Randomized Phase III Study Of Exemestane (Aromasin) For 5 Years Versus Tamoxifen for 2.5 to 3 Years Followed By Exemestane (TEAM)

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ClinicalTrials.gov Identifier: NCT00036270

Recruitment Status : Completed

First Posted : May 9, 2002

Results First Posted : December 4, 2009

Last Update Posted : October 28, 2015

Sponsor:

Information provided by (Responsible Party):

Pfizer

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition	Breast Neoplasms
Interventions	Drug: exemestane (Aromasin) Drug: tamoxifen + exemestane
Enrollment	9779

Participant Flow

Recruitment Details
Pre-assignment Details


Arm/Group Title	Exemestane	Tamoxifen Followed by Exemestane
Arm/Group Description	Exemestane (Aromasin®) 25 milligram...	Tamoxifen 20 mg QD; upon completing...
Arm/Group Description	Exemestane (Aromasin®) 25 milligram (mg) once daily (QD) for 5 years.	Tamoxifen 20 mg QD; upon completing 2.5 years to 3 years of tamoxifen, participants were to be switched to exemestane 25 mg QD and then were to complete a total of 5 years endocrine therapy.
Period Title: Randomized to Study Treatment
Started	4904	4875
Completed	4898	4868
Not Completed	6	7
Reason Not Completed
Withdrawal by Subject	6	7
Period Title: Study Treatment to 5 Year Report
Started	4898	4868
Treated	4852	4814
Completed	2333	1380
Not Completed	2565	3488
Reason Not Completed
Ongoing	1081	736
Disease- Free Survival (DFS) event	507	447
Adverse Event	501	782
Other	277	288
Treatment refusal	113	208
Randomized but not treated	46	54
Protocol Violation	23	91
Intercurrent illness	17	29
Too early switch	0	103
No/too late switch/refusal to switch	0	750

Baseline Characteristics

Arm/Group Title		Exemestane	Tamoxifen Followed by Exemestane	Total
Arm/Group Description		Exemestane (Aromasin®) 25 mg QD for...	Tamoxifen 20 mg QD; upon completing...	Total of all reporting groups
Arm/Group Description		Exemestane (Aromasin®) 25 mg QD for 5 years.	Tamoxifen 20 mg QD; upon completing 2.5 years to 3 years of tamoxifen, participants were to be switched to exemestane 25 mg QD and then were to complete a total of 5 years endocrine therapy.	Total of all reporting groups
Overall Number of Baseline Participants		4898	4868	9766
Baseline Analysis Population Description		[Not Specified]
Baseline Analysis Population Description		[Not Specified]
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	4898 participants	4868 participants	9766 participants
		65 (9)	64 (9)	64 (9)
Age, Customized Measure Type: Number Unit of measure: Participants	Number Analyzed	4898 participants	4868 participants	9766 participants
Less than 50 years		171	160	331
50 to 59 years		1510	1507	3017
60 to 69 years		1835	1896	3731
Greater than and equal to 70 years		1382	1305	2687
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	4898 participants	4868 participants	9766 participants
	Female	4898 100.0%	4868 100.0%	9766 100.0%
	Male	0 0.0%	0 0.0%	0 0.0%

Outcome Measures

1.Primary Outcome


Title	Disease Free Survival (DFS): Number of Events (Disease Relapse or Death) From Baseline up to 2.75 Years
Description	Number of events (disease relapse or death) to time of observation for...
Description	Number of events (disease relapse or death) to time of observation for DFS. DFS defined as time from randomization to earliest documentation of disease relapse or death from any cause in postmenopausal, receptor positive, node negative or node positive breast cancer patients for adjuvant treatment with exemestane compared with adjuvant tamoxifen therapy at 2.75 years. Disease relapse: primary tumor recurrence (locoregional or distant) and ipsilateral or contralateral breast cancer (CBC). Intercurrent death: death without disease relapse.
Time Frame	Baseline (Month 0) up to 2.75 years

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) population: participants randomized to one of the two study arms (all randomized participants); (n) = number of participants at observation for exemestane and tamoxifen, respectively. All participants were censored at 2.75 years.


Arm/Group Title	Exemestane	Tamoxifen Followed by Exemestane
Arm/Group Description:	Exemestane (Aromasin®) 25 mg QD for...	Tamoxifen 20 mg QD; upon completing...
Arm/Group Description:	Exemestane (Aromasin®) 25 mg QD for 5 years.	Tamoxifen 20 mg QD; upon completing 2.5 years to 3 years of tamoxifen, participants were to be switched to exemestane 25 mg QD and then were to complete a total of 5 years endocrine therapy.
Overall Number of Participants Analyzed	4898	4868
Measure Type: Number Unit of Measure: Events (disease relapse or death)
	352	388

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Exemestane, Tamoxifen Followed by Exemestane
	Comments	Analysis at 2.75 years post-randomization. Null hypothesis: no difference in DFS between the two treatments for the first 2.75 years. To maintain overall alpha of 0.05, 2 adjustments made: first, a nominal alpha of 0.0302 was used for the primary endpoint. Second, level of significant was 0.0012 for interim analysis.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.118
	Comments	[Not Specified]
	Method	Log Rank
	Comments	Log rank (Mantel-Cox). Adjusted for overall stratification factor; 1 degree of freedom.

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.89
	Confidence Interval	(2-Sided) 95% 0.77 to 1.03
	Estimation Comments	A hazard ratio less than 1 favors the test treatment (exemestane only arm).

2.Primary Outcome


Title	Disease Free Survival (DFS): Number of Events (Disease Relapse or Death) From Baseline up to 5 Years
Description	Number of events (disease relapse or death) to time of observation for...
Description	Number of events (disease relapse or death) to time of observation for DFS. DFS defined as time from randomization to earliest documentation of disease relapse or death from any cause in postmenopausal, receptor positive, node negative or node positive breast cancer patients for adjuvant treatment with exemestane compared with adjuvant tamoxifen therapy at 5 years. Disease relapse: primary tumor recurrence (locoregional or distant) and ipsilateral or contralateral breast cancer (CBC). Intercurrent death: death without disease relapse.
Time Frame	Baseline (Month 0) up to 5 years

Outcome Measure Data

Analysis Population Description

ITT population included all participants who were randomized to one of the two study arms (all randomized participants); (n) = number of participants at observation for exemestane and tamoxifen, respectively. All participants were censored at the data cut off date of 08 November 2009.


Arm/Group Title	Exemestane	Tamoxifen Followed by Exemestane
Arm/Group Description:	Exemestane (Aromasin®) 25 mg QD for...	Tamoxifen 20 mg QD; upon completing...
Arm/Group Description:	Exemestane (Aromasin®) 25 mg QD for 5 years.	Tamoxifen 20 mg QD; upon completing 2.5 years to 3 years of tamoxifen, participants were to be switched to exemestane 25 mg QD and then were to complete a total of 5 years endocrine therapy.
Overall Number of Participants Analyzed	4898	4868
Measure Type: Number Unit of Measure: Events (disease relapse or death)
	712	714

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Exemestane, Tamoxifen Followed by Exemestane
	Comments	Analysis at 5 years post-randomization. Null hypothesis: no difference in DFS between the two treatments for the first 5 years. To maintain overall alpha of 0.05, a nominal alpha of 0.0302 was used.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.604
	Comments	[Not Specified]
	Method	Log Rank
	Comments	Log rank (Mantel-Cox). Adjusted for overall stratification factor; 1 degree of freedom.

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.97
	Confidence Interval	(2-Sided) 95% 0.88 to 1.08
	Estimation Comments	A hazard ratio less than 1 favors the test treatment (exemestane only arm).

