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Clinical Trial Results:
A Randomized, Double-Blind, Placebo-Controlled, Multi-Center Phase 3 Study to Determine the Treatment Effect of Denosumab in Subjects With Non-Metastatic Breast Cancer Receiving Aromatase Inhibitor Therapy

Summary
EudraCT number	2005-005275-15
Trial protocol	AT SE
Global end of trial date	09 Aug 2020

Results information
Results version number	v1(current)
This version publication date	04 Aug 2023
First version publication date	04 Aug 2023
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

20050209

ISRCTN number

US NCT number

NCT00556374

WHO universal trial number (UTN)

Sponsor organisation name

Amgen Inc.

Sponsor organisation address

One Amgen Center Drive, Thousand Oaks, CA, United States,

Public contact

IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com

Scientific contact

IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

09 Aug 2020

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

09 Aug 2020

Was the trial ended prematurely?

Main objective of the trial

The main objective of this trial was to determine whether denosumab compared to placebo reduced the rate of first (on study) clinical fracture (ie, clinically evident fracture with associated symptoms) in women with non-metastatic breast cancer receiving non-steroidal aromatase inhibitor therapy (AIT).

Protection of trial subjects

This study was conducted in accordance with International Council for Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines.

Background therapy

Evidence for comparator

Actual start date of recruitment

18 Dec 2006

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy

Long term follow-up duration

66 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Austria: 3297

Country: Number of subjects enrolled

Sweden: 123

Worldwide total number of subjects

3420

EEA total number of subjects

3420

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

1734

From 65 to 84 years

1669

85 years and over

Subject disposition

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Recruitment details

Participants were enrolled at 58 centers in Austria and Sweden from December 2006 to August 2020. Data collected during the exploratory ZA substudy were not used for the final analysis of the main study.

Screening details

Participants were randomized in a 1:1 ratio to receive either denosumab or placebo in the double-blind phase. Randomization was stratified by type of hospital, prior aromatase inhibitor usage and total lumbar spine BMD at baseline. Eligible participants continued into the open-label phase and receive denosumab for a maximum of 7 doses.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Placebo

Arm description

Participants randomized to receive the matching placebo subcutaneously (SC) once every 6 months (Q6M) in the double-blind phase. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.

Arm type

Placebo

Investigational medicinal product name

Denosumab

Investigational medicinal product code

Other name

Prolia®

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

60 mg SC Q6M in the open-label phase

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

Matching placebo administered SC Q6M

Denosumab

Arm description

Participants randomized to receive 60 mg denosumab SC once Q6M in the double-blind phase. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.

Arm type

Experimental

Investigational medicinal product name

Denosumab

Investigational medicinal product code

Other name

Prolia®

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

60 mg SC Q6M

Number of subjects in period 1	Placebo	Denosumab
Started	1709	1711
Received Treatment in Double-blind Phase	1699	1700
Received Treatment in Open-label Phase	252 ^[1]	2 ^[2]
Completed	1242	1362
Not completed	467	349
Adverse event, serious fatal	158	127
Consent withdrawn by subject	235	205
Ongoing on Zoledronic Acid Substudy	50	-
Lost to follow-up	24	17

Notes
[1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Number of participants who completed includes both participants who completed either the double-blind phase or open-label phase.
[2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Number of participants who completed includes both participants who completed either the double-blind phase or open-label phase.

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Reporting group title

Denosumab

Reporting group description

Participants randomized to receive 60 mg denosumab SC once Q6M in the double-blind phase. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.

Reporting group values	Placebo	Denosumab	Total
Number of subjects	1709	1711	3420
Age Categorical
Units: Subjects
< 50 years	31	34	65
50 - 59 years	448	473	921
60 - 69 years	755	782	1537
70 - 79 years	414	372	786
≥ 80 years	61	50	111
Age Continuous
Units: years
arithmetic mean (standard deviation)	64.6 ( 8.0 )	64.0 ( 7.9 )	-
Gender Categorical
Units: Subjects
Female	1709	1711	3420
Male	0	0	0
Race
Units: Subjects
White/Caucasian	1700	1702	3402
Asian	7	5	12
Hispanic/Latino	1	3	4
Black/Afro-Caribbean	0	1	1
Missing	1	0	1
Type of Hospital (Strata per Randomization)
Units: Subjects
Major Academic Center	632	633	1265
Other Center	1077	1078	2155
Prior Aromatase Inhibitor Use (Strata per Randomization)
Units: Subjects
No.	269	270	539
Yes.	1440	1441	2881
Total Lumbar Spine Bone Mineral Density T-score (Strata per Randomization)
T-scores are standardized scores that reflect the standard deviations (SDs) above/below the normal mean for young adults. T-score ≥ -1.0: BMD is considered normal. T-score < -1.0: Low BMD.
Units: Subjects
< -1.0	775	773	1548
≥ -1.0	934	938	1872

End points

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Reporting group title

Placebo

Reporting group description

Reporting group title

Denosumab

Reporting group description

Participants randomized to receive 60 mg denosumab SC once Q6M in the double-blind phase. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.

Primary: Time to First Clinical Fracture

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End point title

Time to First Clinical Fracture

End point description

The time to first on-study clinical fracture was defined as the number of days from randomization to the date of the x-ray confirming the clinical fracture. A clinical fracture was any clinically evident fracture with associated symptoms and confirmed by x-ray. Participants who died or withdrew without experiencing a clinical fracture were censored at the date of last contact or study termination whichever was earlier. 99999: No data reported as not reached due to the low number of events.

End point type

Primary

End point timeframe

From randomization until the primary analysis cut-off date of 26 March 2014; maximum time on main study at the cut-off was 87 months

End point values	Placebo	Denosumab
Number of subjects analysed	1709	1711
Units: Days
median (confidence interval 95%)	99999 (99999 to 99999)	99999 (99999 to 99999)

Placebo vs Denosumab

Comparison groups

Placebo v Denosumab

Number of subjects included in analysis

3420

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

< 0.0001 ^[2]

Method

Cox Proportional Hazards Model

Parameter type

Hazard ratio (HR)

Point estimate

0.504

Confidence interval

level

95%

sides

2-sided

lower limit

0.39

upper limit

0.65

Notes
[1] - A hazard ratio < 1.0 indicates a lower average event rate and a longer fracture free time for denosumab relative to placebo.
[2] - Stratification factors are hospital type, prior use of aromatase inhibitor, and baseline lumbar spine BMD. Model includes treatment group as the independent variable and stratified by randomization stratification factors.

Secondary: Percent Change from Baseline in Total Lumbar Spine Bone Mineral Density (BMD) at Month 36

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End point title

Percent Change from Baseline in Total Lumbar Spine Bone Mineral Density (BMD) at Month 36

End point description

BMD was assessed by dual x-ray absorptiometry.

