The Safety of Oseltamivir in Patients with Influenza: Analysis of Healthcare Claims Data from Six Influenza Seasons

William A. Blumentals, PhD; Xue Song, PhD

October 30, 2007

Abstract

Context: Recently, neuropsychiatric events associated with oseltamivir treatment have been reported, mainly in pediatric patients in Japan.
Objective: To explore the influence of oseltamivir treatment on central nervous system (CNS)-related and neuropsychiatric events in adults, children, and adolescents with influenza.
Design: A retrospective cohort study using propensity-matched data for 6 influenza seasons (2000-2006).
Setting: Claims data were obtained from the Thomson Healthcare MarketScan Research Database.
Patients: Patients of all ages and in subgroups aged 12 years or younger, 13-17 years, and 18-49 years diagnosed with influenza.
Main Outcome Measures: Claims for CNS and neuropsychiatric events within 14 and 30 days following influenza diagnosis were compared between patients prescribed oseltamivir and those not prescribed antiviral treatment.
Results: Data for 40,704 patients prescribed oseltamivir (9599 aged 12 years or younger; 4615, 13-17 years; and 16,910, 18-49 years) and 40,704 matched controls (9599 aged 12 years or younger; 4621, 13-17 years; and 16,898, 18-49 years) were analyzed. None of the CNS-related and neuropsychiatric events was more likely to occur in patients prescribed oseltamivir. Overall, CNS-related or neuropsychiatric events (odds ratio [OR] 0.76; 95% confidence intervals [CI]: 0.68, 0.84), psychiatric events (OR 0.82; 95% CI: 0.70, 0.96), and disturbances of consciousness (OR 0.61; 95% CI: 0.48, 0.76) within 14 days after influenza diagnosis were all less likely in patients given oseltamivir. Findings were similar within the 30-day post-index time window and across all age groups.
Conclusions: No increase in CNS-related and neuropsychiatric events was observed in adults, children, or adolescents with influenza who were prescribed oseltamivir in this study.

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International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] Codes for Central Nervous System and Neuropsychiatric Outcomes
Outcome	Diagnosis	ICD-9-CM Code
Psychiatric	Drug-induced psychotic disorders	292.1x
	Pathologic drug intoxication	292.2x
	Other specified drug-induced mental disorders	292.8x
	Unspecified drug-induced mental disorder	292.9
	Transient organic psychotic conditions (delirium, delusion, psychosis)	293.xx
	Acute schizophrenia	295.0x, 295.1x, 295.3x, 295.8x
	Schizophreniform disorder	295.4x
	Other specified episodic mood disorder (mood swings)	296.99
	Other nonorganic psychoses	298.xx
	Anxiety states	300.0x
	Predominant disturbance of emotions	308.0x
	Adjustment reaction	309.xx
	Depressive disorder, not elsewhere classified	311.xx
	Disturbance of emotions specific to childhood and adolescence	313.0x
	Suicide and self-inflicted injury	E950.x-E959.x
Encephalitis	Other encephalitis due to infection classified elsewhere	323.4x
	Post-infectious encephalitis	323.6x
	Other causes of encephalitis	323.8x
	Unspecified cause of encephalitis	323.9x
Disturbance of consciousness	Organic insomnia	327.0x
	Organic hypersomnolence	327.1x
	Alteration of consciousness	780.0x
	Hallucinations	780.1x
	Syncope and collapse	780.2x
	Dizziness and giddiness	780.4x
	Other hypersomnia	780.54
Movement disorder	Abnormal involuntary movements	781.0x
Seizure	Epilepsy	345.xx
Seizure	Convulsions	780.3x
Stroke	Subarachnoid hemorrhage	430.xx
	Intracerebral hemorrhage	431.xx
	Other and unspecified intracranial hemorrhage	432.xx
	Occlusion and stenosis of precerebral arteries	433.xx
	Occlusion of cerebral arteries	434.xx
	Transient cerebral ischemia	435.xx
	Acute, but ill-defined, cerebrovascular disease	436.xx
	Other and ill-defined cerebrovascular disease	437.xx
	Late effects of cerebrovascular disease	438.xx
Other	Dysfunctions of sleep stages (nightmares)	307.47
	Visual disturbances	368.xx
	Insomnia not otherwise specified	780.52
	Taste disturbance	781.1x
	Other symptoms involving nervous and musculoskeletal systems	781.99
	Headache	784.0x

Demographic Characteristics of Patients
Characteristic	Treated (Oseltamivir)		Controls (No Antiviral)
	N = 40,704		N = 40,704
	N	% of Total	N	% of Total
Gender
Male	18,276	44.9	18,275	44.9
Female	22,428	55.1	22,429	55.1
Age group (y)
≤ 12	9599	23.6	9599	23.6
13-17	4615	11.3	4621	11.3
18-49	16,910	41.5	16,898	41.5
50-64	7832	19.2	7830	19.2
65-74	1012	2.5	1008	2.5
75-84	609	1.5	609	1.5
≥ 85	127	0.3	139	0.3
Mean age (SD)	32 (20.47)		32 (20.55)
Geographic region
Northeast	2413	5.9	2439	6.0
North Central	11,058	27.2	11,046	27.1
South	24,587	60.4	24,600	60.4
West	2646	6.5	2619	6.4
Influenza season
2000-2001	2569	6.3	2569	6.3
2001-2002	3762	9.2	3762	9.2
2002-2003	4409	10.8	4409	10.8
2003-2004	9181	22.6	9181	22.6
2004-2005	12,537	30.8	12,537	30.8
2005-2006	8246	20.3	8246	20.3
Payer
Commercial	38,931	95.6	38,931	95.6
Medicare	1773	4.4	1773	4.4