3.Secondary Outcome


Title	Number of Events for Overall Survival (OS)
Description	Number of events (death) to time of observation for OS. OS is the dura...
Description	Number of events (death) to time of observation for OS. OS is the duration from randomization to death. For participants who are alive, overall survival is censored at the last contact.
Time Frame	Baseline (Month 0) up to 5 years

Outcome Measure Data

Analysis Population Description

ITT population: participants randomized to one of the two study arms (all randomized participants); (n) = number of participants at observation for exemestane and tamoxifen, respectively. All participants were censored at the data cut off date of 08 November 2009.


Arm/Group Title	Exemestane	Tamoxifen Followed by Exemestane
Arm/Group Description:	Exemestane (Aromasin®) 25 mg QD for...	Tamoxifen 20 mg QD; upon completing...
Arm/Group Description:	Exemestane (Aromasin®) 25 mg QD for 5 years.	Tamoxifen 20 mg QD; upon completing 2.5 years to 3 years of tamoxifen, participants were to be switched to exemestane 25 mg QD and then were to complete a total of 5 years endocrine therapy.
Overall Number of Participants Analyzed	4898	4868
Measure Type: Number Unit of Measure: Events (death)
	485	476

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Exemestane, Tamoxifen Followed by Exemestane
	Comments	Analysis at 5 years post-randomization. Null hypothesis: no difference in OS between the two treatments for the first 5 years. Overall alpha of 0.05 was maintained.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.951
	Comments	[Not Specified]
	Method	Log Rank
	Comments	Log rank (Mantel-Cox). Adjusted for overall stratification factor; 1 degree of freedom.

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.00
	Confidence Interval	(2-Sided) 95% 0.89 to 1.14
	Estimation Comments	A hazard ratio less than 1 favors the test treatment (exemestane only arm).

4.Secondary Outcome


Title	Time to New Primary Breast Cancers
Description	New primary breast cancers were defined as events of ipsilateral/contr...
Description	New primary breast cancers were defined as events of ipsilateral/contralateral breast cancer (CBC).
Time Frame	Baseline (Month 0) up to 5 years

Outcome Measure Data

Analysis Population Description

Data was not analyzed due to insufficient number of events reported for the endpoint.


Arm/Group Title	Exemestane	Tamoxifen Followed by Exemestane
Arm/Group Description:	Exemestane (Aromasin®) 25 mg QD for...	Tamoxifen 20 mg QD; upon completing...
Arm/Group Description:	Exemestane (Aromasin®) 25 mg QD for 5 years.	Tamoxifen 20 mg QD; upon completing 2.5 years to 3 years of tamoxifen, participants were to be switched to exemestane 25 mg QD and then were to complete a total of 5 years endocrine therapy.
Overall Number of Participants Analyzed	0	0

No data displayed because Outcome Measure has zero total analyzed.

5.Secondary Outcome


Title	Number of Events for Time to Relapse
Description	Number of events to time of observation for relapse. Relapse is define...
Description	Number of events to time of observation for relapse. Relapse is defined as all recurrences of the primary tumor (loco-regional and distant recurrence), second primary breast cancer, contralateral breast cancer.
Time Frame	Baseline (Month 0) up to 5 years

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Exemestane	Tamoxifen Followed by Exemestane
Arm/Group Description:	Exemestane (Aromasin®) 25 mg QD for...	Tamoxifen 20 mg QD; upon completing...
Arm/Group Description:	Exemestane (Aromasin®) 25 mg QD for 5 years.	Tamoxifen 20 mg QD; upon completing 2.5 years to 3 years of tamoxifen, participants were to be switched to exemestane 25 mg QD and then were to complete a total of 5 years endocrine therapy.
Overall Number of Participants Analyzed	4898	4868
Measure Type: Number Unit of Measure: Events (disease relapse)
	499	521

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Exemestane, Tamoxifen Followed by Exemestane
	Comments	Analysis at 5 years post-randomization. Null hypothesis: no difference in time to relapse between the two treatments for the first 5 years. Overall alpha of 0.05 was maintained.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.293
	Comments	[Not Specified]
	Method	Log Rank
	Comments	Log rank (Mantel-Cox). Adjusted for overall stratification factor; 1 degree of freedom.

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.94
	Confidence Interval	(2-Sided) 95% 0.83 to 1.06
	Estimation Comments	A hazard ratio less than 1 favors the test treatment (exemestane only arm).

6.Secondary Outcome


Title	Number of Participants With New Primary Non-breast Cancers
Description	Number of participants with new primary non-breast cancers which inclu...
Description	Number of participants with new primary non-breast cancers which included colorectal cancer, lung cancer, endometrial cancer, ductal carcinoma in situ (DCIS) and other primary cancer types.
Time Frame	Baseline (Month 0) up to 5 years

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Exemestane	Tamoxifen Followed by Exemestane
Arm/Group Description:	Exemestane (Aromasin®) 25 mg QD for...	Tamoxifen 20 mg QD; upon completing...
Arm/Group Description:	Exemestane (Aromasin®) 25 mg QD for 5 years.	Tamoxifen 20 mg QD; upon completing 2.5 years to 3 years of tamoxifen, participants were to be switched to exemestane 25 mg QD and then were to complete a total of 5 years endocrine therapy.
Overall Number of Participants Analyzed	4898	4868
Measure Type: Number Unit of Measure: Participants
Colorectal cancer	43	32
Lung cancer	24	17
Endometrial cancer	7	17
DCIS	3	4
Other primary cancer types	110	106

Adverse Events

Time Frame	[Not Specified]
Adverse Event Reporting Description	The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.