End point type

Secondary

End point timeframe

Baseline and Month 36

End point values	Placebo	Denosumab
Number of subjects analysed	245 ^[3]	230 ^[4]
Units: Percent change in BMD
least squares mean (confidence interval 95%)	-2.75 (-3.44 to -2.07)	7.27 (6.56 to 7.98)

Notes
[3] - All participants with evaluable lumbar spine BMD values at Baseline and Month 36
[4] - All participants with evaluable lumbar spine BMD values at Baseline and Month 36

Placebo vs Denosumab

Comparison groups

Placebo v Denosumab

Number of subjects included in analysis

475

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[5]

Method

ANCOVA

Parameter type

Difference from Placebo

Point estimate

10.02

Confidence interval

level

95%

sides

2-sided

lower limit

9.04

upper limit

11.01

Notes
[5] - Model includes treatment group as the independent variable and adjusted for baseline value and the randomization stratification factors. The Hochberg procedure was used to control for multiplicity.

Secondary: Percent Change from Baseline in Total Hip BMD at Month 36

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End point title

Percent Change from Baseline in Total Hip BMD at Month 36

End point description

End point type

Secondary

End point timeframe

Baseline and Month 36

End point values	Placebo	Denosumab
Number of subjects analysed	237 ^[6]	231 ^[7]
Units: Percent change in BMD
least squares mean (confidence interval 95%)	-3.32 (-4.06 to -2.58)	4.60 (3.85 to 5.35)

Notes
[6] - All participants with total hip BMD evaluable values at Baseline and Month 36
[7] - All participants with total hip BMD evaluable values at Baseline and Month 36

Placebo vs Denosumab

Comparison groups

Placebo v Denosumab

Number of subjects included in analysis

468

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[8]

Method

ANCOVA

Parameter type

Difference from the Placebo

Point estimate

7.92

Confidence interval

level

95%

sides

2-sided

lower limit

6.87

upper limit

8.97

Notes
[8] - Model includes treatment group as the independent variable and adjusted for baseline value and the randomization stratification factors. The Hochberg procedure was used to control for multiplicity.

Secondary: Percent Change from Baseline in Femoral Neck BMD at Month 36

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End point title

Percent Change from Baseline in Femoral Neck BMD at Month 36

End point description

End point type

Secondary

End point timeframe

Baseline and Month 36

End point values	Placebo	Denosumab
Number of subjects analysed	238 ^[9]	231 ^[10]
Units: Percent change in BMD
least squares mean (confidence interval 95%)	-3.10 (-3.72 to -2.48)	3.41 (2.78 to 4.04)

Notes
[9] - All participants with evaluable femoral neck BMD values at Baseline and Month 36
[10] - All participants with evaluable femoral neck BMD values at Baseline and Month 36

Placebo vs Denosumab

Comparison groups

Placebo v Denosumab

Number of subjects included in analysis

469

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[11]

Method

ANCOVA

Parameter type

Difference from Placebo

Point estimate

6.51

Confidence interval

level

95%

sides

2-sided

lower limit

5.62

upper limit

7.39

Notes
[11] - Model includes treatment group as the independent variable and adjusted for baseline value and the randomization stratification factors. The Hochberg procedure was used to control for multiplicity.

Secondary: Bone Metastases-free Survival (BMFS)

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End point title

Bone Metastases-free Survival (BMFS)

End point description

BMFS was defined as the time interval from randomization to first occurrence of bone metastasis or death from any cause, whichever comes first. Participants last known to be alive, who did not experience bone metastasis, were censored at their last assessment (i.e., bone scan) date or at the last contact date, whichever comes first. 99999 = Not reached due to the low number of events.

End point type

Secondary

End point timeframe

From randomization until end of main study, maximum time on main study was 152 months

End point values	Placebo	Denosumab
Number of subjects analysed	1709	1711
Units: Days
median (confidence interval 95%)	99999 (99999 to 99999)	99999 (99999 to 99999)

Placebo vs Denosumab

Statistical analysis description

Analysis of BMFS was conditional on the outcome of DFS due to hierarchical testing strategy, therefore p-value not reported.

Comparison groups

Placebo v Denosumab

Number of subjects included in analysis

3420

Analysis specification

Pre-specified

Analysis type

superiority ^[12]

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.808

Confidence interval

level

95%

sides

2-sided

lower limit

0.654

upper limit

0.997

Notes
[12] - A hazard ratio < 1.0 indicates a lower average event rate and a longer bone metastases-free time for denosumab relative to placebo.

Secondary: Number of Participants With New or Worsening Vertebral Fractures

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End point title

Number of Participants With New or Worsening Vertebral Fractures

End point description

Assessment of vertebral fractures was performed by an expert radiologist at the central imaging center using a semiquantitative grading scale: Grade 1, 20% to 25% reduction in vertebral height (anterior, middle, or posterior); Grade 2, 25% to 40% reduction in height; Grade 3, greater than 40% reduction in height. A new vertebral fracture was defined as a fracture in a previously undeformed vertebrae including new compression fractures, defined as those compression fractures having a decrease in total anterior or posterior height of at least 25% from baseline. New vertebral fractures includes morphometric vertebral fractures identified from on study x-rays and clinical vertebral fractures confirmed by x-rays. Worsening of pre-existing fractures was defined as an increase in fracture severity of at least 1 grade on the semiquantitative scale.

End point type

Secondary

End point timeframe

Month 36

End point values	Placebo	Denosumab
Number of subjects analysed	809 ^[13]	835 ^[14]
Units: Participants	55	31

Notes
[13] - All participants with Baseline and at least 1 post-baseline vertebral x-ray prior to or at Month 36
[14] - All participants with Baseline and at least 1 post-baseline vertebral x-ray prior to or at Month 36

Placebo vs Debisumab

Comparison groups

Placebo v Denosumab

Number of subjects included in analysis

1644

Analysis specification

Pre-specified

Analysis type

superiority ^[15]

P-value

= 0.007 ^[16]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.54

Confidence interval

level

95%

sides

2-sided

lower limit

0.34

upper limit

0.84

Notes
[15] - Values < 1 for Odds Ratio favor denosumab.
[16] - Logistic regression model includes treatment groups as the independent variable and stratified by the randomization stratification factors.

