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Clinical Trial Results:
A Multicenter, Controlled, Open-label Extension (OLE) Study to Assess the Long-term Safety and Efficacy of AMG 145 - OSLER 2

Summary
EudraCT number	2012-004357-83
Trial protocol	IT SE BE GB DE DK NO HU CZ AT NL ES PL
Global end of trial date	31 May 2018

Results information
Results version number	v1(current)
This version publication date	05 Jun 2019
First version publication date	05 Jun 2019
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

20120138

ISRCTN number

-

US NCT number

NCT01854918

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

31 May 2018

Is this the analysis of the primary completion data?

No

Global end of trial reached?

Yes

Global end of trial date

31 May 2018

Was the trial ended prematurely?

Yes

Main objective of the trial

The primary objective was to characterize the safety and tolerability of long-term administration of evolocumab.

Protection of trial subjects

This study was conducted in accordance with International Council for Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines, and Food and Drug Administration (FDA) regulations and guidelines set forth in 21 Code of Federal Regulations parts 11, 50, 54, 56, and 312. The study and all amendments were reviewed by an Independent Ethics Committee (IEC) or Institutional Review Board (IRB) at each center. The investigator or their designee informed the subject of all aspects pertaining to the subject’s participation in the study before any screening procedures were performed.

Background therapy

-

Evidence for comparator

-

Actual start date of recruitment

23 Apr 2013

Long term follow-up planned

No

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Austria: 2

Country: Number of subjects enrolled

Belgium: 109

Country: Number of subjects enrolled

Canada: 399

Country: Number of subjects enrolled

Czech Republic: 300

Country: Number of subjects enrolled

Denmark: 297

Country: Number of subjects enrolled

France: 54

Country: Number of subjects enrolled

Germany: 119

Country: Number of subjects enrolled

Hong Kong: 14

Country: Number of subjects enrolled

Australia: 148

Country: Number of subjects enrolled

Hungary: 80

Country: Number of subjects enrolled

Italy: 62

Country: Number of subjects enrolled

Japan: 337

Country: Number of subjects enrolled

Korea, Republic of: 1

Country: Number of subjects enrolled

Netherlands: 118

Country: Number of subjects enrolled

New Zealand: 13

Country: Number of subjects enrolled

Norway: 23

Country: Number of subjects enrolled

Russian Federation: 65

Country: Number of subjects enrolled

South Africa: 126

Country: Number of subjects enrolled

Spain: 54

Country: Number of subjects enrolled

Sweden: 43

Country: Number of subjects enrolled

Switzerland: 33

Country: Number of subjects enrolled

Taiwan: 5

Country: Number of subjects enrolled

United Kingdom: 163

Country: Number of subjects enrolled

United States: 1116

Worldwide total number of subjects

3681

EEA total number of subjects

1424

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)

2488

From 65 to 84 years

1193

85 years and over

0

Subject disposition

Top of page

Recruitment details

Participants were enrolled at 365 study centers in 24 countries in Europe, North America, and Asia Pacific from 23 April 2013 to 31 August 2015.

Screening details

Participants were randomized in a 2:1 ratio to receive evolocumab plus standard of care (SOC) or SOC alone for the first year. In years 2 and 3 all participants received evolocumab. Randomization was stratified by the parent study and parent study dose frequency (every 2 weeks [Q2W] or once monthly [QM]).

Period 1 title

SOC-controlled Period (Year 1)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Standard of Care

Arm description

Participants received standard of care (SOC) treatment for the first year of the study (SOC-controlled period).

Arm type

Standard of care

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Evolocumab + Standard of Care

Arm description

Participants received subcutaneous evolocumab plus standard of care during the first year of the study (SOC-controlled period). Evolocumab was administered at a dose of 140 mg every 2 weeks (Q2W) or 420 mg every month (QM) based on participant choice.

Arm type

Experimental

Investigational medicinal product name

Evolocumab

Investigational medicinal product code

AMG 145

Other name

Repatha

Pharmaceutical forms

Solution for injection in pre-filled pen

Routes of administration

Subcutaneous use

Dosage and administration details

Administered by subcutaneous injection either every 2 weeks or once a month (patient preference) using a prefilled autoinjector pen.

Number of subjects in period 1	Standard of Care	Evolocumab + Standard of Care
Started	1227	2454
Received Evolocumab	5 ^[1]	2452
Completed	1197	2391
Not completed	30	63
Consent withdrawn by subject	20	49
Decision by Sponsor	2	1
Death	5	5
Lost to follow-up	3	8

Notes
[1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: 5 participants received evolocumab in error

Period 2 title

All-IP Period (Years 2 and 3)

Is this the baseline period?

No

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

SOC / Evolocumab + SOC

Arm description

At week 48, participants began treatment with evolocumab at a dose of either 140 mg every 2 weeks (Q2W) or 420 mg every month (QM), based on participant choice, for approximately 2 years during the all-investigational product [all-IP] period.

Arm type

Experimental

Investigational medicinal product name

Evolocumab

Investigational medicinal product code

AMG 145

Other name

Repatha

Pharmaceutical forms

Solution for injection in pre-filled pen

Routes of administration

Subcutaneous use

Dosage and administration details

Administered by subcutaneous injection either every 2 weeks or once a month (patient preference) using a prefilled autoinjector pen.

Evolocumab + SOC / Evolocumab + SOC

Arm description

Participants continued to receive subcutaneous evolocumab plus standard of care for approximately 2 years during the all-IP period. Evolocumab was administered at a dose of 140 mg every 2 weeks (Q2W) or 420 mg every month (QM) based on participant choice.