Arm/Group Title	Tamoxifen Followed by Exemestane	Exemestane
Arm/Group Description	Tamoxifen 20 mg QD; upon completing...	Exemestane (Aromasin®) 25 mg QD for...
Arm/Group Description	Tamoxifen 20 mg QD; upon completing 2.5 years to 3 years of tamoxifen, participants were to be switched to exemestane 25 mg QD and then were to complete a total of 5 years endocrine therapy.	Exemestane (Aromasin®) 25 mg QD for 5 years
All-Cause Mortality
	Tamoxifen Followed by Exemestane	Exemestane
	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--
Serious Adverse Events Serious Adverse Events
	Tamoxifen Followed by Exemestane	Exemestane
	Affected / at Risk (%)	Affected / at Risk (%)
Total	784/4814 (16.29%)	831/4852 (17.13%)
Blood and lymphatic system disorders
Anaemia ^* 1	5/4814 (0.10%)	12/4852 (0.25%)
Anaemia vitamin B12 deficiency ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Coagulopathy ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Febrile neutropenia ^* 1	0/4814 (0.00%)	2/4852 (0.04%)
Haemorrhagic anaemia ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Iron deficiency anaemia ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Leukocytosis ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Leukopenia ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Lymphadenopathy ^* 1	1/4814 (0.02%)	3/4852 (0.06%)
Neutropenia ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Pancytopenia ^* 1	0/4814 (0.00%)	2/4852 (0.04%)
Thrombocytopenia ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Cardiac disorders
Acute coronary syndrome ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Acute myocardial infarction ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Angina pectoris ^* 1	7/4814 (0.15%)	8/4852 (0.16%)
Angina unstable ^* 1	0/4814 (0.00%)	2/4852 (0.04%)
Aortic valve incompetence ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Aortic valve stenosis ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Arrhythmia ^* 1	0/4814 (0.00%)	4/4852 (0.08%)
Arrhythmia supraventricular ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Atrial fibrillation ^* 1	15/4814 (0.31%)	18/4852 (0.37%)
Atrial flutter ^* 1	1/4814 (0.02%)	2/4852 (0.04%)
Atrial tachycardia ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Atrioventricular block ^* 1	2/4814 (0.04%)	0/4852 (0.00%)
Atrioventricular block complete ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Bradycardia ^* 1	1/4814 (0.02%)	4/4852 (0.08%)
Cardiac arrest ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Cardiac asthma ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Cardiac disorder ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Cardiac failure ^* 1	7/4814 (0.15%)	9/4852 (0.19%)
Cardiac failure congestive ^* 1	6/4814 (0.12%)	12/4852 (0.25%)
Cardiac valve disease ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Cardiomyopathy ^* 1	2/4814 (0.04%)	1/4852 (0.02%)
Cardiopulmonary failure ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Cardiovascular disorder ^* 1	0/4814 (0.00%)	2/4852 (0.04%)
Congestive cardiomyopathy ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Cor pulmonale ^* 1	1/4814 (0.02%)	2/4852 (0.04%)
Coronary artery disease ^* 1	7/4814 (0.15%)	8/4852 (0.16%)
Coronary artery insufficiency ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Coronary artery occlusion ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Coronary artery stenosis ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Cytotoxic cardiomyopathy ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Intracardiac thrombus ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Left ventricular failure ^* 1	0/4814 (0.00%)	4/4852 (0.08%)
Mitral valve incompetence ^* 1	1/4814 (0.02%)	2/4852 (0.04%)
Myocardial infarction ^* 1	18/4814 (0.37%)	18/4852 (0.37%)
Myocardial ischaemia ^* 1	1/4814 (0.02%)	4/4852 (0.08%)
Palpitations ^* 1	2/4814 (0.04%)	0/4852 (0.00%)
Pericardial effusion ^* 1	0/4814 (0.00%)	5/4852 (0.10%)
Pleuropericarditis ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Prinzmetal angina ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Right ventricular failure ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Sick sinus syndrome ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Sinus bradycardia ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Sinus tachycardia ^* 1	0/4814 (0.00%)	2/4852 (0.04%)
Supraventricular tachycardia ^* 1	1/4814 (0.02%)	2/4852 (0.04%)
Tachyarrhythmia ^* 1	0/4814 (0.00%)	3/4852 (0.06%)
Tachycardia ^* 1	4/4814 (0.08%)	1/4852 (0.02%)
Ventricular fibrillation ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Ventricular tachycardia ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Congenital, familial and genetic disorders
Adenomatous polyposis coli ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Congenital musculoskeletal anomaly ^* 1	0/4814 (0.00%)	2/4852 (0.04%)
Dermoid cyst ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Skull malformation ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Spine malformation ^* 1	3/4814 (0.06%)	0/4852 (0.00%)
Ear and labyrinth disorders
Deafness unilateral ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Otosclerosis ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Tinnitus ^* 1	0/4814 (0.00%)	2/4852 (0.04%)
Tympanic membrane disorder ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Vertigo ^* 1	7/4814 (0.15%)	1/4852 (0.02%)
Endocrine disorders
Goitre ^* 1	3/4814 (0.06%)	6/4852 (0.12%)
Hyperparathyroidism ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Hyperthyroidism ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Hypothyroidism ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Thyroid disorder ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Thyroiditis ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Toxic nodular goitre ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Eye disorders
Cataract ^* 1	2/4814 (0.04%)	3/4852 (0.06%)
Eye disorder ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Eye pain ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Glaucoma ^* 1	2/4814 (0.04%)	1/4852 (0.02%)
Retinal detachment ^* 1	0/4814 (0.00%)	3/4852 (0.06%)
Retinal disorder ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Retinal haemorrhage ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Retinal ischaemia ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Retinal vein occlusion ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Visual acuity reduced ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Visual impairment ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Vitreous detachment ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Gastrointestinal disorders
Abdominal distension ^* 1	0/4814 (0.00%)	2/4852 (0.04%)
Abdominal hernia ^* 1	0/4814 (0.00%)	3/4852 (0.06%)
Abdominal pain ^* 1	11/4814 (0.23%)	14/4852 (0.29%)
Abdominal pain lower ^* 1	0/4814 (0.00%)	2/4852 (0.04%)
Abdominal pain upper ^* 1	2/4814 (0.04%)	2/4852 (0.04%)
Acute abdomen ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Anal fissure ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Anal prolapse ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Ascites ^* 1	2/4814 (0.04%)	0/4852 (0.00%)
Colitis ^* 1	0/4814 (0.00%)	3/4852 (0.06%)
Colonic polyp ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Constipation ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Crohn's disease ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Diarrhoea ^* 1	7/4814 (0.15%)	10/4852 (0.21%)
Diarrhoea haemorrhagic ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Diverticulum ^* 1	0/4814 (0.00%)	2/4852 (0.04%)
Diverticulum intestinal ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Duodenal ulcer haemorrhage ^* 1	0/4814 (0.00%)	2/4852 (0.04%)
Enteritis ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Enterocolitis haemorrhagic ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Epigastric discomfort ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Femoral hernia, obstructive ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Gastric haemorrhage ^* 1	2/4814 (0.04%)	0/4852 (0.00%)
Gastric ulcer ^* 1	2/4814 (0.04%)	4/4852 (0.08%)
Gastric ulcer haemorrhage ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Gastric ulcer perforation ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Gastritis ^* 1	2/4814 (0.04%)	6/4852 (0.12%)
Gastritis erosive ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Gastrointestinal disorder ^* 1	4/4814 (0.08%)	1/4852 (0.02%)
Gastrointestinal haemorrhage ^* 1	4/4814 (0.08%)	6/4852 (0.12%)
Gastrointestinal pain ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Gastrointestinal tract irritation ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Gastrooesophageal reflux disease ^* 1	2/4814 (0.04%)	2/4852 (0.04%)
Haematemesis ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Haematochezia ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Haemorrhoids ^* 1	0/4814 (0.00%)	2/4852 (0.04%)
Hiatus hernia ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Ileus ^* 1	2/4814 (0.04%)	2/4852 (0.04%)
Inguinal hernia ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Intestinal ischaemia ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Intestinal obstruction ^* 1	5/4814 (0.10%)	4/4852 (0.08%)
Intestinal perforation ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Intestinal polyp ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Large intestine perforation ^* 1	2/4814 (0.04%)	0/4852 (0.00%)
Melaena ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Mesenteric occlusion ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Nausea ^* 1	3/4814 (0.06%)	5/4852 (0.10%)
Obstruction gastric ^* 1	0/4814 (0.00%)	2/4852 (0.04%)
Oesophageal disorder ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Oesophageal haemorrhage ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Oesophageal stenosis ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Oesophagitis ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Pancreatitis ^* 1	7/4814 (0.15%)	5/4852 (0.10%)
Pancreatitis acute ^* 1	1/4814 (0.02%)	2/4852 (0.04%)
Peptic ulcer ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Peritonitis ^* 1	1/4814 (0.02%)	2/4852 (0.04%)