SD = standard deviation

Demographic Characteristics of Patients
Characteristic	Treated (Oseltamivir)		Controls (No Antiviral)
	N = 40,704		N = 40,704
	N	% of Total	N	% of Total
Gender
Male	18,276	44.9	18,275	44.9
Female	22,428	55.1	22,429	55.1
Age group (y)
≤ 12	9599	23.6	9599	23.6
13-17	4615	11.3	4621	11.3
18-49	16,910	41.5	16,898	41.5
50-64	7832	19.2	7830	19.2
65-74	1012	2.5	1008	2.5
75-84	609	1.5	609	1.5
≥ 85	127	0.3	139	0.3
Mean age (SD)	32 (20.47)		32 (20.55)
Geographic region
Northeast	2413	5.9	2439	6.0
North Central	11,058	27.2	11,046	27.1
South	24,587	60.4	24,600	60.4
West	2646	6.5	2619	6.4
Influenza season
2000-2001	2569	6.3	2569	6.3
2001-2002	3762	9.2	3762	9.2
2002-2003	4409	10.8	4409	10.8
2003-2004	9181	22.6	9181	22.6
2004-2005	12,537	30.8	12,537	30.8
2005-2006	8246	20.3	8246	20.3
Payer
Commercial	38,931	95.6	38,931	95.6
Medicare	1773	4.4	1773	4.4

SD = standard deviation

Demographic Characteristics of Patients
Characteristic	Treated (Oseltamivir)		Controls (No Antiviral)
	N = 40,704		N = 40,704
	N	% of Total	N	% of Total
Gender
Male	18,276	44.9	18,275	44.9
Female	22,428	55.1	22,429	55.1
Age group (y)
≤ 12	9599	23.6	9599	23.6
13-17	4615	11.3	4621	11.3
18-49	16,910	41.5	16,898	41.5
50-64	7832	19.2	7830	19.2
65-74	1012	2.5	1008	2.5
75-84	609	1.5	609	1.5
≥ 85	127	0.3	139	0.3
Mean age (SD)	32 (20.47)		32 (20.55)
Geographic region
Northeast	2413	5.9	2439	6.0
North Central	11,058	27.2	11,046	27.1
South	24,587	60.4	24,600	60.4
West	2646	6.5	2619	6.4
Influenza season
2000-2001	2569	6.3	2569	6.3
2001-2002	3762	9.2	3762	9.2
2002-2003	4409	10.8	4409	10.8
2003-2004	9181	22.6	9181	22.6
2004-2005	12,537	30.8	12,537	30.8
2005-2006	8246	20.3	8246	20.3
Payer
Commercial	38,931	95.6	38,931	95.6
Medicare	1773	4.4	1773	4.4

SD = standard deviation

Medical Histories of Patients Included in the Safety Outcomes Analysis
Medical History	Treated (Oseltamivir)		Controls (No Antiviral)
	N = 40,704		N = 40,704
	N	% of Total	N	% of Total	P Value
Asthma	2009	4.9%	2,084	5.1%	.229
Congestive heart failure	213	0.5%	245	0.6%	.134
Chronic obstructive pulmonary disease	454	1.1%	563	1.4%	.001
Cystic fibrosis	4	0.0%	8	0.0%	.248
Diabetes	1540	3.8%	1,587	3.9%	.391
Emphysema	34	0.1%	53	0.1%	.042
Immunocompromised^*	⁹⁹⁴	^2.4%	⁸⁷⁵	^2.1%	^.005
^{Acute myocardial infarction}	⁵⁶	^0.1%	⁶⁶	^0.2%	^.365
^{Prior respiratory therapy}	⁶⁵⁵⁴	^16.1%	^6,384	^15.7%	^.103
^{Prior oxygen therapy}	²⁶⁷	^0.7%	³⁴¹	^0.8%	^.003
^{Prior respiratory diagnoses}	^20,536	^50.5%	^20,470	^50.3%	^.644
^{Prior pneumonia}	⁸⁸⁰	^2.2%	⁹⁹⁰	^2.4%	^.010
^{Renal disease}	¹⁰⁴	^2.2%	¹²¹	^2.4%	^.010
^{All CNS and neuropsychiatric diagnoses}	⁵⁵¹⁶	^13.6%	⁶¹⁵⁵	^15.1%	^.000
^Psychiatric	²¹⁹⁸	^5.9%	²⁴¹⁶	^5.4%	^.001
^Encephalitis	⁸	^0.0%	⁶	^0.0%	^.593
^{Disturbance of consciousness}	¹¹⁷⁴	^2.9%	¹³⁷⁴	^3.4%	^.000
^{Movement disorder}	⁶⁸	^0.2%	⁸⁶	^0.2%	^.147
^Seizure	³²⁰	^0.8%	⁴⁰⁸	^1.0%	^.001
^Stroke	³⁷⁸	^0.9%	⁴²⁹	^1.1%	^.071
^{Other CNS and neuropsychiatric diagnoses}	²²⁶⁰	^5.6%	²⁵⁵⁵	^6.3%	^.000
^{Influenza test on or before index date}	^11,552	^0.3%	^6,465	^0.3%	^.347
^{Vaccination before index date}	¹⁷⁴⁵	^28.4%	¹⁷⁴³	^15.9%	^.000
	^{Mean (SD)}		^{Mean (SD)}		^{P Value}
^{Charlson Comorbidity Index}	^{0.38 (0.73)}		^{0.36 (0.71)}		^.009
^{Baseline healthcare expenditures ($)}	^{3574 (2711)}		^{3756 (3309)}		^.000

