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Clinical Trial Results:
A Randomized, Double-Blind, Placebo-Controlled, Multi-Center Phase 3 Study of Denosumab on Prolonging Bone Metastasis-Free Survival in Men with Hormone-Refractory Prostate Cancer

Summary
EudraCT number	2005-005485-37
Trial protocol	FI GB CZ BE IE SK HU ES PT DE IT LT LV BG
Global end of trial date	09 Apr 2014

Results information
Results version number	v1(current)
This version publication date	20 Jun 2016
First version publication date	26 Jul 2015
Other versions

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

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

20050147

ISRCTN number

-

US NCT number

NCT00286091

WHO universal trial number (UTN)

-

Sponsor organisation name

Amgen Inc.

Sponsor organisation address

One Amgen Center Drive, Thousand Oaks, CA, United States, 91320

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)

No

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

No

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

No

Analysis stage

Final

Date of interim/final analysis

09 Apr 2014

Is this the analysis of the primary completion data?

No

Global end of trial reached?

Yes

Global end of trial date

09 Apr 2014

Was the trial ended prematurely?

No

Main objective of the trial

The primary objective of this study was to compare the treatment effect of denosumab with placebo on prolonging bone metastasis-free survival in men with hormonerefractory (ie, castrate-resistant) prostate cancer who have no bone metastasis at baseline.

Protection of trial subjects

This study was conducted in accordance with relevant country regulations and the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) guidelines. Before any subject participated in the study, the investigator obtained written informed consent from the subject following adequate explanation of the aims, methods, anticipated benefits, and potential hazards of the study. Informed consent was obtained before any protocol-specific screening procedures were performed or administration of investigational product. The study protocol, subject information, and informed consent forms were reviewed and approved by the independent ethics committee (IEC) or institutional review board (IRB) for each study center.

Background therapy

-

Evidence for comparator

-

Actual start date of recruitment

03 Feb 2006

Long term follow-up planned

No

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 304

Country: Number of subjects enrolled

Canada: 161

Country: Number of subjects enrolled

France: 135

Country: Number of subjects enrolled

Brazil: 115

Country: Number of subjects enrolled

Czech Republic: 53

Country: Number of subjects enrolled

South Africa: 51

Country: Number of subjects enrolled

Argentina: 50

Country: Number of subjects enrolled

Australia: 45

Country: Number of subjects enrolled

Slovakia: 44

Country: Number of subjects enrolled

Poland: 43

Country: Number of subjects enrolled

Ukraine: 39

Country: Number of subjects enrolled

Mexico: 38

Country: Number of subjects enrolled

Spain: 38

Country: Number of subjects enrolled

New Zealand: 34

Country: Number of subjects enrolled

Finland: 32

Country: Number of subjects enrolled

Russian Federation: 30

Country: Number of subjects enrolled

Netherlands: 29

Country: Number of subjects enrolled

India: 26

Country: Number of subjects enrolled

United Kingdom: 25

Country: Number of subjects enrolled

Serbia: 23

Country: Number of subjects enrolled

Portugal: 22

Country: Number of subjects enrolled

Belgium: 21

Country: Number of subjects enrolled

Bulgaria: 18

Country: Number of subjects enrolled

Germany: 17

Country: Number of subjects enrolled

Italy: 10

Country: Number of subjects enrolled

Hungary: 8

Country: Number of subjects enrolled

Lithuania: 7

Country: Number of subjects enrolled

Ireland: 6

Country: Number of subjects enrolled

Latvia: 6

Country: Number of subjects enrolled

Switzerland: 2

Worldwide total number of subjects

1432

EEA total number of subjects

514

Number of subjects enrolled per age group

In utero

0

Preterm newborn - gestational age < 37 wk

0

Newborns (0-27 days)

0

Infants and toddlers (28 days-23 months)

0

Children (2-11 years)

0

Adolescents (12-17 years)

0

Adults (18-64 years)

234

From 65 to 84 years

1066

85 years and over

132

Subject disposition

Top of page

Recruitment details

Eligible subjects were men ≥ 18 years old with histologically-confirmed, castrate-resistant prostate cancer who were chemically or surgically castrated. The first patient was enrolled into the study on 03 February 2006 and the last patient was enrolled on 23 July 2008.

Screening details

Participants were randomized to denosumab or placebo in the double-blind treatment phase. All participants undergoing scheduled assessments were offered open-label denosumab for up to 3 years in the open-label extension phase. Three enrolled patients were excluded from all datasets per ethics committee’s instructions due to eligibility violations.

Period 1 title

Double-blind Treatment Phase

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 received placebo subcutaneous injection every 4 weeks (Q4W) in the double-blind treatment phase.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subcutaneous injection every 4 weeks (Q4W) in the double-blind treatment phase

Denosumab

Arm description

Participants received 120 mg densumab administered by subcutaneous injection every 4 weeks in the double-blind treatment phase.

Arm type

Experimental

Investigational medicinal product name

Denosumab

Investigational medicinal product code

AMG162

Other name

XGEVA®

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

120 mg denosumab administered by subcutaneous injection every 4 weeks

Number of subjects in period 1	Placebo	Denosumab
Started	716	716
Received Treatment	709	716
On Study at Primary Data Analysis Cutoff	164	174
Completed	132	123
Not completed	584	593
Consent withdrawn by subject	103	113
Protocol-Specified Criteria	307	269
Ineligibility Determined	1	2
Adverse event, non-fatal	28	40
Protocol Deviation	1	3
Other	25	33
Death	58	65
Administrative Decision	20	21
Lost to follow-up	11	4
Disease Progression	22	35
Noncompliance	8	8

Period 2 title

Open-label Treatment Phase

Is this the baseline period?

No

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Placebo/Denosumab

Arm description

Participants who received placebo in the double-blind treatment phase then received open-label denosumab 120 mg by subcutaneous injecton once every 4 weeks for up to 3 years in the open-label extension phase.

Arm type

Experimental

Investigational medicinal product name

Denosumab

Investigational medicinal product code

AMG162

Other name

XGEVA®

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

120 mg denosumab administered by subcutaneous injection every 4 weeks

Denosumab/Denosumab

Arm description

Participants who received densumab in the double-blind treatment phase then received open-label denosumab 120 mg by subcutaneous injecton once every 4 weeks for up to 3 years in the open-label extension phase.

Arm type

Experimental

Investigational medicinal product name

Denosumab

Investigational medicinal product code

AMG162

Other name

XGEVA®

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

120 mg denosumab administered by subcutaneous injection every 4 weeks

Number of subjects in period 2 ^[1]	Placebo/Denosumab	Denosumab/Denosumab
Started	110	104
Received Treatment	109	101
Completed	33	33
Not completed	77	71
Consent withdrawn by subject	14	10
Physician decision	24	21
Protocol-Specified Criteria	1	-
Missing End of Study Information	-	1
Adverse event, non-fatal	5	16
Other	11	11
Death	10	7
Lost to follow-up	-	1
Disease Progression	9	3
Noncompliance	3	1

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: Participants in the Czech Republic and United Kingdom were enrolled under a separate protocol for the open-label phase phase per Health Authority request, and are reported separately (Study 20080585; 2010-021846-23).

Baseline characteristics

Top of page

Reporting group title

Placebo

Reporting group description

Participants received placebo subcutaneous injection every 4 weeks (Q4W) in the double-blind treatment phase.

Reporting group title

Denosumab

Reporting group description

Participants received 120 mg densumab administered by subcutaneous injection every 4 weeks in the double-blind treatment phase.