Proctalgia ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Rectal haemorrhage ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Reflux oesophagitis ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Small intestinal obstruction ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Splenic artery aneurysm ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Stomatitis ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Tongue oedema ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Tongue ulceration ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Vomiting ^* 1	9/4814 (0.19%)	6/4852 (0.12%)
General disorders
Adverse drug reaction ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Asthenia ^* 1	3/4814 (0.06%)	6/4852 (0.12%)
Calcinosis ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Cardiac death ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Chest discomfort ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Chest pain ^* 1	15/4814 (0.31%)	16/4852 (0.33%)
Condition aggravated ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Cyst ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Death ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Device breakage ^* 1	0/4814 (0.00%)	2/4852 (0.04%)
Device occlusion ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Disease progression ^* 1	0/4814 (0.00%)	4/4852 (0.08%)
Dysplasia ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Fat necrosis ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Fat tissue increased ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Fatigue ^* 1	4/4814 (0.08%)	4/4852 (0.08%)
Gait disturbance ^* 1	4/4814 (0.08%)	1/4852 (0.02%)
General physical health deterioration ^* 1	2/4814 (0.04%)	2/4852 (0.04%)
Hernia ^* 1	3/4814 (0.06%)	5/4852 (0.10%)
Hyperplasia ^* 1	3/4814 (0.06%)	1/4852 (0.02%)
Ill-defined disorder ^* 1	4/4814 (0.08%)	8/4852 (0.16%)
Impaired healing ^* 1	3/4814 (0.06%)	0/4852 (0.00%)
Implant site fibrosis ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Local swelling ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Malaise ^* 1	3/4814 (0.06%)	1/4852 (0.02%)
Medical device complication ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Multi-organ failure ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Necrosis ^* 1	1/4814 (0.02%)	2/4852 (0.04%)
Nodule ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Oedema ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Oedema due to cardiac disease ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Oedema peripheral ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Pain ^* 1	13/4814 (0.27%)	3/4852 (0.06%)
Polyp ^* 1	4/4814 (0.08%)	1/4852 (0.02%)
Pseudocyst ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Pyrexia ^* 1	7/4814 (0.15%)	5/4852 (0.10%)
Sense of oppression ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Sudden death ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Swelling ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Hepatobiliary disorders
Bile duct stone ^* 1	0/4814 (0.00%)	2/4852 (0.04%)
Biliary colic ^* 1	0/4814 (0.00%)	2/4852 (0.04%)
Cholecystitis ^* 1	13/4814 (0.27%)	11/4852 (0.23%)
Cholecystitis acute ^* 1	2/4814 (0.04%)	0/4852 (0.00%)
Cholecystitis chronic ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Cholelithiasis ^* 1	10/4814 (0.21%)	14/4852 (0.29%)
Gallbladder perforation ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Hepatic cirrhosis ^* 1	2/4814 (0.04%)	0/4852 (0.00%)
Hepatic cyst ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Hepatic function abnormal ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Hepatitis ^* 1	0/4814 (0.00%)	2/4852 (0.04%)
Liver disorder ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Immune system disorders
Anaphylactic reaction ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Hypersensitivity ^* 1	1/4814 (0.02%)	4/4852 (0.08%)
Sarcoidosis ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Infections and infestations
Abscess ^* 1	3/4814 (0.06%)	1/4852 (0.02%)
Abscess limb ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Appendicitis ^* 1	4/4814 (0.08%)	7/4852 (0.14%)
Appendicitis perforated ^* 1	0/4814 (0.00%)	2/4852 (0.04%)
Arthritis bacterial ^* 1	2/4814 (0.04%)	2/4852 (0.04%)
Bacterial infection ^* 1	1/4814 (0.02%)	5/4852 (0.10%)
Breast abscess ^* 1	4/4814 (0.08%)	2/4852 (0.04%)
Breast cellulitis ^* 1	3/4814 (0.06%)	2/4852 (0.04%)
Breast infection ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Bronchitis ^* 1	6/4814 (0.12%)	2/4852 (0.04%)
Bronchopneumonia ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Cellulitis ^* 1	11/4814 (0.23%)	7/4852 (0.14%)
Cystitis ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Device related infection ^* 1	1/4814 (0.02%)	2/4852 (0.04%)
Diverticulitis ^* 1	7/4814 (0.15%)	10/4852 (0.21%)
Endocarditis ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Endometritis ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Erysipelas ^* 1	9/4814 (0.19%)	7/4852 (0.14%)
Escherichia urinary tract infection ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Gangrene ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Gastroenteritis ^* 1	6/4814 (0.12%)	4/4852 (0.08%)
Gastroenteritis salmonella ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Groin abscess ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Hepatitis C ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Herpes zoster ^* 1	1/4814 (0.02%)	2/4852 (0.04%)
Infection ^* 1	5/4814 (0.10%)	11/4852 (0.23%)
Lobar pneumonia ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Localised infection ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Lower respiratory tract infection ^* 1	2/4814 (0.04%)	0/4852 (0.00%)
Lower respiratory tract infection bacterial ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Lung infection ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Lymphangitis ^* 1	2/4814 (0.04%)	0/4852 (0.00%)
Mastitis ^* 1	6/4814 (0.12%)	5/4852 (0.10%)
Meningitis ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Molluscum contagiosum ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Nasopharyngitis ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Osteomyelitis ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Pelvic inflammatory disease ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Pneumonia ^* 1	26/4814 (0.54%)	25/4852 (0.52%)
Pneumonia primary atypical ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Post procedural cellulitis ^* 1	2/4814 (0.04%)	0/4852 (0.00%)
Post procedural infection ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Pseudomembranous colitis ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Pyelonephritis ^* 1	2/4814 (0.04%)	1/4852 (0.02%)
Pyelonephritis acute ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Pyoderma ^* 1	2/4814 (0.04%)	0/4852 (0.00%)
Sepsis ^* 1	10/4814 (0.21%)	4/4852 (0.08%)
Streptococcal sepsis ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Subcutaneous abscess ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Upper respiratory tract infection ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Urinary tract infection ^* 1	6/4814 (0.12%)	7/4852 (0.14%)
Urosepsis ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Vestibular neuronitis ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Viral infection ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Wound infection ^* 1	5/4814 (0.10%)	0/4852 (0.00%)
Injury, poisoning and procedural complications
Acetabulum fracture ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Animal bite ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Ankle fracture ^* 1	6/4814 (0.12%)	8/4852 (0.16%)
Breast injury ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Cervical vertebral fracture ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Clavicle fracture ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Compression fracture ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Concussion ^* 1	1/4814 (0.02%)	2/4852 (0.04%)
Contusion ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Deep vein thrombosis postoperative ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Delayed recovery from anaesthesia ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Fall ^* 1	7/4814 (0.15%)	9/4852 (0.19%)
Femoral neck fracture ^* 1	2/4814 (0.04%)	3/4852 (0.06%)
Femur fracture ^* 1	3/4814 (0.06%)	4/4852 (0.08%)
Fibula fracture ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Foot fracture ^* 1	2/4814 (0.04%)	0/4852 (0.00%)
Forearm fracture ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Fracture ^* 1	15/4814 (0.31%)	27/4852 (0.56%)
Fractured sacrum ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Hand fracture ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Head injury ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Hip fracture ^* 1	3/4814 (0.06%)	8/4852 (0.16%)
Humerus fracture ^* 1	2/4814 (0.04%)	10/4852 (0.21%)
Incisional hernia ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Injury ^* 1	3/4814 (0.06%)	0/4852 (0.00%)
Joint dislocation ^* 1	2/4814 (0.04%)	2/4852 (0.04%)
Joint injury ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Joint sprain ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Laceration ^* 1	2/4814 (0.04%)	1/4852 (0.02%)
Lower limb fracture ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Lumbar vertebral fracture ^* 1	0/4814 (0.00%)	2/4852 (0.04%)
Meniscus lesion ^* 1	1/4814 (0.02%)	2/4852 (0.04%)
Overdose ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Patella fracture ^* 1	0/4814 (0.00%)	2/4852 (0.04%)
Pelvic fracture ^* 1	1/4814 (0.02%)	5/4852 (0.10%)
Poisoning ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Postoperative thrombosis ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Postoperative wound complication ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Procedural pain ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Pubis fracture ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Radiation fibrosis ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Radiation pneumonitis ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Radiation skin injury ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Radius fracture ^* 1	0/4814 (0.00%)	4/4852 (0.08%)
Rib fracture ^* 1	2/4814 (0.04%)	3/4852 (0.06%)
Road traffic accident ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Seroma ^* 1	0/4814 (0.00%)	2/4852 (0.04%)
Spinal column injury ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Spinal compression fracture ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Spinal fracture ^* 1	3/4814 (0.06%)	3/4852 (0.06%)
