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Clinical Trial Results:
A Phase 3b, Multi-center, Open-label Trial to Evaluate the Long Term Safety of Immediate-release Tolvaptan (OPC-41061, 30 mg to 120 mg/day, Split Dose) in Subjects With Autosomal Dominant Polycystic Kidney Disease

Summary
EudraCT number	2014-001516-19
Trial protocol	GB IT SE NL BE PL ES CZ HU DK
Global end of trial date	09 Nov 2018

Results information
Results version number	v1(current)
This version publication date	27 Nov 2019
First version publication date	27 Nov 2019
Other versions

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

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Trial information

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Sponsor protocol code

156-13-211

ISRCTN number

-

US NCT number

NCT02251275

WHO universal trial number (UTN)

-

Sponsor organisation name

Otsuka Pharmaceutical Development & Commercialization, Inc.

Sponsor organisation address

2440 Research Boulevard, Rockville, MD, United States, 20850,

Public contact

Global Clinical Development, Otsuka Pharmaceutical Development & Commercialization, Inc., +1-609 524-6788, clinicaltransparency@otsuka-us.com

Scientific contact

Global Clinical Development, Otsuka Pharmaceutical Development & Commercialization, Inc., +1-609 524-6788, clinicaltransparency@otsuka-us.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

05 Dec 2018

Is this the analysis of the primary completion data?

Yes

Primary completion date

09 Nov 2018

Global end of trial reached?

Yes

Global end of trial date

09 Nov 2018

Was the trial ended prematurely?

No

Main objective of the trial

The purpose of the trial was to evaluate and describe the long term safety of tolvaptan in participants with autosomal dominant polycystic kidney disease (ADPKD).

Protection of trial subjects

This trial was conducted in accordance with International Council on Harmonisation (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which the trial was conducted.

Background therapy

-

Evidence for comparator

-

Actual start date of recruitment

30 Apr 2015

Long term follow-up planned

No

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Argentina: 45

Country: Number of subjects enrolled

Australia: 59

Country: Number of subjects enrolled

Belgium: 90

Country: Number of subjects enrolled

Canada: 62

Country: Number of subjects enrolled

Czech Republic: 26

Country: Number of subjects enrolled

Denmark: 14

Country: Number of subjects enrolled

Germany: 174

Country: Number of subjects enrolled

Hungary: 13

Country: Number of subjects enrolled

Israel: 30

Country: Number of subjects enrolled

Italy: 91

Country: Number of subjects enrolled

Netherlands: 66

Country: Number of subjects enrolled

Norway: 1

Country: Number of subjects enrolled

Poland: 83

Country: Number of subjects enrolled

Romania: 29

Country: Number of subjects enrolled

Russian Federation: 8

Country: Number of subjects enrolled

South Africa: 20

Country: Number of subjects enrolled

Spain: 55

Country: Number of subjects enrolled

Sweden: 17

Country: Number of subjects enrolled

United Kingdom: 116

Country: Number of subjects enrolled

United States: 804

Worldwide total number of subjects

1803

EEA total number of subjects

775

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)

1773

From 65 to 84 years

30

85 years and over

0

Subject disposition

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Recruitment details

Eligible participants could enroll into Trial 156-13-211 after completing follow-up visit(s) of their previous trial (156-13-210, 156-08-271, 156-04-251, or 156-09-290).

Screening details

One participant screened, but withdrew consent on the same day (prior to study drug treatment) and is not included in the study data. Starting doses depended on the participant’s previous trial.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Tolvaptan (From 156-13-210: Tolvaptan)

Arm description

Participants were previously treated with tolvaptan in Trial 156-13-210. Participants initiated on tolvaptan at a split-dose of 45/15 milligrams (mg) with upward titration every 3 to 4 days to 60/30 mg or 90/30 mg per day according to tolerability.

Arm type

Experimental

Investigational medicinal product name

tolvaptan

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

The dose regimens used in this trial are 15/15 mg, 30/15 mg, 45/15 mg, 60/30 mg, and 90/30 mg. All doses were administered orally.

