferred by the Medical Dictionary for Regulatory Activities (MedDRA).¹⁸⁾ DrugBank, a reliable drug database, was utilized as a dictionary for the batch conversion and compilation of drug names.¹⁹⁾

In instances of duplicate entries, we adopted the most recent case number in order to identify duplicate reports of the same patient that come from different reporting sources and excluded these from the analysis as is described in the downloadable file ‘Asc_nts.doc’ from the FAERS database website. Patients with NPAEs were grouped by gender, and each gender group was stratified by age: <10 years, 10–19 years, ≥20 years. We extracted those reports that contained the preferred term (PT) “abnormal behavior” from the MedDRA. To further evaluate the effect of oseltamivir in NPAEs, we selected 57 additional PTs related to NPAEs described in the Japanese package insert of oseltamivir (Table 1).

Table 1. Neuropsychiatric Adverse Events Associated with Oseltamivir in FAERS (January 2004–March 2013)

HLTa)	PTb)	PT code	Total	Casesc)	%	RORd)	(95%CIe))
Total			222029	1347
Disturbances in consciousness NECf)	Altered state of consciousness	10001854	3306	35	2.6	5.2	(3.7–7.2)
	Depressed level of consciousness	10012373	10200	86	6.4	4.1	(3.3–5.1)
	Loss of consciousness	10024855	28249	92	6.8	1.6	(1.3–1.9)
	Stupor	10042264	939	1	0.1	—†
	Breath holding	10006322	29	0	—
	Staring	10041953	647	6	0.4	4.5	(2.0–10.0)
	Regressive behavior	10054720	76	1	0.1	—†
	Abnormal behavior	10061422	11602	489	36.3	23.5	(21.3–25.8)
	Sexually inappropriate behavior	10070240	41	0	—
Deliria	Delirium	10012218	6283	164	12.2	13.3	(11.4–15.6)
	Delirium tremens	10012225	109	0	—
	Delirium febrile	10059267	27	8	0.6	202.4	(88.5–462.5)
Perception disturbances	Hallucination	10019063	12373	286	21.2	12.0	(10.7–13.6)
	Hallucination, auditory	10019070	3119	37	2.7	5.8	(4.2–8.0)
	Hallucination, gustatory	10019071	9	0	—
	Hallucination, olfactory	10019072	81	0	—
	Hallucination, visual	10019075	3921	49	3.6	6.1	(4.6–8.1)
	Hallucination, tactile	10019074	119	0	—
	Hallucinations, mixed	10019079	842	13	1.0	7.5	(4.4–13.0)
	Somatic hallucination	10062684	20	0	—
	Hallucination, synaesthetic	10062824	7	0	—
	Delusional perception	10012258	90	1	0.1	—†
Narcolepsy and associated conditions	Hypnagogic hallucination	10020927	40	1	0.1	—†
	Hypnopompic hallucination	10020928	15	0	—
Delusional symptoms	Delusion	10012239	2973	48	3.6	7.9	(6.0–10.6)
	Delusion of reference	10012244	43	0	—
	Delusion of replacement	10012245	24	0	—
	Delusions, mixed	10012263	2	0	—
	Erotomanic delusion	10015134	4	0	—
	Jealous delusion	10023164	49	0	—
	Persecutory delusion	10034702	537	2	0.1	—†
	Somatic delusion	10041317	76	0	—
	Depressive delusion	10063033	15	0	—
	Delusion of grandeur	10012241	120	0	—
Seizures and seizure disorders NECf)	Convulsion	10010904	33234	174	12.9	2.6	(2.2–3.0)
	Convulsion neonatal	10010911	79	0	—
	Drug withdrawal convulsions	10013752	164	0	—
	Tonic convulsion	10043994	311	2	0.1	—†
	Convulsion in childhood	10052391	4	0	—
	Clonic convulsion	10053398	213	1	0.1	—†
	Convulsions local	10010920	36	0	—
	Febrile convulsion	10016284	295	6	0.4	10.0	(4.4–22.4)
Anxiety symptoms	Agitation	10001497	17046	84	6.2	2.4	(1.9–3.0)
Tremor (excl congenital)	Tremor	10044565	30757	52	3.9	0.8	(0.6–1.1)
	Essential tremor	10015496	143	1	0.1	—†
	Intention tremor	10022520	159	1	0.1	—†
	Orthostatic tremor	10069917	7	0	—
	Resting tremor	10071390	33	0	—
	Psychogenic tremor	10072377	0	0	—
	Action tremor	10072413	1	0	—
	Postural tremor	10073211	1	0	—
Parasomnias	Nightmare	10029412	6557	58	4.3	4.3	(3.3–5.6)
	Abnormal dreams	10000125	7066	13	1.0	0.9	(0.5–1.5)
Neurological signs and symptoms NECf)	Dizziness	10013573	79088	90	6.7	0.5	(0.4–0.7)
	Dizziness exertional	10013576	59	0	—
	Dizziness postural	10013578	1145	3	0.2	1.3	(0.4–3.9)
Apocrine and eccrine gland disorders	Night sweats	10029410	4285	8	0.6	0.9	(0.4–1.8)