Subdural haematoma ^* 1	3/4814 (0.06%)	2/4852 (0.04%)
Tendon rupture ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Tibia fracture ^* 1	2/4814 (0.04%)	2/4852 (0.04%)
Toxicity to various agents ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Ulna fracture ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Upper limb fracture ^* 1	1/4814 (0.02%)	4/4852 (0.08%)
Vascular bypass dysfunction ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Wrist fracture ^* 1	5/4814 (0.10%)	6/4852 (0.12%)
Investigations
Blood calcium increased ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Blood test abnormal ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
CSF test abnormal ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Carbohydrate antigen 15-3 increased ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Clostridium test positive ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Coagulation test ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Electrocardiogram abnormal ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Gamma-glutamyltransferase increased ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Haemoglobin ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Heart rate irregular ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Investigation ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Occult blood positive ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Prothrombin level increased ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Weight decreased ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Metabolism and nutrition disorders
Cachexia ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Dehydration ^* 1	2/4814 (0.04%)	9/4852 (0.19%)
Diabetes mellitus ^* 1	4/4814 (0.08%)	6/4852 (0.12%)
Enzyme abnormality ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Hypercalcaemia ^* 1	1/4814 (0.02%)	3/4852 (0.06%)
Hypercholesterolaemia ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Hyperglycaemia ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Hypoglycaemia ^* 1	2/4814 (0.04%)	1/4852 (0.02%)
Hypokalaemia ^* 1	1/4814 (0.02%)	3/4852 (0.06%)
Hypomagnesaemia ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Hyponatraemia ^* 1	3/4814 (0.06%)	5/4852 (0.10%)
Type 1 diabetes mellitus ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Musculoskeletal and connective tissue disorders
Arthralgia ^* 1	5/4814 (0.10%)	8/4852 (0.16%)
Arthritis ^* 1	11/4814 (0.23%)	14/4852 (0.29%)
Arthropathy ^* 1	3/4814 (0.06%)	7/4852 (0.14%)
Back pain ^* 1	6/4814 (0.12%)	7/4852 (0.14%)
Bone disorder ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Bone pain ^* 1	2/4814 (0.04%)	4/4852 (0.08%)
Bursitis ^* 1	2/4814 (0.04%)	1/4852 (0.02%)
CREST syndrome ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Chondropathy ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Flank pain ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Foot deformity ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Groin pain ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Intervertebral disc protrusion ^* 1	3/4814 (0.06%)	7/4852 (0.14%)
Joint stiffness ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Joint swelling ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Lumbar spinal stenosis ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Monarthritis ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Muscle spasms ^* 1	2/4814 (0.04%)	1/4852 (0.02%)
Muscular weakness ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Musculoskeletal chest pain ^* 1	1/4814 (0.02%)	2/4852 (0.04%)
Musculoskeletal disorder ^* 1	2/4814 (0.04%)	0/4852 (0.00%)
Musculoskeletal pain ^* 1	2/4814 (0.04%)	1/4852 (0.02%)
Myalgia ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Neck pain ^* 1	1/4814 (0.02%)	5/4852 (0.10%)
Osteoarthritis ^* 1	14/4814 (0.29%)	34/4852 (0.70%)
Osteolysis ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Osteonecrosis ^* 1	2/4814 (0.04%)	3/4852 (0.06%)
Osteonecrosis of jaw ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Osteoporosis ^* 1	1/4814 (0.02%)	3/4852 (0.06%)
Osteoporosis postmenopausal ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Osteoporotic fracture ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Pain in extremity ^* 1	3/4814 (0.06%)	0/4852 (0.00%)
Pathological fracture ^* 1	2/4814 (0.04%)	1/4852 (0.02%)
Polyarthritis ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Rotator cuff syndrome ^* 1	3/4814 (0.06%)	0/4852 (0.00%)
Spinal column stenosis ^* 1	0/4814 (0.00%)	3/4852 (0.06%)
Spinal osteoarthritis ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Synovial cyst ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Synovitis ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Systemic sclerosis ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Tendonitis ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acoustic neuroma ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Adenocarcinoma ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Adenoma benign ^* 1	2/4814 (0.04%)	1/4852 (0.02%)
Basal cell carcinoma ^* 1	1/4814 (0.02%)	4/4852 (0.08%)
Benign breast neoplasm ^* 1	4/4814 (0.08%)	2/4852 (0.04%)
Benign lymph node neoplasm ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Benign neoplasm of skin ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Benign ovarian tumour ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Benign renal neoplasm ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Benign respiratory tract neoplasm ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Bile duct cancer ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Bladder cancer recurrent ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Bowen's disease ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Breast cancer ^* 1	2/4814 (0.04%)	3/4852 (0.06%)
Breast cancer metastatic ^* 1	2/4814 (0.04%)	1/4852 (0.02%)
Breast cancer recurrent ^* 1	0/4814 (0.00%)	4/4852 (0.08%)
Cholesteatoma ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Colon cancer ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Colorectal cancer ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Contralateral breast cancer ^* 1	2/4814 (0.04%)	2/4852 (0.04%)
Dermatofibrosarcoma ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Endometrial cancer ^* 1	2/4814 (0.04%)	3/4852 (0.06%)
Fibroadenoma of breast ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Gastrointestinal neoplasm ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Haemangioma ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Hepatic neoplasm ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Hepatic neoplasm malignant ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Laryngeal cancer ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Lipoma ^* 1	2/4814 (0.04%)	1/4852 (0.02%)
Lung neoplasm ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Lung neoplasm malignant ^* 1	0/4814 (0.00%)	2/4852 (0.04%)
Lymphoma ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Malignant melanoma ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Malignant peritoneal neoplasm ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Malignant pleural effusion ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Mantle cell lymphoma ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Meningioma ^* 1	1/4814 (0.02%)	3/4852 (0.06%)
Metastases to bone ^* 1	4/4814 (0.08%)	8/4852 (0.16%)
Metastases to central nervous system ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Metastases to liver ^* 1	2/4814 (0.04%)	2/4852 (0.04%)
Metastases to lung ^* 1	1/4814 (0.02%)	2/4852 (0.04%)
Metastases to pancreas ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Metastases to pleura ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Metastases to skin ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Metastases to spine ^* 1	1/4814 (0.02%)	2/4852 (0.04%)
Metastases to stomach ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Metastasis ^* 1	2/4814 (0.04%)	3/4852 (0.06%)
Mueller's mixed tumour ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Myelodysplastic syndrome ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Neoplasm ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Neoplasm malignant ^* 1	2/4814 (0.04%)	2/4852 (0.04%)
Neoplasm recurrence ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Neuroma ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Ovarian adenoma ^* 1	0/4814 (0.00%)	3/4852 (0.06%)
Ovarian cancer ^* 1	0/4814 (0.00%)	2/4852 (0.04%)
Ovarian germ cell teratoma benign ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Ovarian neoplasm ^* 1	1/4814 (0.02%)	3/4852 (0.06%)
Paget's disease of the breast ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Pancreatic carcinoma ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Pharyngeal neoplasm ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Rectal cancer ^* 1	0/4814 (0.00%)	2/4852 (0.04%)
Thyroid adenoma ^* 1	0/4814 (0.00%)	2/4852 (0.04%)
Thyroid cancer ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Thyroid neoplasm ^* 1	1/4814 (0.02%)	2/4852 (0.04%)
Ureteric cancer ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Uterine cancer ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Uterine leiomyoma ^* 1	2/4814 (0.04%)	4/4852 (0.08%)
Vulval cancer ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Nervous system disorders
Alcoholic seizure ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Aphasia ^* 1	2/4814 (0.04%)	2/4852 (0.04%)
Apraxia ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Ataxia ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Carotid artery stenosis ^* 1	0/4814 (0.00%)	3/4852 (0.06%)
Carotid artery thrombosis ^* 1	2/4814 (0.04%)	1/4852 (0.02%)
Carpal tunnel syndrome ^* 1	2/4814 (0.04%)	3/4852 (0.06%)
Cerebellar infarction ^* 1	0/4814 (0.00%)	2/4852 (0.04%)
Cerebral artery thrombosis ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Cerebral haemorrhage ^* 1	3/4814 (0.06%)	3/4852 (0.06%)
Cerebral infarction ^* 1	3/4814 (0.06%)	6/4852 (0.12%)
Cerebral ischaemia ^* 1	2/4814 (0.04%)	5/4852 (0.10%)
Cerebrovascular accident ^* 1	20/4814 (0.42%)	26/4852 (0.54%)
Cerebrovascular disorder ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Cervicobrachial syndrome ^* 1	0/4814 (0.00%)	2/4852 (0.04%)