Reporting group values	Placebo	Denosumab	Total
Number of subjects	716	716	1432
Age categorical
Units: Subjects
Age Continuous
Units: years
arithmetic mean (standard deviation)	73.2 ( 8.3 )	73.2 ( 8.8 )	-
Gender, Male/Female
Units: participants
Female	0	0	0
Male	716	716	1432
Race/Ethnicity, Customized
Units: Subjects
White or Caucasian	604	606	1210
Black or African American	35	41	76
Hispanic or Latino	37	32	69
Asian	18	17	35
Japanese	2	0	2
American Indian or Alaska Native	2	0	2
Native Hawaiian or Other Pacific Islander	1	0	1
Other	17	18	35
Unknown	0	2	2
Eastern Cooperative Oncology Group (ECOG)Pperformance Status
A scale to assess a patient's disease status. 0 = Fully active, able to carry out all pre-disease performance without restriction; 1 = Restricted in physically strenuous activity, ambulatory and able to carry out work of a light nature; 2 = Ambulatory and capable of all self care, unable to carry out any work activities. Up and about > 50% of waking hours; 3 = Capable of only limited self-care, confined to bed or chair > 50% of waking hours; 4 = Completely disabled, confined to bed or chair; 5 = Dead.
Units: Subjects
Grade 0	514	505	1019
Grade 1	199	210	409
Grade 2	3	1	4
Grade 3	0	0	0
Grade 4	0	0	0
Prostate-Specific Antigen (PSA) Doubling Time
Units: Subjects
≤ 10 months	580	574	1154
> 10 months	136	142	278
Prostate-Specific Antigen (PSA) ≥ 8.0 ng/mL
Units: Subjects
Yes	471	473	944
No	245	243	488
Prior Chemotherapy Regimens
Units: Subjects
Yes	54	63	117
No	662	653	1315

End points

Top of page

Reporting group title

Placebo

Reporting group description

Participants received placebo subcutaneous injection every 4 weeks (Q4W) in the double-blind treatment phase.

Reporting group title

Denosumab

Reporting group description

Participants received 120 mg densumab administered by subcutaneous injection every 4 weeks in the double-blind treatment phase.

Reporting group title

Placebo/Denosumab

Reporting group description

Participants who received placebo in the double-blind treatment phase then received open-label denosumab 120 mg by subcutaneous injecton once every 4 weeks for up to 3 years in the open-label extension phase.

Reporting group title

Denosumab/Denosumab

Reporting group description

Participants who received densumab in the double-blind treatment phase then received open-label denosumab 120 mg by subcutaneous injecton once every 4 weeks for up to 3 years in the open-label extension phase.

Primary: Bone Metastasis-free Survival

Top of page

End point title

Bone Metastasis-free Survival

End point description

The time to the first occurrence of bone metastasis (either symptomatic or asymptomatic) or death from any cause. Participants who did not experience bone metastasis or on-study death were censored at the last on-study contact date or the primary analysis data cutoff date, whichever came first. Median bone metastasis-free survival time was estimated using the Kaplan-Meier method.

End point type

Primary

End point timeframe

From the first dose of investigational product to the primary data cutoff date of 30 July 2010; median time on study was approximately 20 months.

End point values	Placebo	Denosumab
Number of subjects analysed	716	716
Units: days
median (confidence interval 95%)	768 (675 to 897)	897 (773 to 1014)

Analysis of Bone Metastasis-free Survival

Statistical analysis description

Hazard ratio based on the Cox proportional hazards model stratified by PSA ≥ 8.0 ng/mL, PSA doubling time ≤ 10 months and previous or current chemotherapy for prostate cancer. A hazard ratio < 1 favors denosumab.

Comparison groups

Placebo v Denosumab

Number of subjects included in analysis

1432

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

= 0.0284

Method

Wald test

Parameter type

Hazard ratio (HR)

Point estimate

0.85

Confidence interval

level

95%

sides

2-sided

lower limit

0.73

upper limit

0.98

Notes
[1] - Primary and secondary endpoint analyses were conducted hierarchically. To preserve an overall type I error rate of 0.05, a 0.0488 2-sided test of bone metastasis-free survival was performed. If superiority of denosumab over placebo was established, time to first bone metastasis was tested with a 2-sided significance level of 0.050. If superiority of denosumab over placebo was also established, overall survival time was tested at a 2-sided significance level of 0.050.

Secondary: Time to First Bone Metastasis

Top of page

End point title

Time to First Bone Metastasis

End point description

Time from randomization to the date of first occurrence of bone metastasis (either symptomatic or asymptomatic), excluding death. Participants who did not develop bone metastasis were censored at their last on-study bone assessment date or the primary analysis data cut-off date, whichever was first. Median time to first bone metastasis was estimated using the Kaplan-Meier method.

End point type

Secondary

End point timeframe

From the first dose of investigational product to the primary data cutoff date of 30 July 2010; median time on study was approximately 20 months.

End point values	Placebo	Denosumab
Number of subjects analysed	716	716
Units: days
median (confidence interval 95%)	897 (683 to 1009)	1010 (897 to 1156)

Analysis of Time to First Bone Metastasis

Statistical analysis description

Hazard ratio based on the Cox proportional hazards model stratified by PSA ≥ 8.0 ng/mL, PSA doubling time ≤ 10 months and previous or current chemotherapy for prostate cancer. A hazard ratio < 1 favors denosumab.

Comparison groups

Placebo v Denosumab

Number of subjects included in analysis

1432

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0317

Method

Wald test

Parameter type

Hazard ratio (HR)

Point estimate

0.84

Confidence interval

level

95%

sides

2-sided

lower limit

0.71

upper limit

0.98

Secondary: Overall Survival

Top of page

End point title

Overall Survival

End point description

Time from randomization to the date of death. Participants who were still alive or lost to follow-up by the primary analysis data cut-off date were censored at their last contact date (on-study or during survival follow-up) or the primary analysis data cut-off date, whichever was first. "99999" indicates values that could not be estimated due to the low number of events at the time of data cut-off.

End point type

Secondary

End point timeframe

From the first dose of investigational product to the primary data cutoff date of 30 July 2010; median time on study was approximately 20 months.

End point values	Placebo	Denosumab
Number of subjects analysed	716	716
Units: days
median (confidence interval 95%)	1365 (1220 to 99999)	1335 (1221 to 99999)

Analysis of Overall Survival

Statistical analysis description

Hazard ratio based on the Cox proportional hazards model stratified by PSA ≥ 8.0 ng/mL, PSA doubling time ≤ 10 months and previous or current chemotherapy for prostate cancer. A hazard ratio < 1 favors denosumab.

Comparison groups

Placebo v Denosumab

Number of subjects included in analysis

1432

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9125

Method

Wald test

Parameter type

Hazard ratio (HR)

Point estimate

1.01

Confidence interval

level

95%

sides

2-sided

lower limit

0.85

upper limit

1.2

Adverse events

Top of page

Timeframe for reporting adverse events

Median investigational product exposure was 18.4 and 19.3 months in the placebo and denosumab groups respectively during the double blind phase and 23.7 and 24.9 months during the open-label treatment phase.

Adverse event reporting additional description

Four participants who were randomized to placebo received ≥ 1 dose of denosumab; therefore, these participants were included within the denosumab group for the safety analyses.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

17.0

Reporting group title

DB: Placebo

Reporting group description

Participants received placebo subcutaneous injection every 4 weeks (Q4W) in the double-blind (DB) treatment phase.

Reporting group title

DB: Denosumab

Reporting group description

Participants received 120 mg densumab administered by subcutaneous injection every 4 weeks in the double-blind treatment phase.

Reporting group title

OLE: Placebo/ Denosumab

Reporting group description

Participants who received placebo in the double-blind treatment phase received open-label denosumab 120 mg by subcutaneous injecton once every 4 weeks for up to 3 years in the open-label extension (OLE) phase.