Medical Histories of Patients Included in the Safety Outcomes Analysis
Medical History	Treated (Oseltamivir)		Controls (No Antiviral)
	N = 40,704		N = 40,704
	N	% of Total	N	% of Total	P Value
Asthma	2009	4.9%	2,084	5.1%	.229
Congestive heart failure	213	0.5%	245	0.6%	.134
Chronic obstructive pulmonary disease	454	1.1%	563	1.4%	.001
Cystic fibrosis	4	0.0%	8	0.0%	.248
Diabetes	1540	3.8%	1,587	3.9%	.391
Emphysema	34	0.1%	53	0.1%	.042
Immunocompromised^*	⁹⁹⁴	^2.4%	⁸⁷⁵	^2.1%	^.005
^{Acute myocardial infarction}	⁵⁶	^0.1%	⁶⁶	^0.2%	^.365
^{Prior respiratory therapy}	⁶⁵⁵⁴	^16.1%	^6,384	^15.7%	^.103
^{Prior oxygen therapy}	²⁶⁷	^0.7%	³⁴¹	^0.8%	^.003
^{Prior respiratory diagnoses}	^20,536	^50.5%	^20,470	^50.3%	^.644
^{Prior pneumonia}	⁸⁸⁰	^2.2%	⁹⁹⁰	^2.4%	^.010
^{Renal disease}	¹⁰⁴	^2.2%	¹²¹	^2.4%	^.010
^{All CNS and neuropsychiatric diagnoses}	⁵⁵¹⁶	^13.6%	⁶¹⁵⁵	^15.1%	^.000
^Psychiatric	²¹⁹⁸	^5.9%	²⁴¹⁶	^5.4%	^.001
^Encephalitis	⁸	^0.0%	⁶	^0.0%	^.593
^{Disturbance of consciousness}	¹¹⁷⁴	^2.9%	¹³⁷⁴	^3.4%	^.000
^{Movement disorder}	⁶⁸	^0.2%	⁸⁶	^0.2%	^.147
^Seizure	³²⁰	^0.8%	⁴⁰⁸	^1.0%	^.001
^Stroke	³⁷⁸	^0.9%	⁴²⁹	^1.1%	^.071
^{Other CNS and neuropsychiatric diagnoses}	²²⁶⁰	^5.6%	²⁵⁵⁵	^6.3%	^.000
^{Influenza test on or before index date}	^11,552	^0.3%	^6,465	^0.3%	^.347
^{Vaccination before index date}	¹⁷⁴⁵	^28.4%	¹⁷⁴³	^15.9%	^.000
	^{Mean (SD)}		^{Mean (SD)}		^{P Value}
^{Charlson Comorbidity Index}	^{0.38 (0.73)}		^{0.36 (0.71)}		^.009
^{Baseline healthcare expenditures ($)}	^{3574 (2711)}		^{3756 (3309)}		^.000

Medical Histories of Patients Included in the Safety Outcomes Analysis
Medical History	Treated (Oseltamivir)		Controls (No Antiviral)
	N = 40,704		N = 40,704
	N	% of Total	N	% of Total	P Value
Asthma	2009	4.9%	2,084	5.1%	.229
Congestive heart failure	213	0.5%	245	0.6%	.134
Chronic obstructive pulmonary disease	454	1.1%	563	1.4%	.001
Cystic fibrosis	4	0.0%	8	0.0%	.248
Diabetes	1540	3.8%	1,587	3.9%	.391
Emphysema	34	0.1%	53	0.1%	.042
Immunocompromised^*	⁹⁹⁴	^2.4%	⁸⁷⁵	^2.1%	^.005
^{Acute myocardial infarction}	⁵⁶	^0.1%	⁶⁶	^0.2%	^.365
^{Prior respiratory therapy}	⁶⁵⁵⁴	^16.1%	^6,384	^15.7%	^.103
^{Prior oxygen therapy}	²⁶⁷	^0.7%	³⁴¹	^0.8%	^.003
^{Prior respiratory diagnoses}	^20,536	^50.5%	^20,470	^50.3%	^.644
^{Prior pneumonia}	⁸⁸⁰	^2.2%	⁹⁹⁰	^2.4%	^.010
^{Renal disease}	¹⁰⁴	^2.2%	¹²¹	^2.4%	^.010
^{All CNS and neuropsychiatric diagnoses}	⁵⁵¹⁶	^13.6%	⁶¹⁵⁵	^15.1%	^.000
^Psychiatric	²¹⁹⁸	^5.9%	²⁴¹⁶	^5.4%	^.001
^Encephalitis	⁸	^0.0%	⁶	^0.0%	^.593
^{Disturbance of consciousness}	¹¹⁷⁴	^2.9%	¹³⁷⁴	^3.4%	^.000
^{Movement disorder}	⁶⁸	^0.2%	⁸⁶	^0.2%	^.147
^Seizure	³²⁰	^0.8%	⁴⁰⁸	^1.0%	^.001
^Stroke	³⁷⁸	^0.9%	⁴²⁹	^1.1%	^.071
^{Other CNS and neuropsychiatric diagnoses}	²²⁶⁰	^5.6%	²⁵⁵⁵	^6.3%	^.000
^{Influenza test on or before index date}	^11,552	^0.3%	^6,465	^0.3%	^.347
^{Vaccination before index date}	¹⁷⁴⁵	^28.4%	¹⁷⁴³	^15.9%	^.000
	^{Mean (SD)}		^{Mean (SD)}		^{P Value}
^{Charlson Comorbidity Index}	^{0.38 (0.73)}		^{0.36 (0.71)}		^.009
^{Baseline healthcare expenditures ($)}	^{3574 (2711)}		^{3756 (3309)}		^.000