Coma ^* 1	1/4814 (0.02%)	3/4852 (0.06%)
Coma hepatic ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Convulsion ^* 1	1/4814 (0.02%)	2/4852 (0.04%)
Dementia ^* 1	0/4814 (0.00%)	2/4852 (0.04%)
Dementia Alzheimer's type ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Depressed level of consciousness ^* 1	0/4814 (0.00%)	2/4852 (0.04%)
Dizziness ^* 1	5/4814 (0.10%)	4/4852 (0.08%)
Drop attacks ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Dyskinesia ^* 1	0/4814 (0.00%)	2/4852 (0.04%)
Encephalopathy ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Epilepsy ^* 1	1/4814 (0.02%)	3/4852 (0.06%)
Extrapyramidal disorder ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Facial paresis ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Grand mal convulsion ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Headache ^* 1	5/4814 (0.10%)	5/4852 (0.10%)
Hemiparesis ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Hypoaesthesia ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
IIIrd nerve paresis ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Ischaemic stroke ^* 1	1/4814 (0.02%)	2/4852 (0.04%)
Loss of consciousness ^* 1	1/4814 (0.02%)	3/4852 (0.06%)
Mental impairment ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Migraine ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Myelitis transverse ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Myelopathy ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Nervous system disorder ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Neuralgia ^* 1	1/4814 (0.02%)	3/4852 (0.06%)
Neuritis ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Neurological symptom ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Paraesthesia ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Partial seizures ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Sciatica ^* 1	2/4814 (0.04%)	2/4852 (0.04%)
Sedation ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Sensory disturbance ^* 1	2/4814 (0.04%)	0/4852 (0.00%)
Somnolence ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Spinal cord compression ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Subarachnoid haemorrhage ^* 1	0/4814 (0.00%)	2/4852 (0.04%)
Syncope ^* 1	12/4814 (0.25%)	13/4852 (0.27%)
Thalamic infarction ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Transient ischaemic attack ^* 1	11/4814 (0.23%)	11/4852 (0.23%)
Psychiatric disorders
Alcohol abuse ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Anxiety ^* 1	1/4814 (0.02%)	2/4852 (0.04%)
Bipolar I disorder ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Completed suicide ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Confusional state ^* 1	2/4814 (0.04%)	4/4852 (0.08%)
Delirium ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Depression ^* 1	10/4814 (0.21%)	9/4852 (0.19%)
Depression suicidal ^* 1	2/4814 (0.04%)	0/4852 (0.00%)
Emotional distress ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Major depression ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Mental disorder ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Mood altered ^* 1	2/4814 (0.04%)	0/4852 (0.00%)
Suicidal ideation ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Suicide attempt ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Renal and urinary disorders
Bladder prolapse ^* 1	1/4814 (0.02%)	2/4852 (0.04%)
Calculus bladder ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Dysuria ^* 1	0/4814 (0.00%)	2/4852 (0.04%)
Haematuria ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Haemorrhage urinary tract ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Hydronephrosis ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Incontinence ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Nephrolithiasis ^* 1	2/4814 (0.04%)	2/4852 (0.04%)
Renal artery stenosis ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Renal colic ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Renal disorder ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Renal failure ^* 1	4/4814 (0.08%)	7/4852 (0.14%)
Renal failure acute ^* 1	1/4814 (0.02%)	3/4852 (0.06%)
Renal infarct ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Stress urinary incontinence ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Ureteric obstruction ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Urinary bladder polyp ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Urinary incontinence ^* 1	1/4814 (0.02%)	4/4852 (0.08%)
Urinary retention ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Urogenital disorder ^* 1	2/4814 (0.04%)	0/4852 (0.00%)
Reproductive system and breast disorders
Breast calcifications ^* 1	4/4814 (0.08%)	4/4852 (0.08%)
Breast cyst ^* 1	2/4814 (0.04%)	0/4852 (0.00%)
Breast disorder ^* 1	1/4814 (0.02%)	7/4852 (0.14%)
Breast enlargement ^* 1	1/4814 (0.02%)	2/4852 (0.04%)
Breast fibrosis ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Breast haematoma ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Breast hyperplasia ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Breast mass ^* 1	3/4814 (0.06%)	4/4852 (0.08%)
Breast necrosis ^* 1	0/4814 (0.00%)	4/4852 (0.08%)
Cervical dysplasia ^* 1	1/4814 (0.02%)	2/4852 (0.04%)
Cervical polyp ^* 1	4/4814 (0.08%)	0/4852 (0.00%)
Cystocele ^* 1	2/4814 (0.04%)	0/4852 (0.00%)
Endometrial atrophy ^* 1	2/4814 (0.04%)	0/4852 (0.00%)
Endometrial disorder ^* 1	2/4814 (0.04%)	1/4852 (0.02%)
Endometrial hyperplasia ^* 1	17/4814 (0.35%)	0/4852 (0.00%)
Endometrial hypertrophy ^* 1	3/4814 (0.06%)	0/4852 (0.00%)
Female genital tract fistula ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Fibrocystic breast disease ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Genital prolapse ^* 1	3/4814 (0.06%)	0/4852 (0.00%)
Menorrhagia ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Menstruation irregular ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Metrorrhagia ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Nipple disorder ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Ovarian cyst ^* 1	6/4814 (0.12%)	4/4852 (0.08%)
Ovarian disorder ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Pelvic pain ^* 1	3/4814 (0.06%)	1/4852 (0.02%)
Postmenopausal haemorrhage ^* 1	3/4814 (0.06%)	1/4852 (0.02%)
Rectocele ^* 1	3/4814 (0.06%)	1/4852 (0.02%)
Urogenital prolapse ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Uterine atony ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Uterine disorder ^* 1	2/4814 (0.04%)	0/4852 (0.00%)
Uterine haemorrhage ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Uterine polyp ^* 1	12/4814 (0.25%)	1/4852 (0.02%)
Uterine prolapse ^* 1	5/4814 (0.10%)	1/4852 (0.02%)
Vaginal disorder ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Vaginal haemorrhage ^* 1	9/4814 (0.19%)	4/4852 (0.08%)
Vaginal polyp ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Vaginal prolapse ^* 1	3/4814 (0.06%)	1/4852 (0.02%)
Vulval disorder ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Vulval oedema ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Vulvovaginal disorder ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema ^* 1	0/4814 (0.00%)	2/4852 (0.04%)
Acute respiratory failure ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Apnoea ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Aspiration ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Asthma ^* 1	2/4814 (0.04%)	0/4852 (0.00%)
Atelectasis ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Bronchial obstruction ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Bronchitis chronic ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Chronic obstructive pulmonary disease ^* 1	4/4814 (0.08%)	2/4852 (0.04%)
Cough ^* 1	2/4814 (0.04%)	1/4852 (0.02%)
Diaphragmatic disorder ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Dyspnoea ^* 1	13/4814 (0.27%)	28/4852 (0.58%)
Dyspnoea exertional ^* 1	1/4814 (0.02%)	3/4852 (0.06%)
Emphysema ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Eosinophilic pneumonia ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Epistaxis ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Haemoptysis ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Hypoxia ^* 1	2/4814 (0.04%)	1/4852 (0.02%)
Lung disorder ^* 1	5/4814 (0.10%)	7/4852 (0.14%)
Lung infiltration ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Nasal septum deviation ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Nasal turbinate hypertrophy ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Obstructive airways disorder ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Paranasal cyst ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Pleural effusion ^* 1	2/4814 (0.04%)	7/4852 (0.14%)
Pleurisy ^* 1	1/4814 (0.02%)	2/4852 (0.04%)
Pleuritic pain ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Pneumonitis ^* 1	0/4814 (0.00%)	4/4852 (0.08%)
Pneumothorax ^* 1	3/4814 (0.06%)	2/4852 (0.04%)
Productive cough ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Pulmonary congestion ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Pulmonary embolism ^* 1	22/4814 (0.46%)	24/4852 (0.49%)
Pulmonary hypertension ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Pulmonary mass ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Pulmonary oedema ^* 1	2/4814 (0.04%)	2/4852 (0.04%)
Respiratory disorder ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Respiratory distress ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Respiratory failure ^* 1	1/4814 (0.02%)	4/4852 (0.08%)
Sinus disorder ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Skin and subcutaneous tissue disorders
Acute febrile neutrophilic dermatosis ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Dermatitis ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Dermatitis allergic ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Eczema ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Nail disorder ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Panniculitis ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Pruritus ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Rash ^* 1	3/4814 (0.06%)	3/4852 (0.06%)
Scar ^* 1	1/4814 (0.02%)	3/4852 (0.06%)
Skin disorder ^* 1	2/4814 (0.04%)	0/4852 (0.00%)
Skin lesion ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Skin necrosis ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Skin ulcer ^* 1	1/4814 (0.02%)	2/4852 (0.04%)