Secondary: Number of Participants with New Vertebral Fractures

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End point title

Number of Participants with New Vertebral Fractures

End point description

End point type

Secondary

End point timeframe

Month 36

End point values	Placebo	Denosumab
Number of subjects analysed	809 ^[17]	835 ^[18]
Units: Participants	49	27

Notes
[17] - All participants with Baseline and at least 1 post-baseline vertebral x-ray prior to or at Month 36
[18] - All participants with Baseline and at least 1 post-baseline vertebral x-ray prior to or at Month 36

Placebo vs Denosumab

Comparison groups

Placebo v Denosumab

Number of subjects included in analysis

1644

Analysis specification

Pre-specified

Analysis type

superiority ^[19]

P-value

= 0.0088 ^[20]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.53

Confidence interval

level

95%

sides

2-sided

lower limit

0.33

upper limit

0.85

Notes
[19] - Values < 1 for Odds Ratio favor denosumab.
[20] - Logistic regression model includes treatment group as the independent variable and stratified by the randomization stratification factors.

Secondary: Disease-free Survival (DFS)

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End point title

Disease-free Survival (DFS)

End point description

Disease-free survival (DFS) was defined as the time interval from the randomization date to the date of first evidence of local or distant metastases, contra-lateral breast cancer, secondary carcinoma, or death from any cause (whichever occurred first). Participants last known to be alive, who did not experience recurrence of disease, were censored at their last contact date or at the data cut-off date whichever came first. 99999: Not reached due to low number of events.

End point type

Secondary

End point timeframe

From randomization until the DFS data cut-off date of 15 September 2015; maximum time on main study at the cut-off was 102 months

End point values	Placebo	Denosumab
Number of subjects analysed	1709	1711
Units: Days
median (confidence interval 95%)	99999 (99999 to 99999)	99999 (99999 to 99999)

Placebo vs Denosumab

Statistical analysis description

A hazard ratio < 1.0 indicates a lower average event rate and a longer disease free time for denosumab relative to placebo.

Comparison groups

Placebo v Denosumab

Number of subjects included in analysis

3420

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0515 ^[21]

Method

Cox Proportional Hazards Model

Parameter type

Hazard ratio (HR)

Point estimate

0.816

Confidence interval

level

95%

sides

2-sided

lower limit

0.66

upper limit

Notes
[21] - Model includes treatment group as the independent variable and stratified by the randomization stratification factors.

Secondary: Overall Survival (OS)

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End point title

Overall Survival (OS)

End point description

OS was defined as the time from randomization to death from any cause. 99999 = Not reached due to the low number of events.

End point type

Secondary

End point timeframe

Randomization until end of main study, maximum duration of main study was 152 months

End point values	Placebo	Denosumab
Number of subjects analysed	1709	1711
Units: Days
median (confidence interval 95%)	99999 (99999 to 99999)	99999 (99999 to 99999)

Placebo vs Denosumab

Statistical analysis description

Analysis of OS was conditional on the outcome of DFS due to hierarchical testing strategy, therefore p-value not reported.

Comparison groups

Placebo v Denosumab

Number of subjects included in analysis

3420

Analysis specification

Pre-specified

Analysis type

superiority ^[22]

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.802

Confidence interval

level

95%

sides

2-sided

lower limit

0.635

upper limit

1.013

Notes
[22] - A hazard ratio < 1.0 indicates a lower average event rate and a longer overall survival time for denosumab relative to placebo.

Adverse events

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Timeframe for reporting adverse events

Deaths: 1st dose to end of main study, max time: 152 months. AEs: 1st dose to 30 days after the last dose in DB and OL phases, respectively. Median treatment time: 35.4 months (placebo) and 35.5 months (denosumab) in DB phase; 37 months in OL phase

Adverse event reporting additional description

All participants who were randomized and received at least 1 dose of treatment; participants were analyzed according to their actual treatment received. For Deaths, participants who did not receive OL treatment and died in the long-term follow-up phase are included in the DB columns. MedDRA 17.1 used for the DB phase and 24.0 used for the OL phase.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

17.1

Reporting group title

Double-blind (DB) Phase: Placebo

Reporting group description

Participants received the matching placebo SC Q6M in the double-blind phase. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.

Reporting group title

Open-label (OL) Phase: Denosumab/Denosumab

Reporting group description

Participants who received denosumab in the double-blind phase who continued into the open-label phase, where they received denosumab 60 mg SC Q6M for a maximum of 7 additional doses.

Reporting group title

Open Label (OL) Phase: Placebo/Denosumab

Reporting group description

Participants who received the matching placebo in the double-blind phase who continued into the open-label phase, where they received denosumab 60 mg SC Q6M for a maximum of 7 additional doses.

Reporting group title

Double-blind (DB) Phase: Denosumab

Reporting group description

Participants received denosumab SC Q6M in the double-blind phase. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.