Arm type

Experimental

Investigational medicinal product name

Evolocumab

Investigational medicinal product code

AMG 145

Other name

Repatha

Pharmaceutical forms

Solution for injection in pre-filled pen

Routes of administration

Subcutaneous use

Dosage and administration details

Administered by subcutaneous injection either every 2 weeks or once a month (patient preference) using a prefilled autoinjector pen.

Number of subjects in period 2	SOC / Evolocumab + SOC	Evolocumab + SOC / Evolocumab + SOC
Started	1197	2391
Received Evolocumab	1152	2291
Completed	1079	2196
Not completed	118	195
Consent withdrawn by subject	78	117
Decision by Sponsor	8	11
Death	5	16
Lost to follow-up	27	51

Baseline characteristics

Top of page

Reporting group title

Standard of Care

Reporting group description

Participants received standard of care (SOC) treatment for the first year of the study (SOC-controlled period).

Reporting group title

Evolocumab + Standard of Care

Reporting group description

Participants received subcutaneous evolocumab plus standard of care during the first year of the study (SOC-controlled period). Evolocumab was administered at a dose of 140 mg every 2 weeks (Q2W) or 420 mg every month (QM) based on participant choice.

Reporting group values	Standard of Care	Evolocumab + Standard of Care	Total
Number of subjects	1227	2454	3681
Age, Customized
Units: Subjects
< 65 years	823	1665	2488
≥ 65 years	404	789	1193
Age Continuous
Units: years
arithmetic mean (standard deviation)	58.8 ( 10.7 )	58.6 ( 10.7 )	-
Sex: Female, Male
Units: Subjects
Female	560	1176	1736
Male	667	1278	1945
Race/Ethnicity, Customized
Units: Subjects
American Indian or Alaska Native	2	5	7
Asian	152	288	440
Black or African American	49	84	133
Native Hawaiian or Other Pacific Islander	2	2	4
White	1003	2041	3044
Other	16	30	46
Mixed Race	3	4	7
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	58	109	167
Not Hispanic or Latino	1169	2345	3514
Unknown or Not Reported	0	0	0
Region
Units: Subjects
North America	514	1001	1515
Europe	504	1018	1522
Asia Pacific	209	435	644
Parent Study Baseline Low-density Lipoprotein Cholesterol (LDL-C) Concentration
Units: mg/dL
arithmetic mean (standard deviation)	125.8 ( 49.3 )	127.4 ( 51.7 )	-

End points

Top of page

Reporting group title

Standard of Care

Reporting group description

Participants received standard of care (SOC) treatment for the first year of the study (SOC-controlled period).

Reporting group title

Evolocumab + Standard of Care

Reporting group description

Participants received subcutaneous evolocumab plus standard of care during the first year of the study (SOC-controlled period). Evolocumab was administered at a dose of 140 mg every 2 weeks (Q2W) or 420 mg every month (QM) based on participant choice.

Reporting group title

SOC / Evolocumab + SOC

Reporting group description

At week 48, participants began treatment with evolocumab at a dose of either 140 mg every 2 weeks (Q2W) or 420 mg every month (QM), based on participant choice, for approximately 2 years during the all-investigational product [all-IP] period.

Reporting group title

Evolocumab + SOC / Evolocumab + SOC

Reporting group description

Participants continued to receive subcutaneous evolocumab plus standard of care for approximately 2 years during the all-IP period. Evolocumab was administered at a dose of 140 mg every 2 weeks (Q2W) or 420 mg every month (QM) based on participant choice.

Primary: Number of Participants with Adverse Events

Top of page

End point title

Number of Participants with Adverse Events ^[1]

End point description

Adverse event (AE) severity assessments were made using National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) grading, version 4.0, where grade 1 = mild AE, grade 2 = moderate AE, Grade 3 = severe AE, grade 4 = life-threatening AE and Grade 5 = death due to AE.

End point type

Primary

End point timeframe

48 weeks in the SOC-controlled period and up to 2 years in the All-IP period

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal hypothesis was tested. Statistical analyses in this open-label extension study were descriptive in nature.

End point values	Standard of Care	SOC / Evolocumab + SOC	Evolocumab + Standard of Care	Evolocumab + SOC / Evolocumab + SOC
Number of subjects analysed	1227 ^[2]	1152 ^[3]	2454 ^[4]	2291 ^[5]
Units: participants
All adverse events	796	929	1655	1789
Adverse events ≥ grade 2	519	700	1070	1339
Adverse events ≥ grade 3	124	214	225	379
Adverse events ≥ grade 4	7	11	17	35
Serious adverse events	104	178	195	332
AEs leading to discontinuation of evolocumab	0	26	55	42
Fatal adverse events	5	3	5	16
Device related adverse events	0	25	57	45

Notes
[2] - All randomized participants
[3] - Randomized participants on-study with known dosing information in the All-IP period
[4] - All randomized participants
[5] - Randomized participants on-study with known dosing information in the All-IP period

No statistical analyses for this end point

Secondary: Percent Change from Baseline in LDL-C at Weeks 48 and 104

Top of page

End point title

Percent Change from Baseline in LDL-C at Weeks 48 and 104

End point description

End point type

Secondary

End point timeframe

Baseline of the parent study and weeks 48 amd 104

End point values	SOC / Evolocumab + SOC	Evolocumab + SOC / Evolocumab + SOC
Number of subjects analysed	1152 ^[6]	2291 ^[7]
Units: percent change
arithmetic mean (standard deviation)
Week 48 (n = 1115, 2241)	7.43 ( 38.93 )	-51.59 ( 28.88 )
Week 104 (n = 1087, 2166)	-49.96 ( 33.29 )	-50.31 ( 30.34 )

Notes
[6] - Randomized participants on-study and with known dosing information in the All-IP period
[7] - Randomized participants on-study and with known dosing information in the All-IP period