Urticaria ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Surgical and medical procedures
Alcohol detoxification ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Angioplasty ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Aortic valve replacement ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Arterial bypass operation ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Bile duct stent insertion ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Breast lump removal ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Breast operation ^* 1	2/4814 (0.04%)	2/4852 (0.04%)
Breast reconstruction ^* 1	3/4814 (0.06%)	2/4852 (0.04%)
Bunion operation ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Cardiac pacemaker insertion ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Cardiac pacemaker replacement ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Carpal tunnel decompression ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Cast application ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Cataract operation ^* 1	3/4814 (0.06%)	2/4852 (0.04%)
Cholecystectomy ^* 1	5/4814 (0.10%)	4/4852 (0.08%)
Cholelithotomy ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Colporrhaphy ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Coronary arterial stent insertion ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Coronary artery bypass ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Drug therapy ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Eventration procedure ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Female genital operation ^* 1	1/4814 (0.02%)	2/4852 (0.04%)
Gastric bypass ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Gastric operation ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Haemangioma removal ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Hernia repair ^* 1	0/4814 (0.00%)	3/4852 (0.06%)
Hip arthroplasty ^* 1	4/4814 (0.08%)	10/4852 (0.21%)
Hip surgery ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Hospitalisation ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Hysterectomy ^* 1	3/4814 (0.06%)	1/4852 (0.02%)
Inguinal hernia repair ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Intervertebral disc operation ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Joint arthroplasty ^* 1	0/4814 (0.00%)	2/4852 (0.04%)
Knee arthroplasty ^* 1	7/4814 (0.15%)	4/4852 (0.08%)
Knee operation ^* 1	2/4814 (0.04%)	1/4852 (0.02%)
Lipoma excision ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Mastectomy ^* 1	4/4814 (0.08%)	1/4852 (0.02%)
Medical device removal ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Meniscus operation ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Meniscus removal ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Oophorectomy ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Osteosynthesis ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Phlebectomy ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Prolapse repair ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Radical hysterectomy ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Retinal operation ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Rotator cuff repair ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Scar excision ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Shoulder arthroplasty ^* 1	2/4814 (0.04%)	0/4852 (0.00%)
Simple mastectomy ^* 1	2/4814 (0.04%)	0/4852 (0.00%)
Skin neoplasm excision ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Spinal laminectomy ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Surgery ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Tendon operation ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Thyroid nodule removal ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Thyroidectomy ^* 1	0/4814 (0.00%)	5/4852 (0.10%)
Toe amputation ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Toe operation ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Uterine dilation and curettage ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Uterine prolapse repair ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Vaginal operation ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Varicose vein operation ^* 1	0/4814 (0.00%)	2/4852 (0.04%)
Vascular operation ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Vascular disorders
Aneurysm ^* 1	0/4814 (0.00%)	4/4852 (0.08%)
Aortic aneurysm ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Aortic stenosis ^* 1	2/4814 (0.04%)	5/4852 (0.10%)
Arterial occlusive disease ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Arteriosclerosis ^* 1	1/4814 (0.02%)	2/4852 (0.04%)
Arteritis ^* 1	1/4814 (0.02%)	1/4852 (0.02%)
Circulatory collapse ^* 1	1/4814 (0.02%)	3/4852 (0.06%)
Deep vein thrombosis ^* 1	14/4814 (0.29%)	6/4852 (0.12%)
Embolism ^* 1	4/4814 (0.08%)	2/4852 (0.04%)
Femoral arterial stenosis ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Femoral artery occlusion ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Flushing ^* 1	2/4814 (0.04%)	0/4852 (0.00%)
Haematoma ^* 1	3/4814 (0.06%)	0/4852 (0.00%)
Haemorrhage ^* 1	2/4814 (0.04%)	1/4852 (0.02%)
Hot flush ^* 1	2/4814 (0.04%)	0/4852 (0.00%)
Hypertension ^* 1	6/4814 (0.12%)	11/4852 (0.23%)
Hypertensive crisis ^* 1	0/4814 (0.00%)	8/4852 (0.16%)
Hypotension ^* 1	0/4814 (0.00%)	2/4852 (0.04%)
Intermittent claudication ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Ischaemia ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Lymphoedema ^* 1	0/4814 (0.00%)	3/4852 (0.06%)
Peripheral arterial occlusive disease ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Peripheral ischaemia ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Peripheral vascular disorder ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Phlebitis ^* 1	8/4814 (0.17%)	2/4852 (0.04%)
Shock ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Thrombophlebitis ^* 1	5/4814 (0.10%)	0/4852 (0.00%)
Thrombosis ^* 1	13/4814 (0.27%)	6/4852 (0.12%)
Varicophlebitis ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Varicose vein ^* 1	1/4814 (0.02%)	7/4852 (0.14%)
Vasculitis ^* 1	1/4814 (0.02%)	0/4852 (0.00%)
Venoocclusive disease ^* 1	0/4814 (0.00%)	1/4852 (0.02%)
Venous thrombosis ^* 1	6/4814 (0.12%)	2/4852 (0.04%)
* Indicates events were collected by non-systematic assessment 1 Term from vocabulary, MedDRA 14.0
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	2%
	Tamoxifen Followed by Exemestane	Exemestane
	Affected / at Risk (%)	Affected / at Risk (%)
Total	3551/4814 (73.76%)	3567/4852 (73.52%)
Ear and labyrinth disorders
Vertigo ^* 1	78/4814 (1.62%)	96/4852 (1.98%)
Gastrointestinal disorders
Abdominal pain ^* 1	150/4814 (3.12%)	141/4852 (2.91%)
Constipation ^* 1	274/4814 (5.69%)	236/4852 (4.86%)
Diarrhoea ^* 1	258/4814 (5.36%)	302/4852 (6.22%)
Dry mouth ^* 1	98/4814 (2.04%)	70/4852 (1.44%)
Dyspepsia ^* 1	135/4814 (2.80%)	151/4852 (3.11%)
Nausea ^* 1	482/4814 (10.01%)	419/4852 (8.64%)
Vomiting ^* 1	106/4814 (2.20%)	96/4852 (1.98%)
General disorders
Asthenia ^* 1	188/4814 (3.91%)	235/4852 (4.84%)
Chest pain ^* 1	91/4814 (1.89%)	100/4852 (2.06%)
Fatigue ^* 1	800/4814 (16.62%)	796/4852 (16.41%)
Oedema ^* 1	287/4814 (5.96%)	276/4852 (5.69%)
Oedema peripheral ^* 1	214/4814 (4.45%)	166/4852 (3.42%)
Pain ^* 1	492/4814 (10.22%)	541/4852 (11.15%)
Infections and infestations
Bronchitis ^* 1	135/4814 (2.80%)	128/4852 (2.64%)
Cystitis ^* 1	76/4814 (1.58%)	102/4852 (2.10%)
Herpes zoster ^* 1	76/4814 (1.58%)	112/4852 (2.31%)
Infection ^* 1	197/4814 (4.09%)	168/4852 (3.46%)
Nasopharyngitis ^* 1	99/4814 (2.06%)	110/4852 (2.27%)
Urinary tract infection ^* 1	114/4814 (2.37%)	129/4852 (2.66%)
Vaginal infection ^* 1	100/4814 (2.08%)	47/4852 (0.97%)
Investigations
Weight decreased ^* 1	140/4814 (2.91%)	187/4852 (3.85%)
Weight increased ^* 1	415/4814 (8.62%)	339/4852 (6.99%)
Metabolism and nutrition disorders
Decreased appetite ^* 1	118/4814 (2.45%)	132/4852 (2.72%)
Hypercholesterolaemia ^* 1	99/4814 (2.06%)	190/4852 (3.92%)
Hyperglycaemia ^* 1	97/4814 (2.01%)	113/4852 (2.33%)
Musculoskeletal and connective tissue disorders
Arthralgia ^* 1	1002/4814 (20.81%)	1157/4852 (23.85%)
Arthritis ^* 1	130/4814 (2.70%)	161/4852 (3.32%)
Back pain ^* 1	269/4814 (5.59%)	273/4852 (5.63%)
Bone pain ^* 1	230/4814 (4.78%)	261/4852 (5.38%)
Muscle spasms ^* 1	245/4814 (5.09%)	133/4852 (2.74%)
Musculoskeletal pain ^* 1	128/4814 (2.66%)	176/4852 (3.63%)
Myalgia ^* 1	360/4814 (7.48%)	364/4852 (7.50%)
Osteoarthritis ^* 1	142/4814 (2.95%)	165/4852 (3.40%)
Osteoporosis ^* 1	219/4814 (4.55%)	428/4852 (8.82%)
Pain in extremity ^* 1	147/4814 (3.05%)	171/4852 (3.52%)
Nervous system disorders
Amnesia ^* 1	143/4814 (2.97%)	188/4852 (3.87%)
Carpal tunnel syndrome ^* 1	76/4814 (1.58%)	109/4852 (2.25%)
Dizziness ^* 1	289/4814 (6.00%)	243/4852 (5.01%)
Headache ^* 1	372/4814 (7.73%)	369/4852 (7.61%)
Neuropathy peripheral ^* 1	120/4814 (2.49%)	174/4852 (3.59%)
Paraesthesia ^* 1	66/4814 (1.37%)	100/4852 (2.06%)
Psychiatric disorders
Anxiety ^* 1	174/4814 (3.61%)	167/4852 (3.44%)
Depression ^* 1	417/4814 (8.66%)	404/4852 (8.33%)
Insomnia ^* 1	452/4814 (9.39%)	549/4852 (11.31%)
Libido decreased ^* 1	164/4814 (3.41%)	196/4852 (4.04%)
Mood altered ^* 1	147/4814 (3.05%)	151/4852 (3.11%)
Sleep disorder ^* 1	61/4814 (1.27%)	110/4852 (2.27%)
Reproductive system and breast disorders
Breast pain ^* 1	104/4814 (2.16%)	121/4852 (2.49%)
Vaginal discharge ^* 1	316/4814 (6.56%)	111/4852 (2.29%)
Vaginal haemorrhage ^* 1	186/4814 (3.86%)	94/4852 (1.94%)
Vulvovaginal dryness ^* 1	268/4814 (5.57%)	321/4852 (6.62%)
Respiratory, thoracic and mediastinal disorders
Cough ^* 1	252/4814 (5.23%)	235/4852 (4.84%)
Dyspnoea ^* 1	243/4814 (5.05%)	223/4852 (4.60%)
Skin and subcutaneous tissue disorders
Alopecia ^* 1	299/4814 (6.21%)	329/4852 (6.78%)
Dry skin ^* 1	122/4814 (2.53%)	114/4852 (2.35%)
Hyperhidrosis ^* 1	175/4814 (3.64%)	103/4852 (2.12%)
Night sweats ^* 1	102/4814 (2.12%)	87/4852 (1.79%)
Pruritus ^* 1	158/4814 (3.28%)	153/4852 (3.15%)
Rash ^* 1	216/4814 (4.49%)	227/4852 (4.68%)
Vascular disorders
Flushing ^* 1	183/4814 (3.80%)	114/4852 (2.35%)
Hot flush ^* 1	1690/4814 (35.11%)	1517/4852 (31.27%)
Hypertension ^* 1	224/4814 (4.65%)	291/4852 (6.00%)
Lymphoedema ^* 1	247/4814 (5.13%)	227/4852 (4.68%)
* Indicates events were collected by non-systematic assessment 1 Term from vocabulary, MedDRA 14.0