a) HLT: High level terms in MedDRA. b) PT: Preferred terms in MedDRA. c) Patients who reported adverse events taking oseltamivir. d) ROR: Reporting odds ratio. e) CI: Confidence interval. f) NEC: Not elsewhere classified. ^† Number of cases ≤2.

Using established pharmacovigilance indices, “cases” were defined as patients who reported NPAEs, while “non-cases” consisted of patients who reported other side effects.¹⁵⁾ The ROR is the ratio of the odds of reporting an adverse event versus all other events for oseltamivir compared to the odds of reporting an adverse event for all other drugs present in the database.^14,15,20) RORs were expressed as point estimates with a 95% CI. A signal is considered an event when the lower limit of the ROR 95% CI is ≥1,²⁰⁾ and at least 3 cases were required to define the signal. We refined the signal with a dedicated correction to detect possible confounding factors present in the database. The RORs were adjusted for age in the male and female subset groups using logistic regression analysis. To construct the logistic model, we included the terms for reporting year, oseltamivir, age-stratified group, and the co-occurrence of oseltamivir use within the age-stratified groups. The logistic model used to calculate the adjusted ROR was as follows:   

This model can be compared with a model in which no interaction term is present. A likelihood ratio test can be used to evaluate the effect of adding the term. Because the difference in −2 log-likelihood follows a chi-square distribution with one degree of freedom, adding the interaction term in this case is statistically significant (p<0.05). To calculate the adjusted RORs, the ≥20 years group was used as a reference group. Data analyses were performed using JMP version 11.0 (SAS Institute Inc., Cary, NC, U.S.A.).

RESULTS

The FAERS database contains 4746890 reports from January 2004 to March 2013. After excluding duplicates according to the FDA recommendation, there were 3522995 reports that were usable. We excluded a further 1265093 reports because the age and gender were not indicated and finally analyzed 2257902. The total number of reports citing NPAEs and oseltamivir were 222029 and 4696, respectively. In 1347 cases, the NPAEs corresponded to the 57 PTs associated with oseltamivir use.

The data stratified by age and gender are summarized in Table 2. “Abnormal behavior” was primarily reported in people under 20 years of age. The RORs (95%CI) of “abnormal behavior” in Japan, Singapore, and Taiwan were 30.6 (27.0–34.7), 94.4 (18.3–486.8), and 15.3 (4.5–52.5), and those of “NPAEs” were 3.6 (3.3–3.9), 11.1 (5.3–23.4), and 1.3 (0.6–3.1), respectively (Table 3).