Medical Histories of Patients Included in the Safety Outcomes Analysis
Medical History	Treated (Oseltamivir)		Controls (No Antiviral)
	N = 40,704		N = 40,704
	N	% of Total	N	% of Total	P Value
Asthma	2009	4.9%	2,084	5.1%	.229
Congestive heart failure	213	0.5%	245	0.6%	.134
Chronic obstructive pulmonary disease	454	1.1%	563	1.4%	.001
Cystic fibrosis	4	0.0%	8	0.0%	.248
Diabetes	1540	3.8%	1,587	3.9%	.391
Emphysema	34	0.1%	53	0.1%	.042
Immunocompromised^*	⁹⁹⁴	^2.4%	⁸⁷⁵	^2.1%	^.005
^{Acute myocardial infarction}	⁵⁶	^0.1%	⁶⁶	^0.2%	^.365
^{Prior respiratory therapy}	⁶⁵⁵⁴	^16.1%	^6,384	^15.7%	^.103
^{Prior oxygen therapy}	²⁶⁷	^0.7%	³⁴¹	^0.8%	^.003
^{Prior respiratory diagnoses}	^20,536	^50.5%	^20,470	^50.3%	^.644
^{Prior pneumonia}	⁸⁸⁰	^2.2%	⁹⁹⁰	^2.4%	^.010
^{Renal disease}	¹⁰⁴	^2.2%	¹²¹	^2.4%	^.010
^{All CNS and neuropsychiatric diagnoses}	⁵⁵¹⁶	^13.6%	⁶¹⁵⁵	^15.1%	^.000
^Psychiatric	²¹⁹⁸	^5.9%	²⁴¹⁶	^5.4%	^.001
^Encephalitis	⁸	^0.0%	⁶	^0.0%	^.593
^{Disturbance of consciousness}	¹¹⁷⁴	^2.9%	¹³⁷⁴	^3.4%	^.000
^{Movement disorder}	⁶⁸	^0.2%	⁸⁶	^0.2%	^.147
^Seizure	³²⁰	^0.8%	⁴⁰⁸	^1.0%	^.001
^Stroke	³⁷⁸	^0.9%	⁴²⁹	^1.1%	^.071
^{Other CNS and neuropsychiatric diagnoses}	²²⁶⁰	^5.6%	²⁵⁵⁵	^6.3%	^.000
^{Influenza test on or before index date}	^11,552	^0.3%	^6,465	^0.3%	^.347
^{Vaccination before index date}	¹⁷⁴⁵	^28.4%	¹⁷⁴³	^15.9%	^.000
	^{Mean (SD)}		^{Mean (SD)}		^{P Value}
^{Charlson Comorbidity Index}	^{0.38 (0.73)}		^{0.36 (0.71)}		^.009
^{Baseline healthcare expenditures ($)}	^{3574 (2711)}		^{3756 (3309)}		^.000

Medical Histories of Patients Included in the Safety Outcomes Analysis
Medical History	Treated (Oseltamivir)		Controls (No Antiviral)
	N = 40,704		N = 40,704
	N	% of Total	N	% of Total	P Value
Asthma	2009	4.9%	2,084	5.1%	.229
Congestive heart failure	213	0.5%	245	0.6%	.134
Chronic obstructive pulmonary disease	454	1.1%	563	1.4%	.001
Cystic fibrosis	4	0.0%	8	0.0%	.248
Diabetes	1540	3.8%	1,587	3.9%	.391
Emphysema	34	0.1%	53	0.1%	.042
Immunocompromised^*	⁹⁹⁴	^2.4%	⁸⁷⁵	^2.1%	^.005
^{Acute myocardial infarction}	⁵⁶	^0.1%	⁶⁶	^0.2%	^.365
^{Prior respiratory therapy}	⁶⁵⁵⁴	^16.1%	^6,384	^15.7%	^.103
^{Prior oxygen therapy}	²⁶⁷	^0.7%	³⁴¹	^0.8%	^.003
^{Prior respiratory diagnoses}	^20,536	^50.5%	^20,470	^50.3%	^.644
^{Prior pneumonia}	⁸⁸⁰	^2.2%	⁹⁹⁰	^2.4%	^.010
^{Renal disease}	¹⁰⁴	^2.2%	¹²¹	^2.4%	^.010
^{All CNS and neuropsychiatric diagnoses}	⁵⁵¹⁶	^13.6%	⁶¹⁵⁵	^15.1%	^.000
^Psychiatric	²¹⁹⁸	^5.9%	²⁴¹⁶	^5.4%	^.001
^Encephalitis	⁸	^0.0%	⁶	^0.0%	^.593
^{Disturbance of consciousness}	¹¹⁷⁴	^2.9%	¹³⁷⁴	^3.4%	^.000
^{Movement disorder}	⁶⁸	^0.2%	⁸⁶	^0.2%	^.147
^Seizure	³²⁰	^0.8%	⁴⁰⁸	^1.0%	^.001
^Stroke	³⁷⁸	^0.9%	⁴²⁹	^1.1%	^.071
^{Other CNS and neuropsychiatric diagnoses}	²²⁶⁰	^5.6%	²⁵⁵⁵	^6.3%	^.000
^{Influenza test on or before index date}	^11,552	^0.3%	^6,465	^0.3%	^.347
^{Vaccination before index date}	¹⁷⁴⁵	^28.4%	¹⁷⁴³	^15.9%	^.000
	^{Mean (SD)}		^{Mean (SD)}		^{P Value}
^{Charlson Comorbidity Index}	^{0.38 (0.73)}		^{0.36 (0.71)}		^.009
^{Baseline healthcare expenditures ($)}	^{3574 (2711)}		^{3756 (3309)}		^.000