No statistical analyses for this end point

Secondary: Change from Baseline in LDL-C at Weeks 48 and 104

Top of page

End point title

Change from Baseline in LDL-C at Weeks 48 and 104

End point description

End point type

Secondary

End point timeframe

Baseline of the parent study and weeks 48 amd 104

End point values	SOC / Evolocumab + SOC	Evolocumab + SOC / Evolocumab + SOC
Number of subjects analysed	1152 ^[8]	2291 ^[9]
Units: mg/dL
arithmetic mean (standard deviation)
Week 48 (n = 1115, 2241)	0.4 ( 43.9 )	-68.8 ( 46.6 )
Week 104 (n = 1087, 2166)	-66.4 ( 50.1 )	-67.2 ( 46.6 )

Notes
[8] - Randomized participants on-study and with known dosing information in the All-IP period
[9] - Randomized participants on-study and with known dosing information in the All-IP period

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

48 weeks in the SOC-controlled period and up to 2 years in the All-IP period.

Adverse event reporting additional description

Adverse events are reported for all randomized participants in the SOC-controlled period (year 1) and for all randomized participants who entered the All-IP period (years 2 and 3).

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

21.0

Reporting group title

Year 1: Standard of Care

Reporting group description

Participants received standard of care (SOC) treatment for the first year of the study (SOC-controlled period).

Reporting group title

Year 1: Evolocumab + SoC

Reporting group description

Participants received subcutaneous evolocumab plus standard of care during the first year of the study (SOC-controlled period). Evolocumab was administered at a dose of 140 mg every 2 weeks (Q2W) or 420 mg every month (QM) based on participant choice.

Reporting group title

Years 2-3: SoC / Evolocumab + SOC

Reporting group description

At week 48, participants began treatment with evolocumab at a dose of either 140 mg Q2W or 420 mg QM, based on participant choice, plus SOC, for approximately 2 years during the all-IP period.

Reporting group title

Years 2-3: Evolocumab + SoC / Evolocumab + SOC

Reporting group description

Participants continued to receive evolocumab plus SOC for approximately 2 years during the all-IP period. Evolocumab was administered at a dose of 140 mg Q2W or 420 mg QM based on participant choice.

Reporting group title

Years 2-3: Total

Reporting group description

All participants in the All-IP period who received evolocumab plus SOC for approximately 2 years. Evolocumab was administered at a dose of 140 mg Q2W or 420 mg QM based on participant choice.