Table 2. Reporting Odds Ratio for Abnormal Behavior and Neuropsychiatric Adverse Events Stratified by Age and Gender

	Total	Casesa)	RORb)	(95%CIc))
Abnormal behavior	11602	489	23.7	(21.6–26.1)
Male	6396	335	36.9	(32.8–41.5)
0–9 years	1434	167	73.4	(61.4–87.7)
10–19 years	1239	126	89.4	(72.3–110.4)
≥20 years	3723	42	7.5	(5.5–10.2)
Female	5206	154	12.6	(10.7–14.8)
0–9 years	623	79	48.4	(37.8–62.0)
10–19 years	618	27	22.7	(15.2–33.6)
≥20 years	3965	48	5.1	(3.8–6.7)
Neuropsychiatric adverse events (NPAEs)	222029	1347	3.8	(3.5–4.0)
Male	88880	784	5.3	(4.9–5.8)
0–9 years	5449	327	10.5	(8.9–12.3)
10–19 years	6148	238	13.3	(10.9–16.2)
≥20 years	77283	219	2.2	(1.9–2.6)
Female	133149	563	2.6	(2.4–2.9)
0–9 years	3614	186	8.1	(6.6–9.9)
10–19 years	5877	90	4.9	(3.8–6.4)
≥20 years	123658	287	1.6	(1.4–1.9)

a) Patients who reported adverse events taking oseltamivir. b) ROR: Reporting odds ratio. c) CI: Confidence interval.

Table 3. Number and Reporting Odds Ratio for Abnormal Behavior and Neuropsychiatric Adverse Events Stratified by Countries in Asia

	RORa)	(95%CIb))	Casesc)		Reporting number
			n	(%)	Oseltamivir	Adverse events
Abnormal behavior
FAERS	22.2	(20.4–24.3)	551	(8.5)	6508	15113
China	—†		1	(1.6)	61	21
Japan	30.6	(27.0–34.7)	424	(17.5)	2421	1220
Korea	—†		2	(1.9)	104	20
Singapore	94.4	(18.3–486.8)	3	(9.1)	33	6
Taiwan	15.3	(4.5–52.5)	3	(5.5)	55	27
Neuropsychiatric adverse events (NPAEs)
FAERS	3.3	(3.1–3.5)	1528	(23.5)	6508	299707
China	0.6	(0.2–1.9)	3	(4.9)	61	1065
Japan	3.6	(3.3–3.9)	707	(29.2)	2421	12731
Korea	0.4	(0.2–1.2)	4	(3.8)	104	683
Singapore	11.1	(5.3–23.4)	11	(33.3)	33	133
Taiwan	1.3	(0.6–3.1)	6	(10.9)	55	549

a) ROR: Reporting odds ratio. b) CI: Confidence interval. c) Patients who reported adverse events taking oseltamivir. ^† Number of cases ≤2.

The number of cases and the ROR (95%CI) for each PT are summarized in Table 1. The number of cases of “abnormal behavior,” “hallucination,” “convulsion,” and “delirium” were 489 (36.3%), 286 (21.2%), 174 (12.9%), and 164 (12.2%), respectively. The RORs (95%CI) for “abnormal behavior,” “hallucination,” “convulsion,” and “delirium” were 23.5 (21.3–25.8), 12.0 (10.7–13.6), 2.6 (2.2–3.0), and 13.3 (11.4–15.6), respectively. If the patient used oseltamivir, the lower limit of the ROR 95%CI for “abnormal behavior” was ≥1.

The adjusted RORs for “abnormal behavior” and “NPAEs” stratified by age and gender are summarized in Table 4. A likelihood ratio test was used to evaluate the effect of adding the term of oseltamivir* 10–19 years for abnormal behavior in male patients. Adding this interaction term had a statistically significant effect (p=0.0006). The adjusted ROR (95%CI) for “abnormal behavior” when considering oseltamivir* 10–19 years was 96.4 (77.5–119.9). When considering NPAEs, the likelihood ratio tests for oseltamivir* 0–9 years and oseltamivir* 10–19 years were also statistically significant (p<0.0001). The adjusted RORs (95%CI) for oseltamivir* 0–9 years and oseltamivir* 10–19 years were 10.7 (9.2–12.5) and 13.4 (11.0–16.3), respectively.