Serious adverse events	Double-blind (DB) Phase: Placebo	Open-label (OL) Phase: Denosumab/Denosumab	Open Label (OL) Phase: Placebo/Denosumab	Double-blind (DB) Phase: Denosumab
Total subjects affected by serious adverse events
subjects affected / exposed	515 / 1690 (30.47%)	0 / 1 (0.00%)	40 / 245 (16.33%)	521 / 1709 (30.49%)
number of deaths (all causes)	153	0	4	127
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma
subjects affected / exposed	5 / 1690 (0.30%)	0 / 1 (0.00%)	0 / 245 (0.00%)	4 / 1709 (0.23%)
occurrences causally related to treatment / all	0 / 5	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Adenocarcinoma of colon
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Benign breast neoplasm
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Benign lymph node neoplasm
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Benign salivary gland neoplasm
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Breast cancer
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	3 / 245 (1.22%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bladder transitional cell carcinoma recurrent
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bowen's disease
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Breast adenoma
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bladder papilloma
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Breast cancer metastatic
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Breast cancer recurrent
subjects affected / exposed	4 / 1690 (0.24%)	0 / 1 (0.00%)	1 / 245 (0.41%)	3 / 1709 (0.18%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Breast cancer stage III
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Colon adenoma
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	3 / 1709 (0.18%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cervix carcinoma
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholangiocarcinoma
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	1 / 245 (0.41%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chronic lymphocytic leukaemia
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchial carcinoma
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	3 / 1709 (0.18%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Colon cancer
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Colon neoplasm
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Contralateral breast cancer
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	4 / 1709 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemangioma of liver
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fibroadenoma of breast
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastric cancer
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal tract adenoma
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endometrial adenocarcinoma
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic neoplasm
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Inflammatory myofibroblastic tumour
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal adenocarcinoma
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lentigo maligna
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intraductal proliferative breast lesion
subjects affected / exposed	4 / 1690 (0.24%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Invasive ductal breast carcinoma
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Leiomyosarcoma
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	1 / 245 (0.41%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intraductal papilloma of breast
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lip and/or oral cavity cancer
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lipoma
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lobular breast carcinoma in situ
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Malignant pleural effusion
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Lung neoplasm malignant
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Malignant melanoma
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Malignant melanoma in situ
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lung adenocarcinoma
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Mediastinum neoplasm
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Melanocytic naevus
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Meningioma
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to lymph nodes
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to bone
subjects affected / exposed	5 / 1690 (0.30%)	0 / 1 (0.00%)	0 / 245 (0.00%)	5 / 1709 (0.29%)
occurrences causally related to treatment / all	0 / 5	0 / 0	0 / 0	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to liver
subjects affected / exposed	3 / 1690 (0.18%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Metastases to lung
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Meningioma benign
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to peritoneum
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to pleura
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to skin
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ovarian fibroma
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oral fibroma
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ovarian adenoma
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	4 / 1709 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ovarian epithelial cancer
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neuroma
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatic carcinoma
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Papillary thyroid cancer
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Parathyroid tumour benign
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rectal cancer
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	3 / 1709 (0.18%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rectal adenocarcinoma
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rectal adenoma
subjects affected / exposed	3 / 1690 (0.18%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pituitary tumour benign
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal cell carcinoma
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	1 / 245 (0.41%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Salivary gland adenoma
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Schwannoma
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Thyroid neoplasm
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma of lung
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Thyroid adenoma
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Thyroid cancer
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma
subjects affected / exposed	3 / 1690 (0.18%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Transitional cell carcinoma
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Transitional cell carcinoma urethra
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Uterine leiomyoma
subjects affected / exposed	3 / 1690 (0.18%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Uterine leiomyosarcoma
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vulval cancer
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	1 / 245 (0.41%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Hypertension
subjects affected / exposed	6 / 1690 (0.36%)	0 / 1 (0.00%)	1 / 245 (0.41%)	5 / 1709 (0.29%)
occurrences causally related to treatment / all	0 / 6	0 / 0	0 / 1	1 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haematoma
subjects affected / exposed	3 / 1690 (0.18%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Circulatory collapse
subjects affected / exposed	4 / 1690 (0.24%)	0 / 1 (0.00%)	0 / 245 (0.00%)	3 / 1709 (0.18%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	3 / 1690 (0.18%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Femoral artery occlusion
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bleeding varicose vein
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Arteriovenous fistula
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Arterial stenosis
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Aortic dissection
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Subclavian steal syndrome
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Subclavian artery stenosis
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypertensive crisis
subjects affected / exposed	14 / 1690 (0.83%)	0 / 1 (0.00%)	1 / 245 (0.41%)	10 / 1709 (0.59%)
occurrences causally related to treatment / all	0 / 15	0 / 0	0 / 1	0 / 11
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypotension
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Iliac artery occlusion
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intermittent claudication
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lymphoedema
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	5 / 1709 (0.29%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral arterial occlusive disease
subjects affected / exposed	4 / 1690 (0.24%)	0 / 1 (0.00%)	0 / 245 (0.00%)	3 / 1709 (0.18%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 0	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Raynaud's phenomenon
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral venous disease
subjects affected / exposed	4 / 1690 (0.24%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral artery stenosis
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	3 / 1709 (0.18%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Thrombosis
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Thrombophlebitis
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Temporal arteritis
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Venous thrombosis
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vasculitis
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 10	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Varicose vein
subjects affected / exposed	10 / 1690 (0.59%)	0 / 1 (0.00%)	1 / 245 (0.41%)	12 / 1709 (0.70%)
occurrences causally related to treatment / all	0 / 11	0 / 0	0 / 1	0 / 14
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Venous thrombosis limb
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Knee arthroplasty
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Mastectomy
subjects affected / exposed	3 / 1690 (0.18%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intraocular lens implant
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hysterosalpingo-oophorectomy
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Breast reconstruction
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hysterectomy
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Prophylaxis
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oophorectomy
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Fibrosis
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fat necrosis
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Face oedema
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Device dislocation
subjects affected / exposed	4 / 1690 (0.24%)	0 / 1 (0.00%)	0 / 245 (0.00%)	3 / 1709 (0.18%)
occurrences causally related to treatment / all	0 / 5	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chest pain
subjects affected / exposed	7 / 1690 (0.41%)	0 / 1 (0.00%)	1 / 245 (0.41%)	4 / 1709 (0.23%)
occurrences causally related to treatment / all	0 / 9	0 / 0	0 / 1	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cyst
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Device connection issue
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chest discomfort
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Medical device complication
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Local swelling
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Incarcerated hernia
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Impaired healing
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	4 / 1709 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyperplasia
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	3 / 1709 (0.18%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Multi-organ failure
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Non-cardiac chest pain
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	3 / 1709 (0.18%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pain
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Granuloma
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Allergy to arthropod sting
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anaphylactic reaction
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sarcoidosis
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypersensitivity
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Drug hypersensitivity
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Adenomyosis
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Breast disorder
subjects affected / exposed	6 / 1690 (0.36%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 6	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Adnexa uteri mass
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Breast calcifications
subjects affected / exposed	4 / 1690 (0.24%)	0 / 1 (0.00%)	0 / 245 (0.00%)	4 / 1709 (0.23%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Breast cyst
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Breast discharge
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Adnexa uteri cyst
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Breast enlargement
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Breast fibrosis
subjects affected / exposed	3 / 1690 (0.18%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 5	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Breast haematoma
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Breast necrosis