Serious adverse events	Year 1: Standard of Care	Year 1: Evolocumab + SoC	Years 2-3: SoC / Evolocumab + SOC	Years 2-3: Evolocumab + SoC / Evolocumab + SOC	Years 2-3: Total
Total subjects affected by serious adverse events
subjects affected / exposed	104 / 1227 (8.48%)	195 / 2454 (7.95%)	181 / 1197 (15.12%)	344 / 2391 (14.39%)	525 / 3588 (14.63%)
number of deaths (all causes)	5	5	5	16	21
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Adenocarcinoma of colon
subjects affected / exposed	0 / 1227 (0.00%)	2 / 2454 (0.08%)	1 / 1197 (0.08%)	1 / 2391 (0.04%)	2 / 3588 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
Basal cell carcinoma
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Benign anorectal neoplasm
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bladder cancer
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bladder neoplasm
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bladder transitional cell carcinoma
subjects affected / exposed	0 / 1227 (0.00%)	3 / 2454 (0.12%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 5	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Breast cancer
subjects affected / exposed	4 / 1227 (0.33%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Breast cancer metastatic
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	1 / 2391 (0.04%)	2 / 3588 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Breast neoplasm
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
Cancer pain
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cervix carcinoma
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chronic lymphocytic leukaemia
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colon adenoma
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colon cancer
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diffuse large B-cell lymphoma
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Duodenal neoplasm
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Essential thrombocythaemia
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intraductal proliferative breast lesion
subjects affected / exposed	1 / 1227 (0.08%)	1 / 2454 (0.04%)	1 / 1197 (0.08%)	1 / 2391 (0.04%)	2 / 3588 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Invasive breast carcinoma
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Invasive ductal breast carcinoma
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	2 / 1197 (0.17%)	2 / 2391 (0.08%)	4 / 3588 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Invasive papillary breast carcinoma
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Laryngeal squamous cell carcinoma
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lipoma
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung adenocarcinoma
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	1 / 2391 (0.04%)	2 / 3588 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
Lung adenocarcinoma stage IV
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung neoplasm malignant
subjects affected / exposed	1 / 1227 (0.08%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Lymphoma
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Malignant melanoma
subjects affected / exposed	1 / 1227 (0.08%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Malignant melanoma in situ
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Meningioma
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	2 / 2391 (0.08%)	2 / 3588 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to bone
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to central nervous system
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to peritoneum
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
Neoplasm of appendix
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neuroendocrine carcinoma
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Non-Hodgkin's lymphoma
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oral papilloma
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatic carcinoma
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatic carcinoma metastatic
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	2 / 2391 (0.08%)	2 / 3588 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Papillary thyroid cancer
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Papillary tumour of renal pelvis
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Penile neoplasm
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Prostate cancer
subjects affected / exposed	2 / 1227 (0.16%)	3 / 2454 (0.12%)	3 / 1197 (0.25%)	4 / 2391 (0.17%)	7 / 3588 (0.20%)
occurrences causally related to treatment / all	0 / 2	0 / 3	0 / 3	1 / 4	1 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rectal adenocarcinoma
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	1 / 2391 (0.04%)	2 / 3588 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rectal cancer
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal cancer
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	1 / 2391 (0.04%)	2 / 3588 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal cell carcinoma
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	3 / 2391 (0.13%)	3 / 3588 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Salivary gland adenoma
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Salivary gland cancer
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma of lung
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma of the vulva
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Testicular seminoma (pure)
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thyroid adenoma
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thyroid cancer
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thyroid neoplasm
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tongue neoplasm malignant stage unspecified
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Uterine cancer
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Uterine leiomyoma
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vulval cancer
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Accelerated hypertension
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aortic aneurysm
subjects affected / exposed	0 / 1227 (0.00%)	2 / 2454 (0.08%)	1 / 1197 (0.08%)	1 / 2391 (0.04%)	2 / 3588 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aortic dilatation
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aortic dissection
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aortic stenosis
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	4 / 1197 (0.33%)	0 / 2391 (0.00%)	4 / 3588 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 4	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arteriosclerosis
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Artery dissection
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood pressure fluctuation
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haematoma
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypertension
subjects affected / exposed	2 / 1227 (0.16%)	1 / 2454 (0.04%)	1 / 1197 (0.08%)	4 / 2391 (0.17%)	5 / 3588 (0.14%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 1	0 / 4	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypertensive crisis
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypertensive emergency
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypotension
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Labile blood pressure
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Malignant hypertension
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Microangiopathy
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Orthostatic hypotension
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	2 / 1197 (0.17%)	0 / 2391 (0.00%)	2 / 3588 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pelvic venous thrombosis
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral arterial occlusive disease
subjects affected / exposed	0 / 1227 (0.00%)	2 / 2454 (0.08%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral artery aneurysm
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral artery occlusion
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral ischaemia
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral vascular disorder
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subclavian artery stenosis
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thrombophlebitis
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Varicose vein
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	2 / 2391 (0.08%)	2 / 3588 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Venous thrombosis
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Venous thrombosis limb
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chest discomfort
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chest pain
subjects affected / exposed	2 / 1227 (0.16%)	1 / 2454 (0.04%)	3 / 1197 (0.25%)	4 / 2391 (0.17%)	7 / 3588 (0.20%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 3	0 / 5	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Complication associated with device
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Face oedema
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fatigue
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gait disturbance
subjects affected / exposed	0 / 1227 (0.00%)	2 / 2454 (0.08%)	1 / 1197 (0.08%)	1 / 2391 (0.04%)	2 / 3588 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Impaired healing
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injection site erythema
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Malaise
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Multiple organ dysfunction syndrome
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
Non-cardiac chest pain
subjects affected / exposed	3 / 1227 (0.24%)	4 / 2454 (0.16%)	10 / 1197 (0.84%)	8 / 2391 (0.33%)	18 / 3588 (0.50%)
occurrences causally related to treatment / all	0 / 3	0 / 4	0 / 11	0 / 8	0 / 19
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pain
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Polyp
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	2 / 2391 (0.08%)	2 / 3588 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sudden death
subjects affected / exposed	1 / 1227 (0.08%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	1 / 1	0 / 0	0 / 0	0 / 0
Vascular stent occlusion
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular stent stenosis
subjects affected / exposed	1 / 1227 (0.08%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Allergy to arthropod sting
subjects affected / exposed	0 / 1227 (0.00%)	2 / 2454 (0.08%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anaphylactic reaction
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Contrast media allergy
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Drug hypersensitivity
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypersensitivity
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Benign prostatic hyperplasia
subjects affected / exposed	1 / 1227 (0.08%)	2 / 2454 (0.08%)	3 / 1197 (0.25%)	2 / 2391 (0.08%)	5 / 3588 (0.14%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 3	0 / 2	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cystocele
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Genital prolapse
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mastoptosis
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ovarian cyst
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	2 / 1197 (0.17%)	0 / 2391 (0.00%)	2 / 3588 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Prostatic obstruction
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Prostatism
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Prostatitis
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rectocele
subjects affected / exposed	1 / 1227 (0.08%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Uterine haemorrhage
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Uterine polyp
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Uterine prolapse