Limitations and Caveats

Overall Survival was reported as number of events which otherwise reported as time.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.

Results Point of Contact

Layout table for Results Point of Contact information

Name/Title:	Pfizer ClinicalTrials.gov Call Center
Organization:	Pfizer, Inc.
Phone:	1-800-718-1021
EMail:	ClinicalTrials.gov_Inquiries@pfizer.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Noordhoek I, Blok EJ, Meershoek-Klein Kranenbarg E, Putter H, Duijm-de Carpentier M, Rutgers EJT, Seynaeve C, Bartlett JMS, Vannetzel JM, Rea DW, Hasenburg A, Paridaens R, Markopoulos CJ, Hozumi Y, Portielje JEA, Kroep JR, van de Velde CJH, Liefers GJ. Overestimation of Late Distant Recurrences in High-Risk Patients With ER-Positive Breast Cancer: Validity and Accuracy of the CTS5 Risk Score in the TEAM and IDEAL Trials. J Clin Oncol. 2020 Oct 1;38(28):3273-3281. doi: 10.1200/JCO.19.02427. Epub 2020 Jul 24.

Derks MGM, Bastiaannet E, van de Water W, de Glas NA, Seynaeve C, Putter H, Nortier JWR, Rea D, Hasenburg A, Markopoulos C, Dirix LY, Portielje JEA, van de Velde CJH, Liefers GJ. Impact of age on breast cancer mortality and competing causes of death at 10 years follow-up in the adjuvant TEAM trial. Eur J Cancer. 2018 Aug;99:1-8. doi: 10.1016/j.ejca.2018.04.009. Epub 2018 Jun 6.

Bartlett JM, Brookes CL, Piper T, van de Velde CJ, Stocken D, Lyttle N, Hasenburg A, Quintayo MA, Kieback DG, Putter H, Markopoulos C, Kranenbarg EM, Mallon EA, Dirix LY, Seynaeve C, Rea DW. Do type 1 receptor tyrosine kinases inform treatment choice? A prospectively planned analysis of the TEAM trial. Br J Cancer. 2013 Oct 29;109(9):2453-61. doi: 10.1038/bjc.2013.609. Epub 2013 Oct 3.

van de Velde CJ, Rea D, Seynaeve C, Putter H, Hasenburg A, Vannetzel JM, Paridaens R, Markopoulos C, Hozumi Y, Hille ET, Kieback DG, Asmar L, Smeets J, Nortier JW, Hadji P, Bartlett JM, Jones SE. Adjuvant tamoxifen and exemestane in early breast cancer (TEAM): a randomised phase 3 trial. Lancet. 2011 Jan 22;377(9762):321-31. doi: 10.1016/S0140-6736(10)62312-4.

Layout table for additonal information

Responsible Party:	Pfizer
ClinicalTrials.gov Identifier:	NCT00036270
Other Study ID Numbers:	971-ONC-0028-081 A5991026
First Submitted:	May 8, 2002
First Posted:	May 9, 2002
Results First Submitted:	October 30, 2009
Results First Posted:	December 4, 2009
Last Update Posted:	October 28, 2015

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