Reporting group title

OLE: Denosumab/ Denosumab

Reporting group description

Participants who received denosumab in the double-blind treatment phase received open-label denosumab 120 mg by subcutaneous injecton once every 4 weeks for up to 3 years in the open-label extension phase.

Serious adverse events	DB: Placebo	DB: Denosumab	OLE: Placebo/ Denosumab	OLE: Denosumab/ Denosumab
Total subjects affected by serious adverse events
subjects affected / exposed	332 / 705 (47.09%)	341 / 720 (47.36%)	39 / 109 (35.78%)	36 / 101 (35.64%)
number of deaths (all causes)	326	352	23	15
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon
subjects affected / exposed	2 / 705 (0.28%)	2 / 720 (0.28%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 2	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Basal cell carcinoma
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Bladder cancer
subjects affected / exposed	2 / 705 (0.28%)	7 / 720 (0.97%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 8	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bladder cancer recurrent
subjects affected / exposed	0 / 705 (0.00%)	2 / 720 (0.28%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Choroid melanoma
subjects affected / exposed	0 / 705 (0.00%)	0 / 720 (0.00%)	0 / 109 (0.00%)	1 / 101 (0.99%)
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 cancer
subjects affected / exposed	0 / 705 (0.00%)	2 / 720 (0.28%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Colon cancer metastatic
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	1 / 109 (0.92%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Colorectal cancer
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Gastric cancer
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal stromal tumour
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Large intestine benign neoplasm
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Laryngeal cancer
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lip squamous cell carcinoma
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lung neoplasm malignant
subjects affected / exposed	2 / 705 (0.28%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Mantle cell lymphoma
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Meningioma
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to abdominal cavity
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Metastases to bladder
subjects affected / exposed	2 / 705 (0.28%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Metastases to bone
subjects affected / exposed	5 / 705 (0.71%)	10 / 720 (1.39%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 10	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 3	0 / 0	0 / 0
Metastases to central nervous system
subjects affected / exposed	2 / 705 (0.28%)	2 / 720 (0.28%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
Metastases to larynx
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Metastases to liver
subjects affected / exposed	4 / 705 (0.57%)	2 / 720 (0.28%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0
Metastases to lung
subjects affected / exposed	1 / 705 (0.14%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to lymph nodes
subjects affected / exposed	6 / 705 (0.85%)	6 / 720 (0.83%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 6	0 / 7	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 3	0 / 0	0 / 0
Metastases to peritoneum
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Metastases to skin
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Metastases to small intestine
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Metastases to soft tissue
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to spine
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Metastasis
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Metastatic malignant melanoma
subjects affected / exposed	0 / 705 (0.00%)	0 / 720 (0.00%)	1 / 109 (0.92%)	0 / 101 (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
Metastatic pain
subjects affected / exposed	1 / 705 (0.14%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metastatic squamous cell carcinoma
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Myeloproliferative disorder
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Neoplasm prostate
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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-Hodgkin's lymphoma
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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-small cell lung cancer
subjects affected / exposed	0 / 705 (0.00%)	0 / 720 (0.00%)	1 / 109 (0.92%)	0 / 101 (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
Oesophageal adenocarcinoma
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal carcinoma
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatic carcinoma
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Pancreatic neoplasm
subjects affected / exposed	1 / 705 (0.14%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Papillary thyroid cancer
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Papilloma
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Plasma cell myeloma
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Prostate cancer
subjects affected / exposed	21 / 705 (2.98%)	15 / 720 (2.08%)	1 / 109 (0.92%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 27	0 / 16	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 11	0 / 8	0 / 0	0 / 1
Prostate cancer metastatic
subjects affected / exposed	6 / 705 (0.85%)	2 / 720 (0.28%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 6	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0
Prostate cancer recurrent
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	1 / 109 (0.92%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rectal adenocarcinoma
subjects affected / exposed	2 / 705 (0.28%)	2 / 720 (0.28%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Rectal cancer
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Rectosigmoid cancer
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal cancer
subjects affected / exposed	0 / 705 (0.00%)	0 / 720 (0.00%)	1 / 109 (0.92%)	0 / 101 (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
Renal cell carcinoma
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Small cell lung cancer
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Small intestine carcinoma
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tumour haemorrhage
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Aortic aneurysm
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Aortic dilatation
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Arterial thrombosis
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Deep vein thrombosis
subjects affected / exposed	6 / 705 (0.85%)	8 / 720 (1.11%)	0 / 109 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 6	2 / 8	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Embolism
subjects affected / exposed	0 / 705 (0.00%)	0 / 720 (0.00%)	1 / 109 (0.92%)	0 / 101 (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
Haematoma
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Haemorrhage
subjects affected / exposed	0 / 705 (0.00%)	3 / 720 (0.42%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypertension
subjects affected / exposed	3 / 705 (0.43%)	3 / 720 (0.42%)	0 / 109 (0.00%)	3 / 101 (2.97%)
occurrences causally related to treatment / all	0 / 3	0 / 3	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypertensive crisis
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Hypotension
subjects affected / exposed	4 / 705 (0.57%)	5 / 720 (0.69%)	0 / 109 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 4	0 / 5	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intermittent claudication
subjects affected / exposed	1 / 705 (0.14%)	3 / 720 (0.42%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemia
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lymphoedema
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Orthostatic hypotension
subjects affected / exposed	1 / 705 (0.14%)	2 / 720 (0.28%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pelvic venous thrombosis
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral arterial occlusive disease
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Peripheral ischaemia
subjects affected / exposed	1 / 705 (0.14%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Phlebitis
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Shock
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Superior vena cava syndrome
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Thrombophlebitis
subjects affected / exposed	0 / 705 (0.00%)	2 / 720 (0.28%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Thrombosis
subjects affected / exposed	3 / 705 (0.43%)	1 / 720 (0.14%)	1 / 109 (0.92%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Vascular occlusion
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Vasculitis
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Venous thrombosis
subjects affected / exposed	2 / 705 (0.28%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Venous thrombosis limb
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Surgical and medical procedures
Bladder catheterisation
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Cancer surgery
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Cardioversion
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Cataract operation
subjects affected / exposed	2 / 705 (0.28%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Colostomy
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cystostomy
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Debridement
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Finger amputation
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Heart valve operation
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hip arthroplasty
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Inguinal hernia repair
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Knee arthroplasty
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Orchidectomy
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin graft
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Stent placement
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Transurethral prostatectomy
subjects affected / exposed	1 / 705 (0.14%)	2 / 720 (0.28%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	10 / 705 (1.42%)	9 / 720 (1.25%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 10	0 / 10	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chest pain
subjects affected / exposed	3 / 705 (0.43%)	4 / 720 (0.56%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chills
subjects affected / exposed	1 / 705 (0.14%)	1 / 720 (0.14%)	0 / 109 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Death
subjects affected / exposed	4 / 705 (0.57%)	4 / 720 (0.56%)	1 / 109 (0.92%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 4	0 / 4	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 4	0 / 4	0 / 1	0 / 1
Device battery issue
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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 malfunction
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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 occlusion
subjects affected / exposed	1 / 705 (0.14%)	3 / 720 (0.42%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Disease progression
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Fatigue
subjects affected / exposed	0 / 705 (0.00%)	3 / 720 (0.42%)	1 / 109 (0.92%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	3 / 705 (0.43%)	5 / 720 (0.69%)	0 / 109 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 4	0 / 5	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Generalised oedema
subjects affected / exposed	1 / 705 (0.14%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hernia
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Impaired healing
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Local swelling
subjects affected / exposed	1 / 705 (0.14%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Malaise