Central Nervous System-Related and Neuropsychiatric Events Within 14 and 30 Days After the Index Date in all Patients and in Children (aged ≤ 12 years), Adolescents (aged 13-17 years), and Adults (Aged 18-49 years)
Outcome	All Patients		Patients Aged ≤ 12 Years		Patients Aged 13-17 Years		Patients Aged 18-49 Years
	Treated (Oseltamivir)	Controls (No Antiviral)	Treated (Oseltamivir)	Controls (No Antiviral)	Treated (Oseltamivir)	Controls (No Antiviral)	Treated (Oseltamivir)	Controls (No Antiviral)
	N (%)	N (%)	N (%)	N (%)	N (%)	N (%)	N (%)	N (%)
Within 14 days of index date
CNS and neuropsychiatric	694 (1.7)	968 (2.4)*	79 (0.8)	107 (1.1)^‡	71 (1.5)	106 (2.3)^†	335 (2.0)	460 (2.7)*
Psychiatric	293 (0.7)	379 (0.9)*	31 (0.3)	51 (0.5)^‡	41 (0.9)	62 (1.3)^‡	155 (0.9)	172 (1.0)
Encephalitis	1 (<0.1)	2 (<0.1)	0 (0)	0 (0)	0 (0)	0 (0)	1 (<0.1)	0 (0)
Disturbances of consciousness	124 (0.3)	219 (0.5)*	4 (<0.1)	9 (0.1)	9 (0.2)	16 (0.3)	63 (0.4)	98 (0.6)^†
Movement	4 (<0.1)	10 (<0.1)	1 (<0.1)	1 (<0.1)	0 (0)	1 (<0.1)	3 (<0.1)	3 (<0.1)
Seizure	53 (0.1)	72 (0.2)	27 (0.3)	25 (0.3)	1 (<0.1)	18 (0.1)	18 (0.1)	28 (0.2)
Stroke	30 (0.1)	45 (0.1)	0 (0)	0 (0)	0 (0)	0 (0)	6 (<0.1)	4 (<0.1)
Other	224 (0.6)	298 (0.7)^†	16 (0.2)	24 (0.3)	22 (0.5)	47 (0.3)	113 (0.7)	179 (1.1)*
Within 30 days of index date
CNS and neuropsychiatric	1082 (2.7)	1412 (3.5)*	126 (1.3)	158 (1.6)	122 (2.6)	158 (3.4)^‡	506 (3.0)	673 (4.0)*
Psychiatric	502 (1.2)	587 (1.4)^†	54 (0.6)	74 (0.8)	73 (1.6)	96 (2.1)	262 (1.5)	282 (1.7)
Encephalitis	1 (<0.1)	2 (<0.1)	0 (0)	0 (0)	0 (0)	0 (0)	1 (<0.1)	0 (0)
Disturbances of consciousness	175 (0.4)	293 (0.7)*	7 (0.1)	14 (0.1)	15 (0.3)	20 (0.4)	88 (0.5)	125 (0.7)^‡
Movement	6 (<0.1)	15 (<0.1)^‡	1 (<0.1)	1 (<0.1)	1 (<0.1)	1 (<0.1)	4 (<0.1)	6 (<0.1)
Seizure	73 (0.2)	108 (0.3)^†	35 (0.4)	39 (0.4)	3 (0.1)	6 (0.1)	23 (0.1)	43 (0.6)^‡
Stroke	53 (0.1)	79 (0.2)^‡	0 (0)	1 (<0.1)	0 (0)	1 (<0.1)	9 (0.1)	10 (0.1)
Other	336 (0.8)	436 (1.1)*	30 (0.3)	34 (0.4)	37 (0.8)	41 (0.9)	158 (0.9)	248 (1.5)*

Shaded values were significantly lower in the oseltamivir groups than in the control groups (chi-square tests); *P < .001; ^† P < .01; ^‡ P < .05

Central Nervous System-Related and Neuropsychiatric Events Within 14 and 30 Days After the Index Date in all Patients and in Children (aged ≤ 12 years), Adolescents (aged 13-17 years), and Adults (Aged 18-49 years)
Outcome	All Patients		Patients Aged ≤ 12 Years		Patients Aged 13-17 Years		Patients Aged 18-49 Years
	Treated (Oseltamivir)	Controls (No Antiviral)	Treated (Oseltamivir)	Controls (No Antiviral)	Treated (Oseltamivir)	Controls (No Antiviral)	Treated (Oseltamivir)	Controls (No Antiviral)
	N (%)	N (%)	N (%)	N (%)	N (%)	N (%)	N (%)	N (%)
Within 14 days of index date
CNS and neuropsychiatric	694 (1.7)	968 (2.4)*	79 (0.8)	107 (1.1)^‡	71 (1.5)	106 (2.3)^†	335 (2.0)	460 (2.7)*
Psychiatric	293 (0.7)	379 (0.9)*	31 (0.3)	51 (0.5)^‡	41 (0.9)	62 (1.3)^‡	155 (0.9)	172 (1.0)
Encephalitis	1 (<0.1)	2 (<0.1)	0 (0)	0 (0)	0 (0)	0 (0)	1 (<0.1)	0 (0)
Disturbances of consciousness	124 (0.3)	219 (0.5)*	4 (<0.1)	9 (0.1)	9 (0.2)	16 (0.3)	63 (0.4)	98 (0.6)^†
Movement	4 (<0.1)	10 (<0.1)	1 (<0.1)	1 (<0.1)	0 (0)	1 (<0.1)	3 (<0.1)	3 (<0.1)
Seizure	53 (0.1)	72 (0.2)	27 (0.3)	25 (0.3)	1 (<0.1)	18 (0.1)	18 (0.1)	28 (0.2)
Stroke	30 (0.1)	45 (0.1)	0 (0)	0 (0)	0 (0)	0 (0)	6 (<0.1)	4 (<0.1)
Other	224 (0.6)	298 (0.7)^†	16 (0.2)	24 (0.3)	22 (0.5)	47 (0.3)	113 (0.7)	179 (1.1)*
Within 30 days of index date
CNS and neuropsychiatric	1082 (2.7)	1412 (3.5)*	126 (1.3)	158 (1.6)	122 (2.6)	158 (3.4)^‡	506 (3.0)	673 (4.0)*
Psychiatric	502 (1.2)	587 (1.4)^†	54 (0.6)	74 (0.8)	73 (1.6)	96 (2.1)	262 (1.5)	282 (1.7)
Encephalitis	1 (<0.1)	2 (<0.1)	0 (0)	0 (0)	0 (0)	0 (0)	1 (<0.1)	0 (0)
Disturbances of consciousness	175 (0.4)	293 (0.7)*	7 (0.1)	14 (0.1)	15 (0.3)	20 (0.4)	88 (0.5)	125 (0.7)^‡
Movement	6 (<0.1)	15 (<0.1)^‡	1 (<0.1)	1 (<0.1)	1 (<0.1)	1 (<0.1)	4 (<0.1)	6 (<0.1)
Seizure	73 (0.2)	108 (0.3)^†	35 (0.4)	39 (0.4)	3 (0.1)	6 (0.1)	23 (0.1)	43 (0.6)^‡
Stroke	53 (0.1)	79 (0.2)^‡	0 (0)	1 (<0.1)	0 (0)	1 (<0.1)	9 (0.1)	10 (0.1)
Other	336 (0.8)	436 (1.1)*	30 (0.3)	34 (0.4)	37 (0.8)	41 (0.9)	158 (0.9)	248 (1.5)*