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	3 / 1709 (0.18%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Breast pain
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fibrocystic breast disease
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	3 / 1709 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cervical polyp
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	3 / 1709 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cystocele
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dyspareunia
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endometrial hyperplasia
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	3 / 1709 (0.18%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cervical dysplasia
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	4 / 1709 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vaginal prolapse
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hydrometra
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	1 / 245 (0.41%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Uterovaginal prolapse
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Postmenopausal haemorrhage
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	3 / 1709 (0.18%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rectocele
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Uterine adhesions
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Uterine polyp
subjects affected / exposed	3 / 1690 (0.18%)	0 / 1 (0.00%)	0 / 245 (0.00%)	4 / 1709 (0.23%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Uterine prolapse
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ovarian cyst
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	7 / 1709 (0.41%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Atelectasis
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cheyne-Stokes respiration
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	3 / 1709 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cough
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diaphragmatic paralysis
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	4 / 1690 (0.24%)	0 / 1 (0.00%)	0 / 245 (0.00%)	3 / 1709 (0.18%)
occurrences causally related to treatment / all	0 / 5	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea exertional
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	4 / 1709 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Organising pneumonia
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Epistaxis
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyperventilation
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lung disorder
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nasal polyps
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Emphysema
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oropharyngeal pain
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pharyngeal cyst
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pleurisy
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary alveolar haemorrhage
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	11 / 1690 (0.65%)	0 / 1 (0.00%)	1 / 245 (0.41%)	12 / 1709 (0.70%)
occurrences causally related to treatment / all	0 / 11	0 / 0	0 / 1	0 / 14
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary fibrosis
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary hypertension
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary mass
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary oedema
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	1 / 245 (0.41%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sinus polyp
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vocal cord polyp
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sleep apnoea syndrome
subjects affected / exposed	5 / 1690 (0.30%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 6	0 / 0	0 / 0	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Depression
subjects affected / exposed	8 / 1690 (0.47%)	0 / 1 (0.00%)	0 / 245 (0.00%)	8 / 1709 (0.47%)
occurrences causally related to treatment / all	0 / 8	0 / 0	0 / 0	0 / 10
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bipolar disorder
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Burnout syndrome
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Depressed mood
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Alcohol withdrawal syndrome
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Mental disorder
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Panic attack
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Post-traumatic stress disorder
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Stress
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Suicide attempt
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psychosomatic disease
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Weight decreased
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Smear cervix abnormal
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary arterial pressure increased
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Mammogram abnormal
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Glycosylated haemoglobin increased
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Colonoscopy
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood pressure abnormal
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood creatinine increased
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Concussion
subjects affected / exposed	5 / 1690 (0.30%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 5	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bursa injury
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Brain contusion
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bone contusion
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Animal bite
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anastomotic stenosis
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Alcohol poisoning
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Incisional hernia
subjects affected / exposed	3 / 1690 (0.18%)	0 / 1 (0.00%)	0 / 245 (0.00%)	3 / 1709 (0.18%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Joint dislocation
subjects affected / exposed	3 / 1690 (0.18%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Joint injury
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ligament rupture
subjects affected / exposed	3 / 1690 (0.18%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ligament sprain
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Meniscus injury
subjects affected / exposed	24 / 1690 (1.42%)	0 / 1 (0.00%)	0 / 245 (0.00%)	23 / 1709 (1.35%)
occurrences causally related to treatment / all	0 / 24	0 / 0	0 / 0	0 / 25
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemodilution
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Extradural haematoma
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Contusion
subjects affected / exposed	6 / 1690 (0.36%)	0 / 1 (0.00%)	0 / 245 (0.00%)	4 / 1709 (0.23%)
occurrences causally related to treatment / all	0 / 7	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Head injury
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural bile leak
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural complication
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural haematoma
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural haemorrhage
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	1 / 245 (0.41%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural inflammation
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Post-traumatic neck syndrome
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Postoperative hernia
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Postoperative thrombosis
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Procedural intestinal perforation
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Procedural pain
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Radiation alveolitis
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Radiation pneumonitis
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Radiation skin injury
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	4 / 1709 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Road traffic accident
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Scar
subjects affected / exposed	5 / 1690 (0.30%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 5	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Seroma
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin abrasion
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Toxicity to various agents
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Splenic haematoma
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	4 / 1690 (0.24%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Suture rupture
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tendon rupture
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Spinal column injury
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Wound dehiscence
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Traumatic arthrosis
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular bypass dysfunction
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Wound
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Congenital, familial and genetic disorders
Gene mutation
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Developmental hip dysplasia
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Arrhythmia
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	1 / 245 (0.41%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Aortic valve stenosis
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	4 / 1709 (0.23%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Aortic valve incompetence
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	4 / 1690 (0.24%)	0 / 1 (0.00%)	0 / 245 (0.00%)	5 / 1709 (0.29%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 0	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Acute left ventricular failure
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Acute coronary syndrome
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Arteriosclerosis coronary artery
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Atrial tachycardia
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Atrial flutter
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	11 / 1690 (0.65%)	0 / 1 (0.00%)	3 / 245 (1.22%)	14 / 1709 (0.82%)
occurrences causally related to treatment / all	0 / 17	0 / 0	0 / 4	0 / 16
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Atrioventricular block second degree
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bradycardia
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	3 / 1709 (0.18%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	8 / 1709 (0.47%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 9
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Cardio-respiratory arrest
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	5 / 1690 (0.30%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 6	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Congestive cardiomyopathy
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Coronary artery disease
subjects affected / exposed	11 / 1690 (0.65%)	0 / 1 (0.00%)	0 / 245 (0.00%)	10 / 1709 (0.59%)
occurrences causally related to treatment / all	0 / 11	0 / 0	0 / 0	0 / 10
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Mitral valve incompetence
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemic cardiomyopathy
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Coronary artery stenosis
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiomyopathy
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tachycardia
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Supraventricular tachycardia
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Supraventricular extrasystoles
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sinus tachycardia
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sick sinus syndrome
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Palpitations
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Stress cardiomyopathy
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Acoustic neuritis
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Amnesia
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Amnestic disorder
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrovascular disorder
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	9 / 1690 (0.53%)	0 / 1 (0.00%)	0 / 245 (0.00%)	6 / 1709 (0.35%)
occurrences causally related to treatment / all	0 / 11	0 / 0	0 / 0	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral ischaemia
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral infarction
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Carotid artery aneurysm
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Carpal tunnel syndrome
subjects affected / exposed	13 / 1690 (0.77%)	0 / 1 (0.00%)	0 / 245 (0.00%)	14 / 1709 (0.82%)
occurrences causally related to treatment / all	0 / 14	0 / 0	0 / 0	0 / 14
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Carotid artery stenosis
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	1 / 245 (0.41%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Carotid artery disease
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebellar haemorrhage
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diabetic coma
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dizziness
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dementia
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cognitive disorder
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chronic inflammatory demyelinating polyradiculoneuropathy
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cervicobrachial syndrome