subjects affected / exposed	0 / 705 (0.00%)	6 / 720 (0.83%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 6	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Multi-organ failure
subjects affected / exposed	2 / 705 (0.28%)	2 / 720 (0.28%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 2	0 / 0	0 / 0
Non-cardiac chest pain
subjects affected / exposed	2 / 705 (0.28%)	2 / 720 (0.28%)	0 / 109 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	1 / 705 (0.14%)	2 / 720 (0.28%)	1 / 109 (0.92%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Pain
subjects affected / exposed	1 / 705 (0.14%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	5 / 705 (0.71%)	10 / 720 (1.39%)	0 / 109 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 5	0 / 15	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sudden cardiac death
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Sudden death
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
Immune system disorders
Anaphylactic reaction
subjects affected / exposed	1 / 705 (0.14%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Social circumstances
Physical disability
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Benign prostatic hyperplasia
subjects affected / exposed	3 / 705 (0.43%)	2 / 720 (0.28%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pelvic pain
subjects affected / exposed	2 / 705 (0.28%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Perineal pain
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Prostatic haemorrhage
subjects affected / exposed	3 / 705 (0.43%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Prostatic obstruction
subjects affected / exposed	2 / 705 (0.28%)	0 / 720 (0.00%)	4 / 109 (3.67%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Prostatic perforation
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Prostatism
subjects affected / exposed	0 / 705 (0.00%)	0 / 720 (0.00%)	1 / 109 (0.92%)	0 / 101 (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
Prostatomegaly
subjects affected / exposed	2 / 705 (0.28%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Scrotal oedema
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Testicular atrophy
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Testicular pain
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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, thoracic and mediastinal disorders
Acute pulmonary oedema
subjects affected / exposed	0 / 705 (0.00%)	2 / 720 (0.28%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Acute respiratory distress syndrome
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Acute respiratory failure
subjects affected / exposed	0 / 705 (0.00%)	0 / 720 (0.00%)	0 / 109 (0.00%)	1 / 101 (0.99%)
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
Aspiration
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Asthma
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Atelectasis
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchomalacia
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	3 / 705 (0.43%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cough
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Dyspnoea
subjects affected / exposed	7 / 705 (0.99%)	10 / 720 (1.39%)	0 / 109 (0.00%)	3 / 101 (2.97%)
occurrences causally related to treatment / all	0 / 8	0 / 11	0 / 0	0 / 5
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
Emphysema
subjects affected / exposed	0 / 705 (0.00%)	0 / 720 (0.00%)	1 / 109 (0.92%)	0 / 101 (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
Epistaxis
subjects affected / exposed	1 / 705 (0.14%)	1 / 720 (0.14%)	0 / 109 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lung disorder
subjects affected / exposed	2 / 705 (0.28%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Pleural effusion
subjects affected / exposed	5 / 705 (0.71%)	3 / 720 (0.42%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pleuritic pain
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	0 / 705 (0.00%)	0 / 720 (0.00%)	0 / 109 (0.00%)	1 / 101 (0.99%)
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
Pneumonitis
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary arterial hypertension
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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	8 / 705 (1.13%)	9 / 720 (1.25%)	1 / 109 (0.92%)	3 / 101 (2.97%)
occurrences causally related to treatment / all	1 / 8	2 / 9	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 1
Pulmonary fibrosis
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Pulmonary oedema
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory distress
subjects affected / exposed	1 / 705 (0.14%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	3 / 705 (0.43%)	3 / 720 (0.42%)	2 / 109 (1.83%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 3	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 1	0 / 0
Sinus disorder
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sleep apnoea syndrome
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Psychiatric disorders
Abnormal behaviour
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Completed suicide
subjects affected / exposed	1 / 705 (0.14%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
Confusional state
subjects affected / exposed	4 / 705 (0.57%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Delirium
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Depression
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Disorientation
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Mental status changes
subjects affected / exposed	1 / 705 (0.14%)	2 / 720 (0.28%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Aspiration bronchial
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Blood creatinine increased
subjects affected / exposed	2 / 705 (0.28%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Blood potassium decreased
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Blood pressure increased
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Blood urine present
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemoglobin decreased
subjects affected / exposed	2 / 705 (0.28%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Heart rate increased
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Laboratory test abnormal
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ultrasound liver abnormal
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Weight decreased
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Accidental overdose
subjects affected / exposed	0 / 705 (0.00%)	0 / 720 (0.00%)	1 / 109 (0.92%)	0 / 101 (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
Back injury
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Cervical vertebral fracture
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Cystitis radiation
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Facial bones fracture
subjects affected / exposed	1 / 705 (0.14%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	1 / 705 (0.14%)	6 / 720 (0.83%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 6	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Femoral neck fracture
subjects affected / exposed	1 / 705 (0.14%)	3 / 720 (0.42%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	8 / 705 (1.13%)	1 / 720 (0.14%)	1 / 109 (0.92%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 8	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fibula fracture
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Foreign body
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Fracture
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Gastroenteritis radiation
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal stoma complication
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Head injury
subjects affected / exposed	0 / 705 (0.00%)	0 / 720 (0.00%)	1 / 109 (0.92%)	0 / 101 (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
Hip fracture
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Humerus fracture
subjects affected / exposed	2 / 705 (0.28%)	3 / 720 (0.42%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Incisional hernia
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Laceration
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Lumbar vertebral fracture
subjects affected / exposed	2 / 705 (0.28%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural haematuria
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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 haemorrhage
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Radius fracture
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Retinal injury
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Rib fracture
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	1 / 109 (0.92%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Road traffic accident
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Spinal compression fracture
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sternal fracture
subjects affected / exposed	0 / 705 (0.00%)	0 / 720 (0.00%)	1 / 109 (0.92%)	0 / 101 (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
Subdural haematoma
subjects affected / exposed	2 / 705 (0.28%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tendon rupture
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Tibia fracture
subjects affected / exposed	3 / 705 (0.43%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Toxicity to various agents
subjects affected / exposed	3 / 705 (0.43%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Traumatic intracranial haemorrhage
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Wrist fracture
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Phimosis
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Syringomyelia
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Acute coronary syndrome
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	2 / 705 (0.28%)	4 / 720 (0.56%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	3 / 705 (0.43%)	5 / 720 (0.69%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 5	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Angina unstable
subjects affected / exposed	0 / 705 (0.00%)	0 / 720 (0.00%)	0 / 109 (0.00%)	1 / 101 (0.99%)
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
Arrhythmia
subjects affected / exposed	4 / 705 (0.57%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	12 / 705 (1.70%)	6 / 720 (0.83%)	0 / 109 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 14	2 / 6	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Atrial flutter
subjects affected / exposed	0 / 705 (0.00%)	2 / 720 (0.28%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Atrial tachycardia
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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 / 705 (0.28%)	2 / 720 (0.28%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 2	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	3 / 705 (0.43%)	2 / 720 (0.28%)	1 / 109 (0.92%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 3	0 / 2	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 2	0 / 1	0 / 1	0 / 1
Cardiac failure
subjects affected / exposed	3 / 705 (0.43%)	3 / 720 (0.42%)	1 / 109 (0.92%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 3	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 3	0 / 1	0 / 0
Cardiac failure congestive
subjects affected / exposed	7 / 705 (0.99%)	6 / 720 (0.83%)	1 / 109 (0.92%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 7	1 / 6	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac tamponade
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac valve disease
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Cardio-respiratory arrest
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Cardiogenic shock
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Cardiomyopathy
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiopulmonary failure
subjects affected / exposed	0 / 705 (0.00%)	3 / 720 (0.42%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 0
Cardiovascular insufficiency
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cor pulmonale
subjects affected / exposed	0 / 705 (0.00%)	0 / 720 (0.00%)	1 / 109 (0.92%)	0 / 101 (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
Coronary artery disease