Shaded values were significantly lower in the oseltamivir groups than in the control groups (chi-square tests); *P < .001; ^† P < .01; ^‡ P < .05

Central Nervous System-Related and Neuropsychiatric Events Within 14 and 30 Days After the Index Date in all Patients and in Children (aged ≤ 12 years), Adolescents (aged 13-17 years), and Adults (Aged 18-49 years)
Outcome	All Patients		Patients Aged ≤ 12 Years		Patients Aged 13-17 Years		Patients Aged 18-49 Years
	Treated (Oseltamivir)	Controls (No Antiviral)	Treated (Oseltamivir)	Controls (No Antiviral)	Treated (Oseltamivir)	Controls (No Antiviral)	Treated (Oseltamivir)	Controls (No Antiviral)
	N (%)	N (%)	N (%)	N (%)	N (%)	N (%)	N (%)	N (%)
Within 14 days of index date
CNS and neuropsychiatric	694 (1.7)	968 (2.4)*	79 (0.8)	107 (1.1)^‡	71 (1.5)	106 (2.3)^†	335 (2.0)	460 (2.7)*
Psychiatric	293 (0.7)	379 (0.9)*	31 (0.3)	51 (0.5)^‡	41 (0.9)	62 (1.3)^‡	155 (0.9)	172 (1.0)
Encephalitis	1 (<0.1)	2 (<0.1)	0 (0)	0 (0)	0 (0)	0 (0)	1 (<0.1)	0 (0)
Disturbances of consciousness	124 (0.3)	219 (0.5)*	4 (<0.1)	9 (0.1)	9 (0.2)	16 (0.3)	63 (0.4)	98 (0.6)^†
Movement	4 (<0.1)	10 (<0.1)	1 (<0.1)	1 (<0.1)	0 (0)	1 (<0.1)	3 (<0.1)	3 (<0.1)
Seizure	53 (0.1)	72 (0.2)	27 (0.3)	25 (0.3)	1 (<0.1)	18 (0.1)	18 (0.1)	28 (0.2)
Stroke	30 (0.1)	45 (0.1)	0 (0)	0 (0)	0 (0)	0 (0)	6 (<0.1)	4 (<0.1)
Other	224 (0.6)	298 (0.7)^†	16 (0.2)	24 (0.3)	22 (0.5)	47 (0.3)	113 (0.7)	179 (1.1)*
Within 30 days of index date
CNS and neuropsychiatric	1082 (2.7)	1412 (3.5)*	126 (1.3)	158 (1.6)	122 (2.6)	158 (3.4)^‡	506 (3.0)	673 (4.0)*
Psychiatric	502 (1.2)	587 (1.4)^†	54 (0.6)	74 (0.8)	73 (1.6)	96 (2.1)	262 (1.5)	282 (1.7)
Encephalitis	1 (<0.1)	2 (<0.1)	0 (0)	0 (0)	0 (0)	0 (0)	1 (<0.1)	0 (0)
Disturbances of consciousness	175 (0.4)	293 (0.7)*	7 (0.1)	14 (0.1)	15 (0.3)	20 (0.4)	88 (0.5)	125 (0.7)^‡
Movement	6 (<0.1)	15 (<0.1)^‡	1 (<0.1)	1 (<0.1)	1 (<0.1)	1 (<0.1)	4 (<0.1)	6 (<0.1)
Seizure	73 (0.2)	108 (0.3)^†	35 (0.4)	39 (0.4)	3 (0.1)	6 (0.1)	23 (0.1)	43 (0.6)^‡
Stroke	53 (0.1)	79 (0.2)^‡	0 (0)	1 (<0.1)	0 (0)	1 (<0.1)	9 (0.1)	10 (0.1)
Other	336 (0.8)	436 (1.1)*	30 (0.3)	34 (0.4)	37 (0.8)	41 (0.9)	158 (0.9)	248 (1.5)*

Shaded values were significantly lower in the oseltamivir groups than in the control groups (chi-square tests); *P < .001; ^† P < .01; ^‡ P < .05

Central Nervous System-Related and Neuropsychiatric Events Within 14 and 30 Days After the Index Date in all Patients and in Children (aged ≤ 12 years), Adolescents (aged 13-17 years), and Adults (Aged 18-49 years)
Outcome	All Patients		Patients Aged ≤ 12 Years		Patients Aged 13-17 Years		Patients Aged 18-49 Years
	Treated (Oseltamivir)	Controls (No Antiviral)	Treated (Oseltamivir)	Controls (No Antiviral)	Treated (Oseltamivir)	Controls (No Antiviral)	Treated (Oseltamivir)	Controls (No Antiviral)
	N (%)	N (%)	N (%)	N (%)	N (%)	N (%)	N (%)	N (%)
Within 14 days of index date
CNS and neuropsychiatric	694 (1.7)	968 (2.4)*	79 (0.8)	107 (1.1)^‡	71 (1.5)	106 (2.3)^†	335 (2.0)	460 (2.7)*
Psychiatric	293 (0.7)	379 (0.9)*	31 (0.3)	51 (0.5)^‡	41 (0.9)	62 (1.3)^‡	155 (0.9)	172 (1.0)
Encephalitis	1 (<0.1)	2 (<0.1)	0 (0)	0 (0)	0 (0)	0 (0)	1 (<0.1)	0 (0)
Disturbances of consciousness	124 (0.3)	219 (0.5)*	4 (<0.1)	9 (0.1)	9 (0.2)	16 (0.3)	63 (0.4)	98 (0.6)^†
Movement	4 (<0.1)	10 (<0.1)	1 (<0.1)	1 (<0.1)	0 (0)	1 (<0.1)	3 (<0.1)	3 (<0.1)
Seizure	53 (0.1)	72 (0.2)	27 (0.3)	25 (0.3)	1 (<0.1)	18 (0.1)	18 (0.1)	28 (0.2)
Stroke	30 (0.1)	45 (0.1)	0 (0)	0 (0)	0 (0)	0 (0)	6 (<0.1)	4 (<0.1)
Other	224 (0.6)	298 (0.7)^†	16 (0.2)	24 (0.3)	22 (0.5)	47 (0.3)	113 (0.7)	179 (1.1)*
Within 30 days of index date
CNS and neuropsychiatric	1082 (2.7)	1412 (3.5)*	126 (1.3)	158 (1.6)	122 (2.6)	158 (3.4)^‡	506 (3.0)	673 (4.0)*
Psychiatric	502 (1.2)	587 (1.4)^†	54 (0.6)	74 (0.8)	73 (1.6)	96 (2.1)	262 (1.5)	282 (1.7)
Encephalitis	1 (<0.1)	2 (<0.1)	0 (0)	0 (0)	0 (0)	0 (0)	1 (<0.1)	0 (0)
Disturbances of consciousness	175 (0.4)	293 (0.7)*	7 (0.1)	14 (0.1)	15 (0.3)	20 (0.4)	88 (0.5)	125 (0.7)^‡
Movement	6 (<0.1)	15 (<0.1)^‡	1 (<0.1)	1 (<0.1)	1 (<0.1)	1 (<0.1)	4 (<0.1)	6 (<0.1)
Seizure	73 (0.2)	108 (0.3)^†	35 (0.4)	39 (0.4)	3 (0.1)	6 (0.1)	23 (0.1)	43 (0.6)^‡
Stroke	53 (0.1)	79 (0.2)^‡	0 (0)	1 (<0.1)	0 (0)	1 (<0.1)	9 (0.1)	10 (0.1)
Other	336 (0.8)	436 (1.1)*	30 (0.3)	34 (0.4)	37 (0.8)	41 (0.9)	158 (0.9)	248 (1.5)*