Table 4. Adjusted Reporting Odds Ratio for Abnormal Behavior and Neuropsychiatric Adverse Events

	Abnormal behavior			Neuropsychiatric adverse events (NPAEs)
	Likelihood ratio test	Adjusted RORa)	(95%CIb))	Likelihood ratio test	Adjusted ROR	(95%CI)
Male subgroup (N=887157)
Oseltamivir	<0.0001*	8.3	(6.1–11.4)	<0.0001*	2.3	(2.0–2.6)
Reporting year	<0.0001*	0.9	(0.9–0.9)	<0.0001*	0.9	(0.9–0.9)
AGE
0–9 years	<0.0001*	8.7	(8.2–9.3)	<0.0001*	1.8	(1.7–1.8)
10–19 years	<0.0001*	6.1	(5.7–6.5)	<0.0001*	1.6	(1.6–1.7)
Interaction term oseltamivir* AGE
Oseltamivir* 0–9 years	0.5751	80.8	(67.2–97.1)	<0.0001*	10.7	(9.2–12.5)
Oseltamivir* 10–19 years	0.0006*	96.4	(77.5–119.9)	<0.0001*	13.4	(11.0–16.3)
Oseltamivir* ≥20 years (as reference)		1.0			1.0
Female subgroup (N=1370745)
Oseltamivir	<0.0001*	8.5	(6.3–11.3)	<0.0001*	1.7	(1.5–1.9)
Reporting year	<0.0001*	0.9	(0.9–0.9)	<0.0001*	0.9	(0.9–0.9)
AGE
0–9 years	<0.0001*	7.6	(6.9–8.3)	<0.0001*	1.6	(1.5–1.6)
10–19 years	<0.0001*	4.0	(3.7–4.4)	<0.0001*	1.3	(1.2–1.3)
Interaction term oseltamivir* AGE
Oseltamivir* 0–9 years	0.2341	81.3	(63.6–103.9)	<0.0001*	8.3	(6.8–10.2)
Oseltamivir* 10–19 years	0.7107	37.7	(25.3–56.0)	<0.0001*	5.0	(3.8–6.5)
Oseltamivir* ≥20 years (as reference)		1.0			1.0

a) ROR: Reporting odds ratio. b) CI: Confidence interval. * Statistically significant.

Among female patients, the likelihood ratio test for “abnormal behavior” was not statistically significant. When considering NPAEs, the likelihood ratio tests using oseltamivir* 0–9 years and oseltamivir* 10–19 years were statistically significant (p<0.0001). The adjusted RORs (95%CI) for oseltamivir* 0–9 years and oseltamivir* 10–19 years were 8.3 (6.8–10.2) and 5.0 (3.8–6.5), respectively.

DISCUSSION

The ROR was developed to detect unexpected adverse events.¹⁴⁾ The ROR of “abnormal behavior” in Singapore, and Taiwan was ≥1 at 95%CI in Table 3. The ROR of Japan and Singapore were higher than those from other countries. Japan uses more than 75% of the oseltamivir manufactured.¹²⁾ Pediatric use of oseltamivir to treat influenza is higher in Japan than in the United States.¹⁰⁾ Thus, it is not surprising that most NPAE reports are from Japan. One plausible reason for this difference could be inflated numbers of spontaneous event reports due to “notoriety bias,” which was caused by media attention and publicity after regulatory action in Japan.²¹⁾ Genetic profile among Asian populations may reveal similarities, and the observation of NPAEs in Japanese patients treated with oseltamivir may be relevant in other Asian countries. Since prescribing oseltamivir has become more widespread, further epidemiological studies, such as case-control and follow-up studies, are necessary in Asian populations.