subjects affected / exposed	3 / 705 (0.43%)	2 / 720 (0.28%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Coronary artery stenosis
subjects affected / exposed	3 / 705 (0.43%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Coronary artery thrombosis
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Ischaemic cardiomyopathy
subjects affected / exposed	0 / 705 (0.00%)	0 / 720 (0.00%)	1 / 109 (0.92%)	0 / 101 (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
Left ventricular dysfunction
subjects affected / exposed	2 / 705 (0.28%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Myocardial infarction
subjects affected / exposed	10 / 705 (1.42%)	12 / 720 (1.67%)	4 / 109 (3.67%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	1 / 10	0 / 12	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 6	0 / 1	0 / 0
Myocardial ischaemia
subjects affected / exposed	0 / 705 (0.00%)	6 / 720 (0.83%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 7	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pericardial effusion
subjects affected / exposed	0 / 705 (0.00%)	2 / 720 (0.28%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Right ventricular failure
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sick sinus syndrome
subjects affected / exposed	2 / 705 (0.28%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Sinus bradycardia
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Tachycardia
subjects affected / exposed	1 / 705 (0.14%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Trifascicular block
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ventricular hypertrophy
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Ventricular tachycardia
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Aphasia
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ataxia
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Carotid artery stenosis
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Carotid artery thrombosis
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Cerebellar infarction
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Cerebral infarction
subjects affected / exposed	0 / 705 (0.00%)	2 / 720 (0.28%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral ischaemia
subjects affected / exposed	1 / 705 (0.14%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	10 / 705 (1.42%)	8 / 720 (1.11%)	2 / 109 (1.83%)	2 / 101 (1.98%)
occurrences causally related to treatment / all	1 / 13	0 / 8	0 / 2	0 / 2
deaths causally related to treatment / all	1 / 2	0 / 3	0 / 1	0 / 0
Cerebrovascular disorder
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Coma
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Complex partial seizures
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Convulsion
subjects affected / exposed	1 / 705 (0.14%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dementia
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	1 / 109 (0.92%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dizziness
subjects affected / exposed	0 / 705 (0.00%)	4 / 720 (0.56%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Encephalopathy
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	1 / 109 (0.92%)	1 / 101 (0.99%)
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
Epilepsy
subjects affected / exposed	3 / 705 (0.43%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Gait apraxia
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Grand mal convulsion
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hemiparesis
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Hypertonia
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Ischaemic stroke
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lethargy
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Loss of consciousness
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Neuropathy peripheral
subjects affected / exposed	0 / 705 (0.00%)	0 / 720 (0.00%)	0 / 109 (0.00%)	1 / 101 (0.99%)
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
Paraparesis
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Parkinson's disease
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Petit mal epilepsy
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Presyncope
subjects affected / exposed	1 / 705 (0.14%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Somnolence
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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 cord compression
subjects affected / exposed	2 / 705 (0.28%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Syncope
subjects affected / exposed	4 / 705 (0.57%)	8 / 720 (1.11%)	1 / 109 (0.92%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 6	1 / 9	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	1 / 705 (0.14%)	2 / 720 (0.28%)	1 / 109 (0.92%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vertebral artery occlusion
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	12 / 705 (1.70%)	25 / 720 (3.47%)	2 / 109 (1.83%)	3 / 101 (2.97%)
occurrences causally related to treatment / all	0 / 15	2 / 30	0 / 2	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Anaemia of malignant disease
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Bone marrow failure
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Coagulopathy
subjects affected / exposed	1 / 705 (0.14%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	1 / 705 (0.14%)	4 / 720 (0.56%)	0 / 109 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 1	0 / 4	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhagic anaemia
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Iron deficiency anaemia
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lymphadenopathy
subjects affected / exposed	1 / 705 (0.14%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Retroperitoneal lymphadenopathy
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Spontaneous haematoma
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Thrombocytopenia
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	1 / 705 (0.14%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Cataract
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Eyelid ptosis
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Glaucoma
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Optic ischaemic neuropathy
subjects affected / exposed	0 / 705 (0.00%)	0 / 720 (0.00%)	0 / 109 (0.00%)	1 / 101 (0.99%)
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 disorders
Abdominal pain
subjects affected / exposed	6 / 705 (0.85%)	3 / 720 (0.42%)	1 / 109 (0.92%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	1 / 6	0 / 3	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain lower
subjects affected / exposed	0 / 705 (0.00%)	2 / 720 (0.28%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Acute abdomen
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Anal fistula
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anal haemorrhage
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Ascites
subjects affected / exposed	3 / 705 (0.43%)	2 / 720 (0.28%)	1 / 109 (0.92%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Colitis ulcerative
subjects affected / exposed	0 / 705 (0.00%)	2 / 720 (0.28%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	2 / 705 (0.28%)	3 / 720 (0.42%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	1 / 705 (0.14%)	4 / 720 (0.56%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulitis intestinal haemorrhagic
subjects affected / exposed	0 / 705 (0.00%)	0 / 720 (0.00%)	0 / 109 (0.00%)	1 / 101 (0.99%)
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
Diverticulum intestinal
subjects affected / exposed	1 / 705 (0.14%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulum intestinal haemorrhagic
subjects affected / exposed	1 / 705 (0.14%)	2 / 720 (0.28%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Duodenal ulcer
subjects affected / exposed	0 / 705 (0.00%)	2 / 720 (0.28%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dyspepsia
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Enterovesical fistula
subjects affected / exposed	1 / 705 (0.14%)	2 / 720 (0.28%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Faecaloma
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Gastric ulcer
subjects affected / exposed	2 / 705 (0.28%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Gastritis
subjects affected / exposed	1 / 705 (0.14%)	2 / 720 (0.28%)	0 / 109 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal angiodysplasia
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorder
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	2 / 705 (0.28%)	5 / 720 (0.69%)	0 / 109 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 2	0 / 6	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 705 (0.00%)	2 / 720 (0.28%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haematemesis
subjects affected / exposed	2 / 705 (0.28%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Haematochezia
subjects affected / exposed	1 / 705 (0.14%)	2 / 720 (0.28%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhoidal haemorrhage
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Haemorrhoids
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ileus
subjects affected / exposed	1 / 705 (0.14%)	1 / 720 (0.14%)	0 / 109 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ileus paralytic
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	3 / 705 (0.43%)	4 / 720 (0.56%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Inguinal hernia, obstructive
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal haemorrhage
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal mass
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	4 / 705 (0.57%)	2 / 720 (0.28%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intra-abdominal haemorrhage
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Large intestinal stenosis
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Large intestine perforation
subjects affected / exposed	1 / 705 (0.14%)	2 / 720 (0.28%)	1 / 109 (0.92%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Large intestine polyp
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Lower gastrointestinal haemorrhage
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Melaena
subjects affected / exposed	1 / 705 (0.14%)	2 / 720 (0.28%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	3 / 705 (0.43%)	1 / 720 (0.14%)	1 / 109 (0.92%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal rupture
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal stenosis
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oesophagitis
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oral mucosa erosion
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peptic ulcer perforation
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Periodontal disease
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rectal haemorrhage
subjects affected / exposed	4 / 705 (0.57%)	6 / 720 (0.83%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 8	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rectal stenosis
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Small intestinal haemorrhage
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	3 / 705 (0.43%)	0 / 720 (0.00%)	0 / 109 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Subileus
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tongue haemorrhage
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Toothache
subjects affected / exposed	0 / 705 (0.00%)	0 / 720 (0.00%)	0 / 109 (0.00%)	1 / 101 (0.99%)
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
Upper gastrointestinal haemorrhage
subjects affected / exposed	1 / 705 (0.14%)	2 / 720 (0.28%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Varices oesophageal
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Vomiting
subjects affected / exposed	3 / 705 (0.43%)	1 / 720 (0.14%)	1 / 109 (0.92%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Acute hepatic failure
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Bile duct stone
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Cholangitis
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