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vaginal prolapse
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acquired diaphragmatic eventration
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute pulmonary oedema
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Asthma
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	1 / 1197 (0.08%)	2 / 2391 (0.08%)	3 / 3588 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atelectasis
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchospasm
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchostenosis
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	2 / 1197 (0.17%)	3 / 2391 (0.13%)	5 / 3588 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 3	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diaphragmatic paralysis
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	2 / 1227 (0.16%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	4 / 2391 (0.17%)	4 / 3588 (0.11%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0	1 / 7	1 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea exertional
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Epistaxis
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Interstitial lung disease
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nasal polyps
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nasal septum deviation
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	2 / 2391 (0.08%)	2 / 3588 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleurisy
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	1 / 1197 (0.08%)	2 / 2391 (0.08%)	3 / 3588 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	2 / 1227 (0.16%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	4 / 2391 (0.17%)	4 / 3588 (0.11%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	1 / 4	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
Pulmonary hypertension
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	1 / 2391 (0.04%)	2 / 3588 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	1 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
Pulmonary mass
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	1 / 2391 (0.04%)	2 / 3588 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	2 / 2391 (0.08%)	2 / 3588 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sleep apnoea syndrome
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vocal cord polyp
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Adjustment disorder with depressed mood
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Agoraphobia
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Alcoholism
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bipolar I disorder
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bipolar disorder
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Completed suicide
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	1 / 2391 (0.04%)	2 / 3588 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 2
Confusional state
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Depression
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	4 / 2391 (0.17%)	4 / 3588 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Drug dependence
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychotic disorder
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Schizophrenia
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Suicidal ideation
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Suicide attempt
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Product issues
Device leakage
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anticoagulation drug level below therapeutic
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Antimitochondrial antibody positive
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Antinuclear antibody
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood immunoglobulin M increased
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ejection fraction decreased
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intraocular pressure increased
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Liver function test abnormal
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Red blood cell sedimentation rate increased
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Scan myocardial perfusion abnormal
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Accidental overdose
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Alcohol poisoning
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anaemia postoperative
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anastomotic complication
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ankle fracture
subjects affected / exposed	1 / 1227 (0.08%)	2 / 2454 (0.08%)	2 / 1197 (0.17%)	2 / 2391 (0.08%)	4 / 3588 (0.11%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 2	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Back injury
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cartilage injury
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Clavicle fracture
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Comminuted fracture
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Concussion
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	2 / 2391 (0.08%)	3 / 3588 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Contusion
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Craniocerebral injury
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	2 / 2391 (0.08%)	2 / 3588 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
Face injury
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	2 / 2391 (0.08%)	2 / 3588 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Femoral neck fracture
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	2 / 1197 (0.17%)	0 / 2391 (0.00%)	2 / 3588 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	3 / 2391 (0.13%)	3 / 3588 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fibula fracture
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Foot fracture
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fractured coccyx
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis radiation
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hip fracture
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	1 / 2391 (0.04%)	2 / 3588 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Incision site haematoma
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Incisional hernia
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal anastomosis complication
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Jaw fracture
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Joint dislocation
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Laceration
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lower limb fracture
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	1 / 2391 (0.04%)	2 / 3588 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lumbar vertebral fracture
subjects affected / exposed	1 / 1227 (0.08%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Meniscus injury
subjects affected / exposed	0 / 1227 (0.00%)	2 / 2454 (0.08%)	1 / 1197 (0.08%)	2 / 2391 (0.08%)	3 / 3588 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Multiple fractures
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Overdose
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Patella fracture
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pelvic fracture
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural fever
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural haemorrhage
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	4 / 2391 (0.17%)	4 / 3588 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Procedural pain
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Radius fracture
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rib fracture
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Road traffic accident
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal fracture
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	2 / 1197 (0.17%)	0 / 2391 (0.00%)	2 / 3588 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subarachnoid haemorrhage
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	1 / 1227 (0.08%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subdural haemorrhage
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tendon rupture
subjects affected / exposed	1 / 1227 (0.08%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thermal burn
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tibia fracture
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	2 / 2391 (0.08%)	2 / 3588 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Toxicity to various agents
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	2 / 1197 (0.17%)	0 / 2391 (0.00%)	2 / 3588 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper limb fracture
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
VIIIth nerve injury
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular graft complication
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular graft stenosis
subjects affected / exposed	2 / 1227 (0.16%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Wrist fracture
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	2 / 1197 (0.17%)	0 / 2391 (0.00%)	2 / 3588 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Congenital, familial and genetic disorders
Adenomatous polyposis coli
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute coronary syndrome
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	4 / 1227 (0.33%)	8 / 2454 (0.33%)	3 / 1197 (0.25%)	12 / 2391 (0.50%)	15 / 3588 (0.42%)
occurrences causally related to treatment / all	0 / 4	0 / 8	0 / 3	0 / 12	0 / 15
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
Angina pectoris
subjects affected / exposed	0 / 1227 (0.00%)	7 / 2454 (0.29%)	10 / 1197 (0.84%)	8 / 2391 (0.33%)	18 / 3588 (0.50%)
occurrences causally related to treatment / all	0 / 0	0 / 8	0 / 11	0 / 8	0 / 19
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Angina unstable
subjects affected / exposed	6 / 1227 (0.49%)	7 / 2454 (0.29%)	4 / 1197 (0.33%)	11 / 2391 (0.46%)	15 / 3588 (0.42%)
occurrences causally related to treatment / all	0 / 6	1 / 7	0 / 5	0 / 11	0 / 16
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aortic valve disease
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aortic valve incompetence
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aortic valve sclerosis
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aortic valve stenosis
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arrhythmia
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arteriosclerosis coronary artery
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	3 / 1227 (0.24%)	1 / 2454 (0.04%)	7 / 1197 (0.58%)	7 / 2391 (0.29%)	14 / 3588 (0.39%)
occurrences causally related to treatment / all	0 / 5	0 / 1	0 / 9	0 / 7	0 / 16
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrial flutter
subjects affected / exposed	1 / 1227 (0.08%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	3 / 2391 (0.13%)	3 / 3588 (0.08%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrioventricular block
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bradycardia
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	1 / 2391 (0.04%)	2 / 3588 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	4 / 2391 (0.17%)	4 / 3588 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3	0 / 3
Cardiac failure
subjects affected / exposed	1 / 1227 (0.08%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	2 / 2391 (0.08%)	2 / 3588 (0.06%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
Cardiac failure acute
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
Cardiac failure congestive
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	3 / 1197 (0.25%)	6 / 2391 (0.25%)	9 / 3588 (0.25%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 3	0 / 6	0 / 9
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardio-respiratory arrest