Shaded values were significantly lower in the oseltamivir groups than in the control groups (chi-square tests); *P < .001; ^† P < .01; ^‡ P < .05

Central Nervous System-Related and Neuropsychiatric Events Within 14 and 30 Days After the Index Date in all Patients and in Children (aged ≤ 12 years), Adolescents (aged 13-17 years), and Adults (Aged 18-49 years)
Outcome	All Patients		Patients Aged ≤ 12 Years		Patients Aged 13-17 Years		Patients Aged 18-49 Years
	Treated (Oseltamivir)	Controls (No Antiviral)	Treated (Oseltamivir)	Controls (No Antiviral)	Treated (Oseltamivir)	Controls (No Antiviral)	Treated (Oseltamivir)	Controls (No Antiviral)
	N (%)	N (%)	N (%)	N (%)	N (%)	N (%)	N (%)	N (%)
Within 14 days of index date
CNS and neuropsychiatric	694 (1.7)	968 (2.4)*	79 (0.8)	107 (1.1)^‡	71 (1.5)	106 (2.3)^†	335 (2.0)	460 (2.7)*
Psychiatric	293 (0.7)	379 (0.9)*	31 (0.3)	51 (0.5)^‡	41 (0.9)	62 (1.3)^‡	155 (0.9)	172 (1.0)
Encephalitis	1 (<0.1)	2 (<0.1)	0 (0)	0 (0)	0 (0)	0 (0)	1 (<0.1)	0 (0)
Disturbances of consciousness	124 (0.3)	219 (0.5)*	4 (<0.1)	9 (0.1)	9 (0.2)	16 (0.3)	63 (0.4)	98 (0.6)^†
Movement	4 (<0.1)	10 (<0.1)	1 (<0.1)	1 (<0.1)	0 (0)	1 (<0.1)	3 (<0.1)	3 (<0.1)
Seizure	53 (0.1)	72 (0.2)	27 (0.3)	25 (0.3)	1 (<0.1)	18 (0.1)	18 (0.1)	28 (0.2)
Stroke	30 (0.1)	45 (0.1)	0 (0)	0 (0)	0 (0)	0 (0)	6 (<0.1)	4 (<0.1)
Other	224 (0.6)	298 (0.7)^†	16 (0.2)	24 (0.3)	22 (0.5)	47 (0.3)	113 (0.7)	179 (1.1)*
Within 30 days of index date
CNS and neuropsychiatric	1082 (2.7)	1412 (3.5)*	126 (1.3)	158 (1.6)	122 (2.6)	158 (3.4)^‡	506 (3.0)	673 (4.0)*
Psychiatric	502 (1.2)	587 (1.4)^†	54 (0.6)	74 (0.8)	73 (1.6)	96 (2.1)	262 (1.5)	282 (1.7)
Encephalitis	1 (<0.1)	2 (<0.1)	0 (0)	0 (0)	0 (0)	0 (0)	1 (<0.1)	0 (0)
Disturbances of consciousness	175 (0.4)	293 (0.7)*	7 (0.1)	14 (0.1)	15 (0.3)	20 (0.4)	88 (0.5)	125 (0.7)^‡
Movement	6 (<0.1)	15 (<0.1)^‡	1 (<0.1)	1 (<0.1)	1 (<0.1)	1 (<0.1)	4 (<0.1)	6 (<0.1)
Seizure	73 (0.2)	108 (0.3)^†	35 (0.4)	39 (0.4)	3 (0.1)	6 (0.1)	23 (0.1)	43 (0.6)^‡
Stroke	53 (0.1)	79 (0.2)^‡	0 (0)	1 (<0.1)	0 (0)	1 (<0.1)	9 (0.1)	10 (0.1)
Other	336 (0.8)	436 (1.1)*	30 (0.3)	34 (0.4)	37 (0.8)	41 (0.9)	158 (0.9)	248 (1.5)*

Shaded values were significantly lower in the oseltamivir groups than in the control groups (chi-square tests); *P < .001; ^† P < .01; ^‡ P < .05