subjects affected / exposed	1 / 705 (0.14%)	2 / 720 (0.28%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	2 / 705 (0.28%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	3 / 705 (0.43%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Cholestasis
subjects affected / exposed	1 / 705 (0.14%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic failure
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Hepatitis
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Hyperbilirubinaemia
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Jaundice
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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 and subcutaneous tissue disorders
Angioedema
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dermatitis contact
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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 ulcer
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Anuria
subjects affected / exposed	1 / 705 (0.14%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Azotaemia
subjects affected / exposed	0 / 705 (0.00%)	5 / 720 (0.69%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 5	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bladder dilatation
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bladder neck obstruction
subjects affected / exposed	1 / 705 (0.14%)	3 / 720 (0.42%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bladder neck sclerosis
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bladder obstruction
subjects affected / exposed	1 / 705 (0.14%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bladder outlet obstruction
subjects affected / exposed	2 / 705 (0.28%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bladder perforation
subjects affected / exposed	0 / 705 (0.00%)	2 / 720 (0.28%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Calculus bladder
subjects affected / exposed	3 / 705 (0.43%)	3 / 720 (0.42%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Calculus ureteric
subjects affected / exposed	0 / 705 (0.00%)	3 / 720 (0.42%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Calculus urinary
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Cystitis haemorrhagic
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cystitis noninfective
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dysuria
subjects affected / exposed	3 / 705 (0.43%)	7 / 720 (0.97%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 8	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haematinuria
subjects affected / exposed	0 / 705 (0.00%)	2 / 720 (0.28%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 5	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haematuria
subjects affected / exposed	25 / 705 (3.55%)	37 / 720 (5.14%)	2 / 109 (1.83%)	5 / 101 (4.95%)
occurrences causally related to treatment / all	0 / 36	1 / 45	0 / 2	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhage urinary tract
subjects affected / exposed	2 / 705 (0.28%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hydronephrosis
subjects affected / exposed	11 / 705 (1.56%)	15 / 720 (2.08%)	0 / 109 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 11	0 / 18	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Hydroureter
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Incontinence
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Micturition disorder
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Micturition urgency
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	1 / 705 (0.14%)	2 / 720 (0.28%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nocturia
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Obstructive uropathy
subjects affected / exposed	2 / 705 (0.28%)	2 / 720 (0.28%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Oliguria
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Pollakiuria
subjects affected / exposed	1 / 705 (0.14%)	6 / 720 (0.83%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 6	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Polyuria
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal failure
subjects affected / exposed	9 / 705 (1.28%)	16 / 720 (2.22%)	1 / 109 (0.92%)	2 / 101 (1.98%)
occurrences causally related to treatment / all	0 / 11	0 / 17	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 2	0 / 6	0 / 0	0 / 0
Renal failure acute
subjects affected / exposed	16 / 705 (2.27%)	12 / 720 (1.67%)	4 / 109 (3.67%)	2 / 101 (1.98%)
occurrences causally related to treatment / all	0 / 17	0 / 14	0 / 4	0 / 2
deaths causally related to treatment / all	0 / 3	0 / 2	0 / 1	0 / 0
Renal failure chronic
subjects affected / exposed	3 / 705 (0.43%)	2 / 720 (0.28%)	1 / 109 (0.92%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ureteric dilatation
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ureteric obstruction
subjects affected / exposed	4 / 705 (0.57%)	3 / 720 (0.42%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Ureteric stenosis
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Urethral obstruction
subjects affected / exposed	3 / 705 (0.43%)	2 / 720 (0.28%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urethral pain
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urethral stenosis
subjects affected / exposed	4 / 705 (0.57%)	3 / 720 (0.42%)	1 / 109 (0.92%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 4	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary bladder haemorrhage
subjects affected / exposed	0 / 705 (0.00%)	2 / 720 (0.28%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary hesitation
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Urinary incontinence
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	1 / 109 (0.92%)	0 / 101 (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
Urinary retention
subjects affected / exposed	33 / 705 (4.68%)	56 / 720 (7.78%)	6 / 109 (5.50%)	5 / 101 (4.95%)
occurrences causally related to treatment / all	0 / 40	0 / 68	0 / 7	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Urinary tract disorder
subjects affected / exposed	1 / 705 (0.14%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract obstruction
subjects affected / exposed	12 / 705 (1.70%)	5 / 720 (0.69%)	1 / 109 (0.92%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 12	1 / 5	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract pain
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Urine abnormality
subjects affected / exposed	0 / 705 (0.00%)	0 / 720 (0.00%)	0 / 109 (0.00%)	1 / 101 (0.99%)
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
Urogenital haemorrhage
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	2 / 705 (0.28%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Arthritis
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Back pain
subjects affected / exposed	7 / 705 (0.99%)	9 / 720 (1.25%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 7	0 / 9	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bone pain
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Exostosis of jaw
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Flank pain
subjects affected / exposed	2 / 705 (0.28%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fracture nonunion
subjects affected / exposed	0 / 705 (0.00%)	0 / 720 (0.00%)	0 / 109 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypercreatinaemia
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral disc degeneration
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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 disorder
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Jaw disorder
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Joint effusion
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lumbar spinal stenosis
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	1 / 109 (0.92%)	0 / 101 (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
Muscular weakness
subjects affected / exposed	1 / 705 (0.14%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Musculoskeletal chest pain
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal pain
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Myalgia
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neck pain
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Osteitis
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	4 / 705 (0.57%)	7 / 720 (0.97%)	0 / 109 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 4	1 / 8	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Osteonecrosis of jaw
subjects affected / exposed	0 / 705 (0.00%)	12 / 720 (1.67%)	1 / 109 (0.92%)	5 / 101 (4.95%)
occurrences causally related to treatment / all	0 / 0	13 / 13	1 / 1	5 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	1 / 705 (0.14%)	1 / 720 (0.14%)	0 / 109 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rhabdomyolysis
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rheumatoid arthritis
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Rotator cuff syndrome
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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 osteoarthritis
subjects affected / exposed	0 / 705 (0.00%)	0 / 720 (0.00%)	0 / 109 (0.00%)	1 / 101 (0.99%)
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
Weight bearing difficulty
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Infections and infestations
Abscess
subjects affected / exposed	1 / 705 (0.14%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abscess jaw
subjects affected / exposed	0 / 705 (0.00%)	0 / 720 (0.00%)	1 / 109 (0.92%)	0 / 101 (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
Abscess of salivary gland
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Acute sinusitis
subjects affected / exposed	0 / 705 (0.00%)	0 / 720 (0.00%)	1 / 109 (0.92%)	0 / 101 (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
Anal infection
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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 bacterial
subjects affected / exposed	0 / 705 (0.00%)	0 / 720 (0.00%)	0 / 109 (0.00%)	1 / 101 (0.99%)
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
Arthritis infective
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	0 / 705 (0.00%)	2 / 720 (0.28%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	4 / 705 (0.57%)	2 / 720 (0.28%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchopneumonia
subjects affected / exposed	0 / 705 (0.00%)	3 / 720 (0.42%)	1 / 109 (0.92%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac infection
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	4 / 705 (0.57%)	6 / 720 (0.83%)	1 / 109 (0.92%)	2 / 101 (1.98%)
occurrences causally related to treatment / all	0 / 4	0 / 6	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chest wall abscess
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chronic sinusitis
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Clostridium bacteraemia
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Clostridium colitis
subjects affected / exposed	0 / 705 (0.00%)	0 / 720 (0.00%)	0 / 109 (0.00%)	1 / 101 (0.99%)
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	1 / 705 (0.14%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dental fistula
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Device related infection
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Device related sepsis
subjects affected / exposed	0 / 705 (0.00%)	2 / 720 (0.28%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	1 / 705 (0.14%)	2 / 720 (0.28%)	1 / 109 (0.92%)	2 / 101 (1.98%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Empyema
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endocarditis
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Enterococcal infection
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Epiglottitis
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Gangrene
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Gastroenteritis
subjects affected / exposed	2 / 705 (0.28%)	1 / 720 (0.14%)	0 / 109 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal infection
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Gingival abscess
subjects affected / exposed	0 / 705 (0.00%)	0 / 720 (0.00%)	1 / 109 (0.92%)	0 / 101 (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
Herpes zoster