In Table 4, we demonstrated a possible relationship between oseltamivir use and “abnormal behavior” in male patients between the ages of 10 and 19 years using the adjusted ROR and logistic regression analysis. Previous reports using the FAERS database discussed only a small number of reported cases where abnormal behavior was increased by oseltamivir, as assessed using the RORs.³⁾ The ROR does not allow for the evaluation of comparative strength of causality and offers only a rough indication of the strength of the signal.²²⁾ The adjusted RORs were increased in male and female patients under the age of 20 years. As for “abnormal behavior,” the adjusted RORs for oseltamivir in the male patients aged 10–19 years had the highest values. The effects of the interaction terms for oseltamivir in the male patients aged 10–19 years were statistically significant, and the estimated values for this term in the logistic regression exceed 0. We refined the covariates for female patients the likelihood ratio test for “abnormal behavior” was not statistically significant in female patient. “Abnormal behavior” may not be influenced by oseltamivir in females.

In contrast, some NPAEs may be associated with oseltamivir use in both genders. This may be because the PTs for NPAEs were determined using the Japanese package insert for oseltamivir, which contains a number of symptoms related to “abnormal behavior” in clinical practices. Thus, it may be crucial to address NPAEs in a clinical setting among patients under 20 years of age.

Toovey et al. reported that the largest category of NPAEs in the FAERS database from 2007 to 2010 was abnormal behavior (25.3%).¹⁰⁾ NPAEs were also more common in children, representing 59.4% of adverse events in people under the age of 16 years.¹⁰⁾ Most NPAEs were reported in patients less than 20 years of age (Table 2). Our study supports previous observations that the FAERS database contains a disproportionately high number of reports involving NPAEs linked to oseltamivir.

The relationship between oseltamivir use and NPAEs is poorly understood, since similar NPAEs were observed in the absence of oseltamivir.^10,12,13) Influenza is associated with a variety of neurological and behavioral symptoms, including hallucinations, delirium, and abnormal behavior. These events may occur in the setting of encephalitis or encephalopathy.²³⁾

The risk of NPAEs associated with oseltamivir has been controversial, and has been predominantly indicated in case reports, but not in controlled studies and preclinical research. A number of publications suggested that there is no evidence, nor plausible mechanism of action, to link oseltamivir with NPAEs.^10,12,13) They concluded that the risk of abnormal behavior was increased by influenza, and not by oseltamivir use. Urushihara et al. reported that the number of abnormal behavior reports in Japan was consistently dependent on the size of the population treated with antivirals except for the reporting for oseltamivir in fiscal year 2007.⁸⁾ They considered that potential biases introduced in the spontaneous adverse events reporting system might be substantial, making results difficult to interpret.

An epidemiologic study was conducted in Japan in 2006–2007 to evaluate the relationship between oseltamivir and NPAEs.¹¹⁾ The research group also concluded that no positive associations were detected between oseltamivir and abnormal behaviors. In contrast, Yorifuji et al. disagreed and proposed correct analysis (based on the person-time approach) and recalculated the estimated crude rate ratio of 1.57 (95%CI 1.34–1.83).^7,24,25) Fujita et al. indicated a slightly increased risk of NPAEs in the cohort study.³⁾ Hoffman et al. reported that FAERS data suggest disproportionally elevated reporting of certain NPAEs linked to oseltamivir in 2013.⁴⁾ In 2014, members of the Cochrane Collaboration and others reported that NPAEs were increased in the combined on- and off-treatment periods in oseltamivir prophylaxis studies.^2,26) Against such a background, we provide new information to the on-going controversy regarding NPAEs related to oseltamivir. Despite the limitations, we hope these findings offer an update for clinicians.