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Coronary artery disease
subjects affected / exposed	4 / 1227 (0.33%)	3 / 2454 (0.12%)	2 / 1197 (0.17%)	7 / 2391 (0.29%)	9 / 3588 (0.25%)
occurrences causally related to treatment / all	0 / 4	1 / 3	0 / 2	0 / 8	0 / 10
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
Coronary artery occlusion
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Coronary artery stenosis
subjects affected / exposed	0 / 1227 (0.00%)	2 / 2454 (0.08%)	1 / 1197 (0.08%)	3 / 2391 (0.13%)	4 / 3588 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 3	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Left ventricular failure
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mitral valve incompetence
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	2 / 1227 (0.16%)	5 / 2454 (0.20%)	0 / 1197 (0.00%)	2 / 2391 (0.08%)	2 / 3588 (0.06%)
occurrences causally related to treatment / all	0 / 2	0 / 5	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
Myocardial ischaemia
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	4 / 2391 (0.17%)	5 / 3588 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 4	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 2
Palpitations
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	1 / 2391 (0.04%)	2 / 3588 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pericardial effusion
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pericarditis
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rheumatic heart disease
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sinus node dysfunction
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	2 / 1197 (0.17%)	1 / 2391 (0.04%)	3 / 3588 (0.08%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Supraventricular tachycardia
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tachycardia
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tricuspid valve incompetence
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ventricular extrasystoles
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ventricular fibrillation
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ventricular tachycardia
subjects affected / exposed	0 / 1227 (0.00%)	2 / 2454 (0.08%)	0 / 1197 (0.00%)	2 / 2391 (0.08%)	2 / 3588 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Ataxia
subjects affected / exposed	1 / 1227 (0.08%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Carotid artery aneurysm
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Carotid artery stenosis
subjects affected / exposed	1 / 1227 (0.08%)	2 / 2454 (0.08%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Carpal tunnel syndrome
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebellar haemorrhage
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Cerebral haemorrhage
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral ischaemia
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	1 / 1227 (0.08%)	1 / 2454 (0.04%)	1 / 1197 (0.08%)	7 / 2391 (0.29%)	8 / 3588 (0.22%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 7	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cervical radiculopathy
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dizziness
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	2 / 2391 (0.08%)	2 / 3588 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dysaesthesia
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhage intracranial
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
Haemorrhagic stroke
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	2 / 2391 (0.08%)	2 / 3588 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hydrocephalus
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypoaesthesia
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypoglycaemic seizure
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intracranial aneurysm
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lacunar infarction
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lumbar radiculopathy
subjects affected / exposed	1 / 1227 (0.08%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolic encephalopathy
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Migraine
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myelopathy
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nerve root compression
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Paresis
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Polyneuropathy
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Presyncope
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	4 / 2391 (0.17%)	4 / 3588 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sciatica
subjects affected / exposed	1 / 1227 (0.08%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	0 / 1227 (0.00%)	2 / 2454 (0.08%)	0 / 1197 (0.00%)	2 / 2391 (0.08%)	2 / 3588 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal cord haematoma
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	3 / 1227 (0.24%)	1 / 2454 (0.04%)	2 / 1197 (0.17%)	5 / 2391 (0.21%)	7 / 3588 (0.20%)
occurrences causally related to treatment / all	0 / 3	0 / 1	1 / 2	0 / 6	1 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Transient global amnesia
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	3 / 1227 (0.24%)	0 / 2454 (0.00%)	3 / 1197 (0.25%)	5 / 2391 (0.21%)	8 / 3588 (0.22%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 3	0 / 5	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tremor
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vertebrobasilar insufficiency
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Visual field defect
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	1 / 1197 (0.08%)	1 / 2391 (0.04%)	2 / 3588 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemolysis
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhagic anaemia
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lymphadenopathy
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thrombocytopenic purpura
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Deafness neurosensory
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tinnitus
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vertigo
subjects affected / exposed	1 / 1227 (0.08%)	2 / 2454 (0.08%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vertigo positional
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Blindness transient
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cataract
subjects affected / exposed	1 / 1227 (0.08%)	1 / 2454 (0.04%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Macular fibrosis
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Retinal vein occlusion
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal hernia
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	0 / 1227 (0.00%)	3 / 2454 (0.12%)	0 / 1197 (0.00%)	2 / 2391 (0.08%)	2 / 3588 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anal skin tags
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colitis ischaemic
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	2 / 2391 (0.08%)	2 / 3588 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	2 / 2391 (0.08%)	3 / 3588 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulum intestinal
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Duodenal ulcer haemorrhage
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Duodenitis
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Enterovesical fistula
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastric haemorrhage
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastric ulcer
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	2 / 1197 (0.17%)	2 / 2391 (0.08%)	4 / 3588 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroduodenal ulcer
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	2 / 2391 (0.08%)	3 / 3588 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	1 / 1197 (0.08%)	3 / 2391 (0.13%)	4 / 3588 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 3	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhoids
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hiatus hernia
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	1 / 1197 (0.08%)	2 / 2391 (0.08%)	3 / 3588 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ileus
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	2 / 2391 (0.08%)	2 / 3588 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Incarcerated inguinal hernia
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	0 / 1227 (0.00%)	2 / 2454 (0.08%)	3 / 1197 (0.25%)	3 / 2391 (0.13%)	6 / 3588 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 3	0 / 3	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal perforation
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Intra-abdominal haematoma
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intussusception
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Large intestinal obstruction
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Large intestine perforation
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	2 / 2391 (0.08%)	2 / 3588 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Large intestine polyp
subjects affected / exposed	1 / 1227 (0.08%)	1 / 2454 (0.04%)	1 / 1197 (0.08%)	3 / 2391 (0.13%)	4 / 3588 (0.11%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 3	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lower gastrointestinal haemorrhage
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mechanical ileus
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal ulcer
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal ulcer haemorrhage
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oesophagitis
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	1 / 1227 (0.08%)	1 / 2454 (0.04%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Salivary gland calculus
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Short-bowel syndrome
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Umbilical hernia
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Bile duct stenosis
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bile duct stone
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholangitis
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	3 / 1197 (0.25%)	3 / 2391 (0.13%)	6 / 3588 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3	0 / 3	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	3 / 1197 (0.25%)	3 / 2391 (0.13%)	6 / 3588 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3	0 / 3	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis chronic
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	0 / 1227 (0.00%)	3 / 2454 (0.12%)	5 / 1197 (0.42%)	0 / 2391 (0.00%)	5 / 3588 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 6	0 / 0	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gallbladder necrosis
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic function abnormal
subjects affected / exposed	1 / 1227 (0.08%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Non-alcoholic fatty liver
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sphincter of Oddi dysfunction
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Angioedema
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dermatitis contact
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperhidrosis
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin lesion
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Toxic skin eruption
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	2 / 2391 (0.08%)	3 / 3588 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bladder fibrosis
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Calculus bladder
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Calculus urinary
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	1 / 1197 (0.08%)	2 / 2391 (0.08%)	3 / 3588 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chronic kidney disease
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haematuria
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hydronephrosis