subjects affected / exposed	0 / 705 (0.00%)	2 / 720 (0.28%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Human ehrlichiosis
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Infected skin ulcer
subjects affected / exposed	0 / 705 (0.00%)	0 / 720 (0.00%)	1 / 109 (0.92%)	0 / 101 (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
Liver abscess
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lobar pneumonia
subjects affected / exposed	2 / 705 (0.28%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Localised infection
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Lower respiratory tract infection
subjects affected / exposed	1 / 705 (0.14%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lung infection
subjects affected / exposed	0 / 705 (0.00%)	2 / 720 (0.28%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Neutropenic infection
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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 candidiasis
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Orchitis
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Osteomyelitis
subjects affected / exposed	0 / 705 (0.00%)	4 / 720 (0.56%)	1 / 109 (0.92%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 6	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Osteomyelitis acute
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Osteomyelitis chronic
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Penile infection
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Perineal abscess
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Perineal infection
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Pneumonia
subjects affected / exposed	16 / 705 (2.27%)	13 / 720 (1.81%)	2 / 109 (1.83%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 16	1 / 14	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 5	0 / 0	0 / 0	0 / 0
Pneumonia pneumococcal
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pseudomonal sepsis
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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 tuberculosis
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	2 / 705 (0.28%)	2 / 720 (0.28%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rectal abscess
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Scrotal abscess
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	8 / 705 (1.13%)	6 / 720 (0.83%)	0 / 109 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 8	0 / 6	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 4	0 / 0	0 / 0
Septic shock
subjects affected / exposed	1 / 705 (0.14%)	1 / 720 (0.14%)	2 / 109 (1.83%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 2	0 / 0
Sialoadenitis
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tooth infection
subjects affected / exposed	0 / 705 (0.00%)	0 / 720 (0.00%)	1 / 109 (0.92%)	0 / 101 (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
Upper respiratory tract infection
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Urinary tract infection
subjects affected / exposed	15 / 705 (2.13%)	15 / 720 (2.08%)	2 / 109 (1.83%)	3 / 101 (2.97%)
occurrences causally related to treatment / all	0 / 15	0 / 19	0 / 2	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection bacterial
subjects affected / exposed	0 / 705 (0.00%)	0 / 720 (0.00%)	0 / 109 (0.00%)	1 / 101 (0.99%)
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
Urosepsis
subjects affected / exposed	4 / 705 (0.57%)	3 / 720 (0.42%)	0 / 109 (0.00%)	2 / 101 (1.98%)
occurrences causally related to treatment / all	0 / 5	0 / 3	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
Viral infection
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Wound infection
subjects affected / exposed	1 / 705 (0.14%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Cachexia
subjects affected / exposed	3 / 705 (0.43%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
Decreased appetite
subjects affected / exposed	2 / 705 (0.28%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	9 / 705 (1.28%)	7 / 720 (0.97%)	0 / 109 (0.00%)	3 / 101 (2.97%)
occurrences causally related to treatment / all	0 / 11	0 / 7	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diabetes mellitus
subjects affected / exposed	1 / 705 (0.14%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diabetes mellitus inadequate control
subjects affected / exposed	2 / 705 (0.28%)	2 / 720 (0.28%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Electrolyte imbalance
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gout
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Hyperkalaemia
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypocalcaemia
subjects affected / exposed	1 / 705 (0.14%)	1 / 720 (0.14%)	2 / 109 (1.83%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	2 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	1 / 705 (0.14%)	3 / 720 (0.42%)	0 / 109 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 2	0 / 4	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	0 / 705 (0.00%)	1 / 720 (0.14%)	1 / 109 (0.92%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypovolaemia
subjects affected / exposed	0 / 705 (0.00%)	0 / 720 (0.00%)	1 / 109 (0.92%)	0 / 101 (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
Iron deficiency
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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
Malnutrition
subjects affected / exposed	1 / 705 (0.14%)	1 / 720 (0.14%)	0 / 109 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Type 2 diabetes mellitus
subjects affected / exposed	1 / 705 (0.14%)	0 / 720 (0.00%)	0 / 109 (0.00%)	0 / 101 (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	DB: Placebo	DB: Denosumab	OLE: Placebo/ Denosumab	OLE: Denosumab/ Denosumab
Total subjects affected by non serious adverse events
subjects affected / exposed	585 / 705 (82.98%)	599 / 720 (83.19%)	80 / 109 (73.39%)	74 / 101 (73.27%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastases to bone
subjects affected / exposed	58 / 705 (8.23%)	56 / 720 (7.78%)	0 / 109 (0.00%)	1 / 101 (0.99%)
occurrences all number	58	64	0	1
Vascular disorders
Hot flush
subjects affected / exposed	32 / 705 (4.54%)	41 / 720 (5.69%)	1 / 109 (0.92%)	1 / 101 (0.99%)
occurrences all number	36	48	2	1
Hypertension
subjects affected / exposed	49 / 705 (6.95%)	59 / 720 (8.19%)	5 / 109 (4.59%)	6 / 101 (5.94%)
occurrences all number	54	74	6	11
General disorders and administration site conditions
Asthenia
subjects affected / exposed	91 / 705 (12.91%)	92 / 720 (12.78%)	8 / 109 (7.34%)	11 / 101 (10.89%)
occurrences all number	145	157	9	17
Fatigue
subjects affected / exposed	82 / 705 (11.63%)	98 / 720 (13.61%)	5 / 109 (4.59%)	8 / 101 (7.92%)
occurrences all number	109	153	8	13
Oedema peripheral
subjects affected / exposed	88 / 705 (12.48%)	94 / 720 (13.06%)	5 / 109 (4.59%)	11 / 101 (10.89%)
occurrences all number	116	129	8	17
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	60 / 705 (8.51%)	55 / 720 (7.64%)	6 / 109 (5.50%)	4 / 101 (3.96%)
occurrences all number	87	69	8	5
Dyspnoea
subjects affected / exposed	57 / 705 (8.09%)	61 / 720 (8.47%)	4 / 109 (3.67%)	4 / 101 (3.96%)
occurrences all number	68	78	5	10
Psychiatric disorders
Insomnia
subjects affected / exposed	44 / 705 (6.24%)	46 / 720 (6.39%)	4 / 109 (3.67%)	2 / 101 (1.98%)
occurrences all number	49	51	5	2
Investigations
Weight decreased
subjects affected / exposed	42 / 705 (5.96%)	39 / 720 (5.42%)	4 / 109 (3.67%)	6 / 101 (5.94%)
occurrences all number	47	41	5	6
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	42 / 705 (5.96%)	36 / 720 (5.00%)	3 / 109 (2.75%)	3 / 101 (2.97%)
occurrences all number	51	50	5	3
Nervous system disorders
Dizziness
subjects affected / exposed	56 / 705 (7.94%)	63 / 720 (8.75%)	7 / 109 (6.42%)	6 / 101 (5.94%)
occurrences all number	66	83	9	7
Headache
subjects affected / exposed	54 / 705 (7.66%)	67 / 720 (9.31%)	3 / 109 (2.75%)	5 / 101 (4.95%)
occurrences all number	62	91	6	9
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	74 / 705 (10.50%)	80 / 720 (11.11%)	12 / 109 (11.01%)	10 / 101 (9.90%)
occurrences all number	110	122	15	17
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	47 / 705 (6.67%)	59 / 720 (8.19%)	3 / 109 (2.75%)	7 / 101 (6.93%)
occurrences all number	59	75	4	10
Constipation
subjects affected / exposed	124 / 705 (17.59%)	128 / 720 (17.78%)	13 / 109 (11.93%)	15 / 101 (14.85%)
occurrences all number	154	164	19	19
Dental caries
subjects affected / exposed	10 / 705 (1.42%)	16 / 720 (2.22%)	3 / 109 (2.75%)	6 / 101 (5.94%)
occurrences all number	12	17	3	9
Diarrhoea
subjects affected / exposed	102 / 705 (14.47%)	110 / 720 (15.28%)	8 / 109 (7.34%)	10 / 101 (9.90%)
occurrences all number	141	195	11	17
Nausea
subjects affected / exposed	95 / 705 (13.48%)	98 / 720 (13.61%)	4 / 109 (3.67%)	14 / 101 (13.86%)
occurrences all number	120	152	4	18
Toothache
subjects affected / exposed	16 / 705 (2.27%)	32 / 720 (4.44%)	1 / 109 (0.92%)	6 / 101 (5.94%)
occurrences all number	20	41	1	12
Vomiting
subjects affected / exposed	55 / 705 (7.80%)	59 / 720 (8.19%)	3 / 109 (2.75%)	10 / 101 (9.90%)
occurrences all number	63	81	3	15
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	32 / 705 (4.54%)	37 / 720 (5.14%)	2 / 109 (1.83%)	3 / 101 (2.97%)
occurrences all number	42	48	2	3
Renal and urinary disorders
Dysuria
subjects affected / exposed	66 / 705 (9.36%)	73 / 720 (10.14%)	5 / 109 (4.59%)	7 / 101 (6.93%)
occurrences all number	85	95	8	8
Haematuria
subjects affected / exposed	90 / 705 (12.77%)	87 / 720 (12.08%)	17 / 109 (15.60%)	11 / 101 (10.89%)
occurrences all number	128	128	33	19
Nocturia
subjects affected / exposed	26 / 705 (3.69%)	39 / 720 (5.42%)	3 / 109 (2.75%)	3 / 101 (2.97%)
occurrences all number	34	45	3	3
Pollakiuria
subjects affected / exposed	50 / 705 (7.09%)	61 / 720 (8.47%)	1 / 109 (0.92%)	2 / 101 (1.98%)
occurrences all number	57	84	1	2
Urinary incontinence
subjects affected / exposed	30 / 705 (4.26%)	30 / 720 (4.17%)	8 / 109 (7.34%)	4 / 101 (3.96%)
occurrences all number	34	35	9	4
Urinary retention
subjects affected / exposed	63 / 705 (8.94%)	73 / 720 (10.14%)	6 / 109 (5.50%)	7 / 101 (6.93%)
occurrences all number	87	84	9	7
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	116 / 705 (16.45%)	123 / 720 (17.08%)	11 / 109 (10.09%)	9 / 101 (8.91%)
occurrences all number	174	192	15	12
Back pain
subjects affected / exposed	159 / 705 (22.55%)	166 / 720 (23.06%)	24 / 109 (22.02%)	8 / 101 (7.92%)
occurrences all number	232	280	31	9
Muscle spasms
subjects affected / exposed	28 / 705 (3.97%)	46 / 720 (6.39%)	6 / 109 (5.50%)	1 / 101 (0.99%)
occurrences all number	35	69	7	1
Musculoskeletal pain
subjects affected / exposed	59 / 705 (8.37%)	58 / 720 (8.06%)	8 / 109 (7.34%)	5 / 101 (4.95%)
occurrences all number	68	86	10	8
Osteoarthritis
subjects affected / exposed	24 / 705 (3.40%)	24 / 720 (3.33%)	6 / 109 (5.50%)	1 / 101 (0.99%)
occurrences all number	29	27	7	1
Osteonecrosis of jaw
subjects affected / exposed	0 / 705 (0.00%)	17 / 720 (2.36%)	1 / 109 (0.92%)	12 / 101 (11.88%)
occurrences all number	0	20	2	13
Pain in extremity
subjects affected / exposed	88 / 705 (12.48%)	101 / 720 (14.03%)	12 / 109 (11.01%)	10 / 101 (9.90%)
occurrences all number	124	136	17	11
Pain in jaw
subjects affected / exposed	7 / 705 (0.99%)	25 / 720 (3.47%)	2 / 109 (1.83%)	6 / 101 (5.94%)
occurrences all number	9	29	2	9
Infections and infestations
Bronchitis
subjects affected / exposed	32 / 705 (4.54%)	40 / 720 (5.56%)	3 / 109 (2.75%)	3 / 101 (2.97%)
occurrences all number	42	48	3	4
Influenza
subjects affected / exposed	38 / 705 (5.39%)	49 / 720 (6.81%)	7 / 109 (6.42%)	6 / 101 (5.94%)
occurrences all number	46	65	10	6
Nasopharyngitis
subjects affected / exposed	72 / 705 (10.21%)	68 / 720 (9.44%)	7 / 109 (6.42%)	4 / 101 (3.96%)
occurrences all number	90	100	9	5
Upper respiratory tract infection
subjects affected / exposed	23 / 705 (3.26%)	46 / 720 (6.39%)	8 / 109 (7.34%)	8 / 101 (7.92%)
occurrences all number	25	59	10	8
Urinary tract infection
subjects affected / exposed	96 / 705 (13.62%)	108 / 720 (15.00%)	15 / 109 (13.76%)	14 / 101 (13.86%)
occurrences all number	159	187	28	28
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	61 / 705 (8.65%)	63 / 720 (8.75%)	7 / 109 (6.42%)	5 / 101 (4.95%)
occurrences all number	70	95	9	5