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	3 / 1709 (0.18%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cervical radiculopathy
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cervical myelopathy
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intercostal neuralgia
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Guillain-Barre syndrome
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Generalised tonic-clonic seizure
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Facial paresis
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Facial neuralgia
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Drop attacks
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Monoplegia
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Morton's neuralgia
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Migraine
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Meralgia paraesthetica
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Medication overuse headache
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lumbar radiculopathy
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Loss of consciousness
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intracranial aneurysm
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Motor neurone disease
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nerve compression
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorder
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neuralgia
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Paraesthesia
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Paresis
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	1 / 245 (0.41%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peroneal nerve palsy
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Polyneuropathy
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Radicular syndrome
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sciatica
subjects affected / exposed	4 / 1690 (0.24%)	0 / 1 (0.00%)	1 / 245 (0.41%)	7 / 1709 (0.41%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 1	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Senile dementia
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Transient global amnesia
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	3 / 1709 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Speech disorder
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Spinal claudication
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	4 / 1690 (0.24%)	0 / 1 (0.00%)	0 / 245 (0.00%)	6 / 1709 (0.35%)
occurrences causally related to treatment / all	0 / 5	0 / 0	0 / 0	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Small fibre neuropathy
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
VIIth nerve paralysis
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular encephalopathy
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Lymphadenopathy
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lymphadenitis
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Leukopenia
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Iron deficiency anaemia
subjects affected / exposed	3 / 1690 (0.18%)	0 / 1 (0.00%)	0 / 245 (0.00%)	3 / 1709 (0.18%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood loss anaemia
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	1 / 245 (0.41%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anaemia
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	3 / 1709 (0.18%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Agranulocytosis
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Deafness unilateral
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Deafness
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ear canal stenosis
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Meniere's disease
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sudden hearing loss
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tinnitus
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vertigo
subjects affected / exposed	10 / 1690 (0.59%)	0 / 1 (0.00%)	0 / 245 (0.00%)	9 / 1709 (0.53%)
occurrences causally related to treatment / all	0 / 10	0 / 0	0 / 0	0 / 9
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vertigo positional
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	4 / 1709 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vestibular disorder
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Retinal detachment
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Open angle glaucoma
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Retinal degeneration
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Macular fibrosis
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Macular degeneration
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Glaucoma
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	1 / 245 (0.41%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Exfoliation glaucoma
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diabetic retinopathy
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cataract nuclear
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	3 / 1709 (0.18%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cataract cortical
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cataract
subjects affected / exposed	28 / 1690 (1.66%)	0 / 1 (0.00%)	2 / 245 (0.82%)	16 / 1709 (0.94%)
occurrences causally related to treatment / all	0 / 39	0 / 0	0 / 3	0 / 23
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blepharochalasis
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Retinal tear
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	1 / 245 (0.41%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vitreous haemorrhage
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vitreous opacities
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal adhesions
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal discomfort
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anal fissure
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal wall haematoma
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abnormal faeces
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal hernia
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chronic gastritis
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	3 / 1690 (0.18%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Colitis ischaemic
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Colon dysplasia
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Crohn's disease
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dental caries
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diaphragmatic hernia
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	4 / 1690 (0.24%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 6	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diverticular perforation
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulum
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulum intestinal
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Duodenitis
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Enteritis
subjects affected / exposed	3 / 1690 (0.18%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastric antral vascular ectasia
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastric haemorrhage
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastritis erosive
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal motility disorder
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal angiodysplasia
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastritis haemorrhagic
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	7 / 1690 (0.41%)	0 / 1 (0.00%)	1 / 245 (0.41%)	7 / 1709 (0.41%)
occurrences causally related to treatment / all	0 / 7	0 / 0	0 / 1	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Incarcerated umbilical hernia
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal perforation
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ileus
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Large intestinal stenosis
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal polyp
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hiatus hernia
subjects affected / exposed	4 / 1690 (0.24%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhoids
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	4 / 1709 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haematochezia
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal necrosis
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatic pseudocyst
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	3 / 1709 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peritoneal necrosis
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rectal polyp
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Large intestine perforation
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Painful defaecation
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal motility disorder
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Mallory-Weiss syndrome
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Large intestine polyp
subjects affected / exposed	4 / 1690 (0.24%)	0 / 1 (0.00%)	0 / 245 (0.00%)	8 / 1709 (0.47%)
occurrences causally related to treatment / all	0 / 6	0 / 0	0 / 0	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Subileus
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Umbilical hernia
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	4 / 1709 (0.23%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Swollen tongue
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Bile duct stone
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Biliary cirrhosis primary
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Biliary colic
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholangitis
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	8 / 1709 (0.47%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis chronic
subjects affected / exposed	3 / 1690 (0.18%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	9 / 1690 (0.53%)	0 / 1 (0.00%)	0 / 245 (0.00%)	14 / 1709 (0.82%)
occurrences causally related to treatment / all	0 / 9	0 / 0	0 / 0	0 / 15
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Drug-induced liver injury
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gallbladder polyp
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic cirrhosis
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Jaundice
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Dermatitis allergic
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diabetic foot
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Angioedema
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Acquired epidermolysis bullosa
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dermal cyst
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Drug eruption
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Erythema
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Eczema
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Erythema nodosum
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyperkeratosis
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Keloid scar
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lichen sclerosus
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Panniculitis
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rash
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rash maculo-papular
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Stasis dermatitis
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin ulcer
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	3 / 1709 (0.18%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urticaria
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Scar pain
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin necrosis
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute prerenal failure
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Acute kidney injury
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	1 / 245 (0.41%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Calculus ureteric
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cystitis haemorrhagic
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diabetic nephropathy
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hydronephrosis
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	1 / 245 (0.41%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal failure acute
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Incontinence
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	1 / 245 (0.41%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal artery stenosis
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal colic
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypertonic bladder
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Stress urinary incontinence
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	4 / 1709 (0.23%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urethral disorder
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urge incontinence
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 6	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary incontinence
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Basedow's disease
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Goitre
subjects affected / exposed	12 / 1690 (0.71%)	0 / 1 (0.00%)	1 / 245 (0.41%)	21 / 1709 (1.23%)
occurrences causally related to treatment / all	0 / 12	0 / 0	0 / 1	0 / 22
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyperparathyroidism
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyperthyroidism
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Acquired claw toe
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Exostosis
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dupuytren's contracture