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	0 / 1227 (0.00%)	4 / 2454 (0.16%)	1 / 1197 (0.08%)	4 / 2391 (0.17%)	5 / 3588 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 5	0 / 1	0 / 4	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal artery stenosis
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal cyst
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal failure
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal impairment
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal infarct
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	1 / 2391 (0.04%)	2 / 3588 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ureteral spasm
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ureteric stenosis
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ureterolithiasis
subjects affected / exposed	0 / 1227 (0.00%)	3 / 2454 (0.12%)	0 / 1197 (0.00%)	2 / 2391 (0.08%)	2 / 3588 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urethral stenosis
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary incontinence
subjects affected / exposed	1 / 1227 (0.08%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Goitre
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperparathyroidism primary
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperthyroidism
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypothyroidism
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	2 / 2391 (0.08%)	2 / 3588 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arthritis
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	5 / 2391 (0.21%)	5 / 3588 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 7	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arthropathy
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	2 / 2391 (0.08%)	3 / 3588 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Back pain
subjects affected / exposed	1 / 1227 (0.08%)	2 / 2454 (0.08%)	1 / 1197 (0.08%)	2 / 2391 (0.08%)	3 / 3588 (0.08%)
occurrences causally related to treatment / all	0 / 1	1 / 2	0 / 1	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bursitis
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cervical spinal stenosis
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diffuse idiopathic skeletal hyperostosis
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dupuytren's contracture
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Femoroacetabular impingement
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fibromyalgia
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Foot deformity
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	3 / 2391 (0.13%)	3 / 3588 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fracture nonunion
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gouty arthritis
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral disc degeneration
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	3 / 2391 (0.13%)	3 / 3588 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral disc protrusion
subjects affected / exposed	1 / 1227 (0.08%)	1 / 2454 (0.04%)	6 / 1197 (0.50%)	6 / 2391 (0.25%)	12 / 3588 (0.33%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 6	0 / 6	0 / 12
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Joint effusion
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Knee deformity
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lumbar spinal stenosis
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	2 / 1197 (0.17%)	4 / 2391 (0.17%)	6 / 3588 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 4	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metatarsalgia
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Muscle haemorrhage
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal chest pain
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal pain
subjects affected / exposed	1 / 1227 (0.08%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myalgia
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	5 / 1227 (0.41%)	12 / 2454 (0.49%)	22 / 1197 (1.84%)	22 / 2391 (0.92%)	44 / 3588 (1.23%)
occurrences causally related to treatment / all	0 / 5	0 / 12	0 / 27	1 / 24	1 / 51
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteonecrosis
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Polymyalgia rheumatica
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rhabdomyolysis
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rotator cuff syndrome
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	2 / 1197 (0.17%)	2 / 2391 (0.08%)	4 / 3588 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal column stenosis
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	1 / 1197 (0.08%)	4 / 2391 (0.17%)	5 / 3588 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 4	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal deformity
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal osteoarthritis
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal pain
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tendon disorder
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vertebral foraminal stenosis
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Abdominal abscess
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abscess jaw
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abscess neck
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	2 / 1227 (0.16%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	3 / 2391 (0.13%)	4 / 3588 (0.11%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 3	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Appendicitis perforated
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arthritis bacterial
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	2 / 2391 (0.08%)	2 / 3588 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchopulmonary aspergillosis
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Campylobacter infection
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	3 / 1197 (0.25%)	3 / 2391 (0.13%)	6 / 3588 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3	0 / 3	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Clostridium difficile infection
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Cystitis
subjects affected / exposed	1 / 1227 (0.08%)	2 / 2454 (0.08%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Device related infection
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	2 / 1227 (0.16%)	1 / 2454 (0.04%)	2 / 1197 (0.17%)	5 / 2391 (0.21%)	7 / 3588 (0.20%)
occurrences causally related to treatment / all	0 / 4	0 / 1	0 / 3	0 / 5	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Endocarditis
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Epididymitis
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis bacterial
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis viral
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haematoma infection
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	2 / 2391 (0.08%)	2 / 3588 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatitis B
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infected dermal cyst
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infective exacerbation of chronic obstructive airways disease
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	2 / 2391 (0.08%)	3 / 3588 (0.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral discitis
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Liver abscess
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Localised infection
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	0 / 1227 (0.00%)	2 / 2454 (0.08%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Meningitis viral
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neurosyphilis
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteomyelitis
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Otitis externa
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Parotitis
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pelvic inflammatory disease
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peritonitis
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	4 / 1197 (0.33%)	12 / 2391 (0.50%)	16 / 3588 (0.45%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 5	1 / 12	2 / 17
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia pneumococcal
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia viral
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural infection
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Postoperative abscess
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Postoperative wound infection
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyelitis
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	1 / 2391 (0.04%)	2 / 3588 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis acute
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	1 / 1197 (0.08%)	1 / 2391 (0.04%)	2 / 3588 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
Sinusitis
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Staphylococcal infection
subjects affected / exposed	1 / 1227 (0.08%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tonsillitis
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	1 / 1197 (0.08%)	1 / 2391 (0.04%)	2 / 3588 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	0 / 1227 (0.00%)	2 / 2454 (0.08%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	1 / 2391 (0.04%)	2 / 3588 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fluid overload
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gout
subjects affected / exposed	0 / 1227 (0.00%)	1 / 2454 (0.04%)	0 / 1197 (0.00%)	0 / 2391 (0.00%)	0 / 3588 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypocalcaemia
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	1 / 2391 (0.04%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	2 / 1227 (0.16%)	0 / 2454 (0.00%)	1 / 1197 (0.08%)	0 / 2391 (0.00%)	1 / 3588 (0.03%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Obesity
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	2 / 2391 (0.08%)	2 / 3588 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Type 2 diabetes mellitus
subjects affected / exposed	0 / 1227 (0.00%)	0 / 2454 (0.00%)	0 / 1197 (0.00%)	2 / 2391 (0.08%)	2 / 3588 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Year 1: Standard of Care	Year 1: Evolocumab + SoC	Years 2-3: SoC / Evolocumab + SOC	Years 2-3: Evolocumab + SoC / Evolocumab + SOC	Years 2-3: Total
Total subjects affected by non serious adverse events
subjects affected / exposed	334 / 1227 (27.22%)	681 / 2454 (27.75%)	498 / 1197 (41.60%)	928 / 2391 (38.81%)	1426 / 3588 (39.74%)
Vascular disorders
Hypertension
subjects affected / exposed	56 / 1227 (4.56%)	87 / 2454 (3.55%)	78 / 1197 (6.52%)	180 / 2391 (7.53%)	258 / 3588 (7.19%)
occurrences all number	57	90	88	192	280
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	38 / 1227 (3.10%)	106 / 2454 (4.32%)	80 / 1197 (6.68%)	162 / 2391 (6.78%)	242 / 3588 (6.74%)
occurrences all number	40	119	94	191	285
Back pain
subjects affected / exposed	35 / 1227 (2.85%)	83 / 2454 (3.38%)	78 / 1197 (6.52%)	147 / 2391 (6.15%)	225 / 3588 (6.27%)
occurrences all number	36	90	88	173	261
Myalgia
subjects affected / exposed	43 / 1227 (3.50%)	88 / 2454 (3.59%)	61 / 1197 (5.10%)	67 / 2391 (2.80%)	128 / 3588 (3.57%)
occurrences all number	46	113	75	83	158
Infections and infestations
Bronchitis
subjects affected / exposed	43 / 1227 (3.50%)	78 / 2454 (3.18%)	70 / 1197 (5.85%)	132 / 2391 (5.52%)	202 / 3588 (5.63%)
occurrences all number	44	83	89	170	259
Influenza
subjects affected / exposed	28 / 1227 (2.28%)	66 / 2454 (2.69%)	60 / 1197 (5.01%)	115 / 2391 (4.81%)	175 / 3588 (4.88%)
occurrences all number	34	80	71	142	213
Nasopharyngitis
subjects affected / exposed	108 / 1227 (8.80%)	201 / 2454 (8.19%)	151 / 1197 (12.61%)	253 / 2391 (10.58%)	404 / 3588 (11.26%)
occurrences all number	131	246	209	395	604
Upper respiratory tract infection
subjects affected / exposed	55 / 1227 (4.48%)	104 / 2454 (4.24%)	99 / 1197 (8.27%)	178 / 2391 (7.44%)	277 / 3588 (7.72%)
occurrences all number	65	122	135	253	388