Central Nervous System-Related and Neuropsychiatric Events Within 14 and 30 Days After the Index Date in all Patients and in Children (aged ≤ 12 years), Adolescents (aged 13-17 years), and Adults (Aged 18-49 years)
Outcome	All Patients		Patients Aged ≤ 12 Years		Patients Aged 13-17 Years		Patients Aged 18-49 Years
	Treated (Oseltamivir)	Controls (No Antiviral)	Treated (Oseltamivir)	Controls (No Antiviral)	Treated (Oseltamivir)	Controls (No Antiviral)	Treated (Oseltamivir)	Controls (No Antiviral)
	N (%)	N (%)	N (%)	N (%)	N (%)	N (%)	N (%)	N (%)
Within 14 days of index date
CNS and neuropsychiatric	694 (1.7)	968 (2.4)*	79 (0.8)	107 (1.1)^‡	71 (1.5)	106 (2.3)^†	335 (2.0)	460 (2.7)*
Psychiatric	293 (0.7)	379 (0.9)*	31 (0.3)	51 (0.5)^‡	41 (0.9)	62 (1.3)^‡	155 (0.9)	172 (1.0)
Encephalitis	1 (<0.1)	2 (<0.1)	0 (0)	0 (0)	0 (0)	0 (0)	1 (<0.1)	0 (0)
Disturbances of consciousness	124 (0.3)	219 (0.5)*	4 (<0.1)	9 (0.1)	9 (0.2)	16 (0.3)	63 (0.4)	98 (0.6)^†
Movement	4 (<0.1)	10 (<0.1)	1 (<0.1)	1 (<0.1)	0 (0)	1 (<0.1)	3 (<0.1)	3 (<0.1)
Seizure	53 (0.1)	72 (0.2)	27 (0.3)	25 (0.3)	1 (<0.1)	18 (0.1)	18 (0.1)	28 (0.2)
Stroke	30 (0.1)	45 (0.1)	0 (0)	0 (0)	0 (0)	0 (0)	6 (<0.1)	4 (<0.1)
Other	224 (0.6)	298 (0.7)^†	16 (0.2)	24 (0.3)	22 (0.5)	47 (0.3)	113 (0.7)	179 (1.1)*
Within 30 days of index date
CNS and neuropsychiatric	1082 (2.7)	1412 (3.5)*	126 (1.3)	158 (1.6)	122 (2.6)	158 (3.4)^‡	506 (3.0)	673 (4.0)*
Psychiatric	502 (1.2)	587 (1.4)^†	54 (0.6)	74 (0.8)	73 (1.6)	96 (2.1)	262 (1.5)	282 (1.7)
Encephalitis	1 (<0.1)	2 (<0.1)	0 (0)	0 (0)	0 (0)	0 (0)	1 (<0.1)	0 (0)
Disturbances of consciousness	175 (0.4)	293 (0.7)*	7 (0.1)	14 (0.1)	15 (0.3)	20 (0.4)	88 (0.5)	125 (0.7)^‡
Movement	6 (<0.1)	15 (<0.1)^‡	1 (<0.1)	1 (<0.1)	1 (<0.1)	1 (<0.1)	4 (<0.1)	6 (<0.1)
Seizure	73 (0.2)	108 (0.3)^†	35 (0.4)	39 (0.4)	3 (0.1)	6 (0.1)	23 (0.1)	43 (0.6)^‡
Stroke	53 (0.1)	79 (0.2)^‡	0 (0)	1 (<0.1)	0 (0)	1 (<0.1)	9 (0.1)	10 (0.1)
Other	336 (0.8)	436 (1.1)*	30 (0.3)	34 (0.4)	37 (0.8)	41 (0.9)	158 (0.9)	248 (1.5)*

Shaded values were significantly lower in the oseltamivir groups than in the control groups (chi-square tests); *P < .001; ^† P < .01; ^‡ P < .05

International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] Codes for Central Nervous System and Neuropsychiatric Outcomes
Outcome	Diagnosis	ICD-9-CM Code
Psychiatric	Drug-induced psychotic disorders	292.1x
	Pathologic drug intoxication	292.2x
	Other specified drug-induced mental disorders	292.8x
	Unspecified drug-induced mental disorder	292.9
	Transient organic psychotic conditions (delirium, delusion, psychosis)	293.xx
	Acute schizophrenia	295.0x, 295.1x, 295.3x, 295.8x
	Schizophreniform disorder	295.4x
	Other specified episodic mood disorder (mood swings)	296.99
	Other nonorganic psychoses	298.xx
	Anxiety states	300.0x
	Predominant disturbance of emotions	308.0x
	Adjustment reaction	309.xx
	Depressive disorder, not elsewhere classified	311.xx
	Disturbance of emotions specific to childhood and adolescence	313.0x
	Suicide and self-inflicted injury	E950.x-E959.x
Encephalitis	Other encephalitis due to infection classified elsewhere	323.4x
	Post-infectious encephalitis	323.6x
	Other causes of encephalitis	323.8x
	Unspecified cause of encephalitis	323.9x
Disturbance of consciousness	Organic insomnia	327.0x
	Organic hypersomnolence	327.1x
	Alteration of consciousness	780.0x
	Hallucinations	780.1x
	Syncope and collapse	780.2x
	Dizziness and giddiness	780.4x
	Other hypersomnia	780.54
Movement disorder	Abnormal involuntary movements	781.0x
Seizure	Epilepsy	345.xx
Seizure	Convulsions	780.3x
Stroke	Subarachnoid hemorrhage	430.xx
	Intracerebral hemorrhage	431.xx
	Other and unspecified intracranial hemorrhage	432.xx
	Occlusion and stenosis of precerebral arteries	433.xx
	Occlusion of cerebral arteries	434.xx
	Transient cerebral ischemia	435.xx
	Acute, but ill-defined, cerebrovascular disease	436.xx
	Other and ill-defined cerebrovascular disease	437.xx
	Late effects of cerebrovascular disease	438.xx
Other	Dysfunctions of sleep stages (nightmares)	307.47
	Visual disturbances	368.xx
	Insomnia not otherwise specified	780.52
	Taste disturbance	781.1x
	Other symptoms involving nervous and musculoskeletal systems	781.99
	Headache	784.0x

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