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chondropathy
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	6 / 1709 (0.35%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chondromalacia
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cervical spinal stenosis
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bursitis
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bone pain
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bone cyst
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Arthralgia
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	6 / 1709 (0.35%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Arthritis
subjects affected / exposed	4 / 1690 (0.24%)	0 / 1 (0.00%)	1 / 245 (0.41%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Back pain
subjects affected / exposed	8 / 1690 (0.47%)	0 / 1 (0.00%)	0 / 245 (0.00%)	10 / 1709 (0.59%)
occurrences causally related to treatment / all	0 / 8	0 / 0	0 / 0	0 / 10
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ligament disorder
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Joint instability
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Joint effusion
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral disc protrusion
subjects affected / exposed	15 / 1690 (0.89%)	0 / 1 (0.00%)	5 / 245 (2.04%)	14 / 1709 (0.82%)
occurrences causally related to treatment / all	0 / 18	0 / 0	0 / 7	0 / 20
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lumbar spinal stenosis
subjects affected / exposed	6 / 1690 (0.36%)	0 / 1 (0.00%)	1 / 245 (0.41%)	8 / 1709 (0.47%)
occurrences causally related to treatment / all	0 / 9	0 / 0	0 / 1	0 / 11
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral disc degeneration
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemarthrosis
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Foot deformity
subjects affected / exposed	12 / 1690 (0.71%)	0 / 1 (0.00%)	0 / 245 (0.00%)	13 / 1709 (0.76%)
occurrences causally related to treatment / all	0 / 13	0 / 0	0 / 0	0 / 14
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fistula
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral disc disorder
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	59 / 1690 (3.49%)	0 / 1 (0.00%)	2 / 245 (0.82%)	62 / 1709 (3.63%)
occurrences causally related to treatment / all	0 / 77	0 / 0	0 / 2	1 / 78
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Osteochondrosis
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Osteonecrosis
subjects affected / exposed	3 / 1690 (0.18%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 7	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Meniscal degeneration
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Mobility decreased
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal chest pain
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal pain
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Polyarthritis
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	4 / 1709 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Polymyalgia rheumatica
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Spinal column stenosis
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	3 / 1709 (0.18%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rheumatoid arthritis
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rotator cuff syndrome
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	3 / 1709 (0.18%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Scoliosis
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pseudarthrosis
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Spinal osteoarthritis
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Spinal pain
subjects affected / exposed	3 / 1690 (0.18%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Spinal stenosis
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	1 / 245 (0.41%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Synovitis
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Spondyloarthropathy
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Spondylolisthesis
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Synovial cyst
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	1 / 245 (0.41%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Spinal synovial cyst
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	1 / 245 (0.41%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tendon disorder
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	3 / 1709 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tenosynovitis
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tenosynovitis stenosans
subjects affected / exposed	4 / 1690 (0.24%)	0 / 1 (0.00%)	0 / 245 (0.00%)	9 / 1709 (0.53%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 0	1 / 10
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Trigger finger
subjects affected / exposed	6 / 1690 (0.36%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 7	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vertebral foraminal stenosis
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	4 / 1709 (0.23%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Torticollis
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Bacterial infection
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Arthritis infective
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	5 / 1709 (0.29%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anal abscess
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abscess limb
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abscess jaw
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abscess
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cystitis
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chronic sinusitis
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	1 / 245 (0.41%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis infective
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Device related infection
subjects affected / exposed	3 / 1690 (0.18%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchopneumonia
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	6 / 1709 (0.35%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	1 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Breast abscess
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Borrelia infection
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Campylobacter gastroenteritis
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	1 / 245 (0.41%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Encephalitis
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	10 / 1690 (0.59%)	0 / 1 (0.00%)	1 / 245 (0.41%)	15 / 1709 (0.88%)
occurrences causally related to treatment / all	0 / 13	0 / 0	0 / 1	0 / 23
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Escherichia sepsis
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Escherichia urinary tract infection
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Eye infection bacterial
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Febrile infection
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	6 / 1709 (0.35%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal infection
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haematoma infection
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Helicobacter gastritis
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	3 / 1690 (0.18%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	9 / 1690 (0.53%)	0 / 1 (0.00%)	3 / 245 (1.22%)	9 / 1709 (0.53%)
occurrences causally related to treatment / all	0 / 10	0 / 0	0 / 5	0 / 13
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infective exacerbation of chronic obstructive airways disease
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infection
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal candidiasis
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nasopharyngitis
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Meningitis aseptic
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	1 / 245 (0.41%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Mastitis
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Localised infection
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	1 / 245 (0.41%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Joint abscess
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Implant site infection
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Incision site abscess
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infected seroma
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural infection
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia legionella
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	1 / 245 (0.41%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia bacterial
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	7 / 1690 (0.41%)	0 / 1 (0.00%)	1 / 245 (0.41%)	9 / 1709 (0.53%)
occurrences causally related to treatment / all	0 / 8	0 / 0	0 / 1	0 / 13
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pharyngitis
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	3 / 1709 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Postoperative wound infection
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Paronychia
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Otitis media chronic
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	1 / 245 (0.41%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Otitis media
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ophthalmic herpes zoster
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peritoneal abscess
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Salpingitis
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rhinitis
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	1 / 245 (0.41%)	4 / 1709 (0.23%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	2 / 1690 (0.12%)	0 / 1 (0.00%)	0 / 245 (0.00%)	3 / 1709 (0.18%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psoas abscess
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tonsillitis
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Subcutaneous abscess
subjects affected / exposed	3 / 1690 (0.18%)	0 / 1 (0.00%)	0 / 245 (0.00%)	6 / 1709 (0.35%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Soft tissue infection
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin infection
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sinusitis
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	4 / 1709 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tooth abscess
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	1 / 245 (0.41%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tracheobronchitis
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Viral infection
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	1 / 245 (0.41%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vestibular neuronitis
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	9 / 1690 (0.53%)	0 / 1 (0.00%)	0 / 245 (0.00%)	7 / 1709 (0.41%)
occurrences causally related to treatment / all	0 / 11	0 / 0	0 / 0	0 / 9
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Type 2 diabetes mellitus
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	3 / 1709 (0.18%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Obesity
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolic acidosis
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	1 / 245 (0.41%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Insulin resistance
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypocalcaemia
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Electrolyte imbalance
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	2 / 1709 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diabetes mellitus
subjects affected / exposed	0 / 1690 (0.00%)	0 / 1 (0.00%)	0 / 245 (0.00%)	1 / 1709 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	1 / 1690 (0.06%)	0 / 1 (0.00%)	0 / 245 (0.00%)	0 / 1709 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Double-blind (DB) Phase: Placebo	Open-label (OL) Phase: Denosumab/Denosumab	Open Label (OL) Phase: Placebo/Denosumab	Double-blind (DB) Phase: Denosumab
Total subjects affected by non serious adverse events
subjects affected / exposed	838 / 1690 (49.59%)	0 / 1 (0.00%)	0 / 245 (0.00%)	882 / 1709 (51.61%)
Vascular disorders
Hot flush
subjects affected / exposed	234 / 1690 (13.85%)	0 / 1 (0.00%)	0 / 245 (0.00%)	270 / 1709 (15.80%)
occurrences all number	260	0	0	297
Hypertension
subjects affected / exposed	94 / 1690 (5.56%)	0 / 1 (0.00%)	0 / 245 (0.00%)	111 / 1709 (6.50%)
occurrences all number	99	0	0	116
General disorders and administration site conditions
Fatigue
subjects affected / exposed	100 / 1690 (5.92%)	0 / 1 (0.00%)	0 / 245 (0.00%)	109 / 1709 (6.38%)
occurrences all number	107	0	0	121
Skin and subcutaneous tissue disorders
Scar pain
subjects affected / exposed	86 / 1690 (5.09%)	0 / 1 (0.00%)	0 / 245 (0.00%)	78 / 1709 (4.56%)
occurrences all number	92	0	0	82
Musculoskeletal and connective tissue disorders
Bone pain
subjects affected / exposed	111 / 1690 (6.57%)	0 / 1 (0.00%)	0 / 245 (0.00%)	139 / 1709 (8.13%)
occurrences all number	122	0	0	151
Back pain
subjects affected / exposed	146 / 1690 (8.64%)	0 / 1 (0.00%)	0 / 245 (0.00%)	151 / 1709 (8.84%)
occurrences all number	167	0	0	163
Arthralgia
subjects affected / exposed	446 / 1690 (26.39%)	0 / 1 (0.00%)	0 / 245 (0.00%)	441 / 1709 (25.80%)
occurrences all number	595	0	0	627
Spinal pain
subjects affected / exposed	73 / 1690 (4.32%)	0 / 1 (0.00%)	0 / 245 (0.00%)	89 / 1709 (5.21%)
occurrences all number	83	0	0	99
Pain in extremity
subjects affected / exposed	85 / 1690 (5.03%)	0 / 1 (0.00%)	0 / 245 (0.00%)	107 / 1709 (6.26%)
occurrences all number	95	0	0	126
Osteoarthritis
subjects affected / exposed	61 / 1690 (3.61%)	0 / 1 (0.00%)	0 / 245 (0.00%)	89 / 1709 (5.21%)
occurrences all number	76	0	0	104