More information

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Were there any global substantial amendments to the protocol? Yes

08 Jun 2007

The screening visit window was increased to ≤ weeks to allow greater flexibility in scheduling the screening procedures. The requirement for an end-of-study bone scan was removed if bone metastasis had been confirmed by the central imaging vendor. The radiology component of the study was clarified: at baseline, full body radioisotope bone scans were required for the exclusion of bone metastasis and on-study full body radioisotope bone scans were required for the detection of bone metastasis.

30 Oct 2009

The double-blind treatment phase was extended to allow subjects to receive investigational product until the benefit:risk profile for denosumab compared with placebo was determined based on the primary analysis results. An open-label extension phase was added, with enrollment dependent on the benefit:risk profile. Specifically, if denosumab's benefit:risk profile was positive, subjects currently undergoing Q4W scheduled assessments were to be given the option to receive open-label denosumab 120 mg Q4W until subjects develop a bone metastasis, for up to 3 years, or until denosumab is commercially available, whichever comes first. If the benefit:risk profile was not positive, subjects were to complete an end-of-study visit within 4 weeks of the last dose of blinded investigational product and be followed for survival for a period of 3 years. For countries that required a separate protocol for the open-label extension phase and, thus, did not accept protocol amendment 2 (ie, United Kingdom and Czech Republic), the protocol was amended to extend the double-blind treatment phase only (ie, to allow subjects to receive investigational product until the benefit:risk profile for denosumab was determined based upon the primary analysis results). For these countries, the open-label extension will be conducted under protocol number 20080585. The planned statistical analyses were revised to reflect the extended double-blind treatment phase and open-label treatment phase and other changes to the statistical analysis plan.

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.

None reported

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