As for possible mechanism of neuropsychiatric adverse events in patients treated with oseltamivir, one plausible mechanism of action might be based on an increase in the penetration rate of the active metabolite (oseltamivir carboxylate) from the plasma to the central nervous system (CNS). Toovey et al. indicated that the penetration into the CNS of both oseltamivir and active metabolite was low in adults, and that they were and no specific CNS/behavioral effects after administration of doses corresponding to>or=100 times the clinical dose in animal studies.¹²⁾ On the other hand, it has recently been reported that developmental changes in p-glycoprotein function in the blood brain barrier of rhesus monkeys using positron emission tomography (PET) with R-(11)C-oseltamivir, and this change may be closely related to the observed difference in drug responses in the brains of children and adult humans.²⁷⁾ Another group, using PET and autoradiography, radioactivity observed in the brains of infant, juvenile and adult rats after injection of [(11)C] oseltamivir.²⁸⁾ The highest radioactivity was found in the infant brain and the radioactivity level decreased with age.²⁸⁾ Furthermore, in acute encephalopathies and encephalitis, there is usually brain edema with evidence of damage to the blood brain barrier, which might be considered to cause an increase in the penetration of oseltamivir into the CNS.²⁹⁾ To the best of our knowledge, there have been no reports on the relationship between the concentrations of the active metabolite in the plasma (or in the CNS) and NPAEs in children. Wherever feasible, retrospective or prospective research using the data from oseltamivir clinical trials in children should be undertaken in the future.

We do not have a conclusive explanation for the gender difference in NPAEs in patients treated with oseltamivir. Hoshino et al. reported that no gender difference was noted in acute encephalopathy.³⁰⁾ Several reports suggest that in patients with attention deficit hyperactivity disorder (ADHD), boys are likely to be more hyperactive and impulsive and to have more comorbid externalizing disorder.^31,32) The objection will no doubt be raised that ADHD and NPAEs in patients treated with oseltamivir are different; however, the gender difference in ADHD might be a thought-provoking observation in the interpretation of our results.

Our disproportionality analysis has several limitations. Because of common errors within spontaneous reporting databases, such as reporting bias, the cases reported in the FAERS databases do not always contain sufficient information to properly evaluate an event. We partially mitigate the confounding factors using the logistic regression method. Potential signals of adverse events are likely to be small and difficult to detect. The marked under-reporting that is common in FAERS may have resulted in ROR being underestimated. Further, it might be difficult to evaluate causality between oseltamivir and NAPEs, since there is a lack of information on dose response or withdrawal in patients. Despite the limitations, our results indicate that oseltamivir influences “abnormal behavior” in male patients between the ages of 10 and 19 years. Furthermore, oseltamivir may influence NPAEs in patients of both genders under the age of 20 years. Thus, young male patients should be closely monitored for the occurrence of “abnormal behavior” or “NPAEs” when they are prescribed oseltamivir. We hope that these data will enhance the information available to clinicians and be useful for improving the management of influenza.

Acknowledgment

This research was partially supported by JSPS KAKENHI Grant Number, 24390126.

Conflict of Interest

JA is an employee of Medical Database. The rest of the authors have no conflict of interest.