More information

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Were there any global substantial amendments to the protocol? Yes

12 Jun 2006

* Allowed for the use, with approval by the DMC, of DXA scans or x-ray films available within a 60-day window (rather than 35-day window) from the date of randomization. * Added information to the Patient Information Sheet about the reversibility of increased BMD after discontinuation of denosumab.

06 Apr 2010

* Increased the sample size from 2800 participants to 3400 participants and increased the estimated overall study duration to 96 months, including an enrolment period of approximately 71 months. * Removed an interim analysis for futility due to the availability of data from phase 3 studies evaluating denosumab’s effects on BMD and fracture rate. * Changed the incidence of new or new and worsening vertebral fracture at month 12 and month 24 and change of BMD from baseline to month 12 and month 24 to exploratory endpoints. Endpoints at month 36 remained as secondary endpoints. * Changed the disease outcome-related endpoints from exploratory endpoints to secondary endpoints. * Further extended the time window for DXA scans and xrays to within 120 days of randomization.

15 Aug 2012

* The definition of postmenopausal status for participants * 60 years of age was clarified to require FSH and estradiol levels to be in the postmenopausal range. * The amendment removed requirement for a pregnancy test for participants < 60 years of age who have had a hysterectomy. * The definition of termination date was updated to the PADCD and a 1-year or 5-year follow-up period was added. * The investigational product was switched from vials to pre-filled syringes.

25 Jan 2016

* Extension of the long-term follow-up to 66 months after PADCD, as disease-free survival (DFS) interim results did not indicate futility * Addition of an open-label phase (OLP) during which denosumab was administered to participants who previously received placebo during the double-blind phase of the study * Added study procedural information for placebo-treated participants who did not continue into the OLP and for participants who entered the open label phase. * Added exploratory objective to investigate the potential prognostic and predictive impact of the effects of denosumab in the body, an exploratory objective was added to investigate potential bone turnover biomarkers, hormone serum levels, tumor biomarkers, RANK/L pathway and body mass index using biological material (eg, blood and tumor samples), and their impact on treatment outcomes.

01 Apr 2019

* Added a ZA study extension to the protocol. Consenting participants still on open label denosumab were to be randomized to be treated with either a bisphosphonate or standard of care upon denosumab discontinuation * Added exploratory objective to evaluate the impact of a single intravenous (IV) ZA administration on BMD and fracture rates post-denosumab open-label discontinuation.

15 Jul 2019

* Reconfigured protocol so that the additional ZA administration study was structured and submitted as a substudy based on ethics committee recommendation. * Description of ZA substudy was removed from the body of the protocol to appendix.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

Per protocol, only adverse events of special interest (oral events) and serious adverse events were collected in the open-label phase. Therefore, only these specific events are reported in the Adverse Events section for the open-label groups.

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Clinical trials

Clinical Trial Results:
A Randomized, Double-Blind, Placebo-Controlled, Multi-Center Phase 3 Study to Determine the Treatment Effect of Denosumab in Subjects With Non-Metastatic Breast Cancer Receiving Aromatase Inhibitor Therapy

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Time to First Clinical Fracture

Primary: Time to First Clinical Fracture

Secondary: Percent Change from Baseline in Total Lumbar Spine Bone Mineral Density (BMD) at Month 36

Secondary: Percent Change from Baseline in Total Lumbar Spine Bone Mineral Density (BMD) at Month 36

Secondary: Percent Change from Baseline in Total Hip BMD at Month 36

Secondary: Percent Change from Baseline in Total Hip BMD at Month 36

Secondary: Percent Change from Baseline in Femoral Neck BMD at Month 36

Secondary: Percent Change from Baseline in Femoral Neck BMD at Month 36

Secondary: Bone Metastases-free Survival (BMFS)

Secondary: Bone Metastases-free Survival (BMFS)

Secondary: Number of Participants With New or Worsening Vertebral Fractures

Secondary: Number of Participants With New or Worsening Vertebral Fractures

Secondary: Number of Participants with New Vertebral Fractures

Secondary: Number of Participants with New Vertebral Fractures

Secondary: Disease-free Survival (DFS)

Secondary: Disease-free Survival (DFS)

Secondary: Overall Survival (OS)

Secondary: Overall Survival (OS)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Clinical trials

Clinical Trial Results: A Randomized, Double-Blind, Placebo-Controlled, Multi-Center Phase 3 Study to Determine the Treatment Effect of Denosumab in Subjects With Non-Metastatic Breast Cancer Receiving Aromatase Inhibitor Therapy

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Time to First Clinical Fracture

Primary: Time to First Clinical Fracture

Secondary: Percent Change from Baseline in Total Lumbar Spine Bone Mineral Density (BMD) at Month 36

Secondary: Percent Change from Baseline in Total Lumbar Spine Bone Mineral Density (BMD) at Month 36

Secondary: Percent Change from Baseline in Total Hip BMD at Month 36

Secondary: Percent Change from Baseline in Total Hip BMD at Month 36

Secondary: Percent Change from Baseline in Femoral Neck BMD at Month 36

Secondary: Percent Change from Baseline in Femoral Neck BMD at Month 36

Secondary: Bone Metastases-free Survival (BMFS)

Secondary: Bone Metastases-free Survival (BMFS)

Secondary: Number of Participants With New or Worsening Vertebral Fractures

Secondary: Number of Participants With New or Worsening Vertebral Fractures

Secondary: Number of Participants with New Vertebral Fractures

Secondary: Number of Participants with New Vertebral Fractures

Secondary: Disease-free Survival (DFS)

Secondary: Disease-free Survival (DFS)

Secondary: Overall Survival (OS)

Secondary: Overall Survival (OS)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Randomized, Double-Blind, Placebo-Controlled, Multi-Center Phase 3 Study to Determine the Treatment Effect of Denosumab in Subjects With Non-Metastatic Breast Cancer Receiving Aromatase Inhibitor Therapy