More information

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Were there any global substantial amendments to the protocol? Yes

12 Feb 2013

- added a standard of care group for the first year to better understand incidence of reported adverse events and increase the scientific rigor of the study - reduced the study duration to 2 years - added the Q2W dose regimen for consistency with other phase 3 studies and the opportunity to allow subjects to choose between dosing regimens - aligned assessments with other long-term evolocumab studies for purposes of pooling data - added extra visits for evolocumab-naïve subjects requiring training on use of prefilled AI/pen in order to improve opportunity for successful in-home use administration of evolocumab

30 Apr 2013

- added language to clarify visit schedule for SoC group, ie, had telephone visits at weeks 2, 4 and 8 - added statement ¡§if a procedure is not included as part of EOS visit, it must be conducted on day 1 OLE visit¡¨ to ensure that all subjects start with the same set of assessments - added updated safety template language that was not available at time of current protocol version: "The investigator may report an SAE, irrespective of relatedness, to Amgen after the protocol-reporting timeframe has ended."

23 May 2013

- added 1 blue triangle on day 1 indicating in-clinic administration of IP to Study Design and Treatment Schema

15 Nov 2013

- added vitamin E testing to the protocol, when LDL-C is < 25 mg/dL - added language for the use of the automated mini doser (AMD). - clarified visit schedule to list exact timing of visit, replacing reference to quarterly visits - added “Investigator Responsibilities for Data Collection” - removed collection of non-coronary revascularizations to be consistent with DMC charter

15 Apr 2014

- updated the schedule of assessments schema for clarification and ease of use - added a patient questionnaire for patients experiencing a change in the device used to deliver evolocumab

19 Dec 2014

- extended the treatment duration of the study by an additional 1 year to further characterize the safety and tolerability of evolocumab (AMG 145) over 3 years of exposure consistent with the primary objective for this study. - updated the expected sample size to account for additional studies that are scheduled to complete to permit the timely analysis and disclosure of results. Rather than extend the duration of other studies, allowing patients into this open label extension study to contribute to the evidence for safety and tolerability of up to 3 years of exposure of evolocumab - updated the schedule of assessments and schema for clarification and ease of use - updated exclusion criteria regarding effective methods of birth control to align with current Amgen standards; it is noted that this change is not a consequence of a change in the safety profile of evolocumab. - clarified reporting process for adverse events and serious adverse events - updated process for Pregnancy and Lactation Reporting - removed the external data monitoring committee (DMC) following the DMC’s expressed preference to not review open-label, uncontrolled safety data. Safety monitoring will continue to be performed by AMGEN.

03 Apr 2015

- updated exclusion criteria to include methods of effective birth control in the protocol language

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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