REFERENCES

• 1) U.S. Department of Health and Human Services. “HHS pandemic influenza plan.2005.”: ‹http://www.flu.gov/planning-preparedness/federal/hhspandemicinfluenzaplan.pdf›, cited 17 March, 2015.
• 2) Jefferson T, Jones M, Doshi P, Spencer EA, Onakpoya I, Heneghan CJ. Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments. BMJ, 348 (apr09 2), g2545 (2014).
• 3) Fujita T, Fujii Y, Watanabe Y, Osaka H, Wada T, Mori M, Yokota S. A pharmacoepidemiologic study on the relationship between neuropsychiatric symptoms and therapeutic drugs after influenza infection. Jpn. J. Pharmacoepidemiol., 15, 73–95 (2010).
• 4) Hoffman KB, Demakas A, Erdman CB, Dimbil M, Doraiswamy PM. Neuropsychiatric adverse effects of oseltamivir in the FDA Adverse Event Reporting System, 1999–2012. BMJ, 347 (jul23 3), f4656 (2013).
• 5) Ho LN, Chung JP, Choy KL. Oseltamivir-induced mania in a patient with H1N1. Am. J. Psychiatry, 167, 350 (2010).
• 6) Chung S, Joung YS. Oseltamivir (tamiflu) induced depressive episode in a female adolescent. Psychiatry Investig., 7, 302–304 (2010).
• 7) Yorifuji T, Suzuki E, Tsuda T. Oseltamivir and abnormal behaviours: true or not? Epidemiology, 20, 619–621 (2009).
• 8) Urushihara H, Doi Y, Arai M, Matsunaga T, Fujii Y, Iino N, Kawamura T, Kawakami K. Oseltamivir prescription and regulatory actions vis-à-via abnormal behavior risk in Japan: drug utilization study using a nationwide pharmacy database. PLoS ONE, 6, e28483 (2011).
• 9) Jefferson T, Jones M, Doshi P, Del Mar C. Possible harms of oseltamivir—a call for urgent action. Lancet, 374, 1312–1313 (2009).
• 10) Toovey S, Prinssen EP, Rayner CR, Thakrar BT, Dutkowski R, Koerner A, Chu T, Sirzen-Zelenskaya A, Britschgi M, Bansod S, Donner B. Post-marketing assessment of neuropsychiatric adverse events in influenza patients treated with oseltamivir: an updated review. Adv. Ther., 29, 826–848 (2012).
• 11) Hirota Y. Survey research on the emergence of influenza-associated symptoms: 2007/2008 research subteam report. Research on evidence and methods for improving vaccine usefulness. MHLW Scientific Research Fund Pharmaceutical and Medical Device Regulatory Science Integrated Research Initiative, Tokyo (2009).
• 12) Toovey S, Rayner C, Prinssen E, Chu T, Donner B, Thakrar B, Dutkowski R, Hoffmann G, Breidenbach A, Lindemann L, Carey E, Boak L, Gieschke R, Sacks S, Solsky J, Small I, Reddy D. Assessment of neuropsychiatric adverse events in influenza patients treated with oseltamivir: a comprehensive review. Drug Saf., 31, 1097–1114 (2008).
• 13) Greene SK, Li L, Shay DK, Fry AM, Lee GM, Jacobsen SJ, Baxter R, Irving SA, Jackson ML, Naleway AL, Nordin JD, Narwaney KJ, Lieu TA. Risk of adverse events following oseltamivir treatment in influenza outpatients, Vaccine Safety Datalink Project, 2007–2010. Pharmacoepidemiol. Drug Saf., 22, 335–344 (2013).
• 14) Sakaeda T, Tamon A, Kadoyama K, Okuno Y. Data mining of the public version of the FDA Adverse Event Reporting System. Int. J. Med. Sci., 10, 796–803 (2013).
• 15) Egberts AC, Meyboom RH, van Puijenbroek EP. Use of measures of disproportionality in pharmacovigilance: three Dutch examples. Drug Saf., 25, 453–458 (2002).
• 16) Montastruc JL, Sommet A, Bagheri H, Lapeyre-Mestre M. Benefits and strengths of the disproportionality analysis for identification of adverse drug reactions in a pharmacovigilance database. Br. J. Clin. Pharmacol., 72, 905–908 (2011).
• 17) van Puijenbroek EP, Egberts AC, Heerdink ER, Leufkens HG. Detecting drug-drug interactions using a database for spontaneous adverse drug reactions: an example with diuretics and non-steroidal anti-inflammatory drugs. Eur. J. Clin. Pharmacol., 56, 733–738 (2000).
• 18) U.S. Food and Drug Administration. “FDA Adverse Event Reporting System.”: ‹http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/›, cited 18 March, 2015.
• 19) The Metabolomics Innovation Centre (TMIC). “DrugBank.”: ‹http://www.drugbank.ca/›, cited 18 March, 2015.
• 20) van Puijenbroek EP, van Grootheest K, Diemont WL, Leufkens HG, Egberts AC. Determinants of signal selection in a spontaneous reporting system for adverse drug reactions. Br. J. Clin. Pharmacol., 52, 579–586 (2001).
• 21) Pariente A, Gregoire F, Fourrier-Reglat A, Haramburu F, Moore N. Impact of safety alerts on measures of disproportionality in spontaneous reporting databases: the notoriety bias. Drug Saf., 30, 891–898 (2007).
• 22) Bate A, Evans SJ. Quantitative signal detection using spontaneous ADR reporting. Pharmacoepidemiol. Drug Saf., 18, 427–436 (2009).
• 23) Morishima T, Togashi T, Yokota S, Okuno Y, Miyazaki C, Tashiro M, Okabe N, Collaborative Study Group on Influenza-Associated Encephalopathy in Japan. Encephalitis and encephalopathy associated with an influenza epidemic in Japan. Clin. Infect. Dis., 35, 512–517 (2002).
• 24) Yorifuji T, Suzuki E, Tsuda T. Oseltamivir and abnormal behavior: the author respond. Epidemiology, 21, 916 (2010).
• 25) Peng MM, Robinson NJ. Oseltamivir and abnormal behavior: to the Editors. Epidemiology, 21, 915–916 (2010).
• 26) Jefferson T, Jones MA, Doshi P, Del Mar CB, Hama R, Thompson MJ, Spencer EA, Onakpoya IJ, Mahtani KR, Nunan D, Howick J, Heneghan CJ. Neuraminidase inhibitors for preventing and treating influenza in adults and children. issue 4, The Cochrane Library, John Wiley & Sons, Ltd., New Jersey (2014).
• 27) Takashima T, Yokoyama C, Mizuma H, Yamanaka H, Wada Y, Onoe K, Nagata H, Tazawa S, Doi H, Takahashi K, Morita M, Kanai M, Shibasaki M, Kusuhara H, Sugiyama Y, Onoe H, Watanabe Y. Developmental changes in P-glycoprotein function in the blood-brain barrier of nonhuman primates: PET study with R-11C-verapamil and 11C-oseltamivir. J. Nucl. Med., 52, 950–957 (2011).
• 28) Hatori A, Yui J, Yanamoto K, Yamasaki T, Kawamura K, Takei M, Arai T, Fukumura T, Zhang MR. Determination of radioactivity in infant, juvenile and adult rat brains after injection of anti-influenza drug [¹¹C]oseltamivir using PET and autoradiography. Neurosci. Lett., 495, 187–191 (2011).
• 29) Nakai Y, Itoh M, Mizuguchi M, Ozawa H, Okazaki E, Kobayashi Y, Takahashi M, Ohtani K, Ogawa A, Narita M, Togashi T, Takashima S. Apoptosis and microglial activation in influenza encephalopathy. Acta Neuropathol., 105, 233–239 (2003).
• 30) Hoshino A, Saitoh M, Oka A, Okumura A, Kubota M, Saito Y, Takanashi J, Hirose S, Yamagata T, Yamanouchi H, Mizuguchi M. Epidemiology of acute encephalopathy in Japan, with emphasis on the association of viruses and syndromes. Brain Dev., 34, 337–343 (2012).
• 31) Hasson R, Fine JG. Gender differences among children with ADHD on continuous performance tests: a meta-analytic review. J. Atten. Disord., 16, 190–198 (2012).
• 32) Gaub M, Carlson CL. Gender differences in ADHD: a meta-analysis and critical review. J. Am. Acad. Child Adolesc. Psychiatry, 36, 1036–1045 (1997).