Tolvaptan (From 156-13-210: Placebo)

Arm description

Participants were previously treated with placebo in Trial 156-13-210. Participants initiated on tolvaptan at a split-dose of 45/15 mg with upward titration every 3 to 4 days to 60/30 mg or 90/30 mg per day according to tolerability.

Arm type

Experimental

Investigational medicinal product name

tolvaptan

Investigational medicinal product code

OPC-41061

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

The dose regimens used in this trial were 15/15 mg, 30/15 mg, 45/15 mg, 60/30 mg, and 90/30 mg. All doses were administered orally.

Tolvaptan (From 156-08-271: Tolvaptan)

Arm description

Participants were previously treated with tolvaptan in Trial 156-08-271. Participants retained the last dose level of tolvaptan received in the trial (45/15 mg, 60/30 mg, or 90/30 mg) and started at that same dose in Trial 156-13-211.

Arm type

Experimental

Investigational medicinal product name

tolvaptan

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

The dose regimens used in this trial are 15/15 mg, 30/15 mg, 45/15 mg, 60/30 mg, and 90/30 mg. All doses were administered orally.

Tolvaptan (From Other: Tolvaptan)

Arm description

Participants were previously treated with tolvaptan in Other Trials (156-04-251 and 156-09-290). Participants initiated on tolvaptan at a split-dose of 45/15 mg with upward titration every 3 to 4 days to 60/30 mg or 90/30 mg per day according to tolerability.

Arm type

Experimental

Investigational medicinal product name

tolvaptan

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

The dose regimens used in this trial are 15/15 mg, 30/15 mg, 45/15 mg, 60/30 mg, and 90/30 mg. All doses were administered orally.

Tolvaptan (From Other: Placebo)

Arm description

Participants were previously treated with placebo in Other Trials (156-04-251 and 156-09-290). Participants initiated on tolvaptan at a split-dose of 45/15 mg with upward titration every 3 to 4 days to 60/30 mg or 90/30 mg per day according to tolerability.

Arm type

Experimental

Investigational medicinal product name

tolvaptan

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

The dose regimens used in this trial are 15/15 mg, 30/15 mg, 45/15 mg, 60/30 mg, and 90/30 mg. All doses were administered orally.

Number of subjects in period 1	Tolvaptan (From 156-13-210: Tolvaptan)	Tolvaptan (From 156-13-210: Placebo)	Tolvaptan (From 156-08-271: Tolvaptan)	Tolvaptan (From Other: Tolvaptan)	Tolvaptan (From Other: Placebo)
Started	506	570	718	6	3
Received at Least 1 Dose of Study Drug	505	569	717	6	3
Completed	434	423	624	5	2
Not completed	72	147	94	1	1
Consent withdrawn by subject	25	51	35	1	-
Physician decision	19	30	26	-	1
Adverse event, non-fatal	23	60	28	-	-
Protocol Deviation	-	-	1	-	-
Lost to follow-up	5	6	4	-	-

Baseline characteristics

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Reporting group title

Tolvaptan (From 156-13-210: Tolvaptan)

Reporting group description

Participants were previously treated with tolvaptan in Trial 156-13-210. Participants initiated on tolvaptan at a split-dose of 45/15 milligrams (mg) with upward titration every 3 to 4 days to 60/30 mg or 90/30 mg per day according to tolerability.

Reporting group title

Tolvaptan (From 156-13-210: Placebo)

Reporting group description

Participants were previously treated with placebo in Trial 156-13-210. Participants initiated on tolvaptan at a split-dose of 45/15 mg with upward titration every 3 to 4 days to 60/30 mg or 90/30 mg per day according to tolerability.

Reporting group title

Tolvaptan (From 156-08-271: Tolvaptan)

Reporting group description

Participants were previously treated with tolvaptan in Trial 156-08-271. Participants retained the last dose level of tolvaptan received in the trial (45/15 mg, 60/30 mg, or 90/30 mg) and started at that same dose in Trial 156-13-211.

Reporting group title

Tolvaptan (From Other: Tolvaptan)

Reporting group description

Participants were previously treated with tolvaptan in Other Trials (156-04-251 and 156-09-290). Participants initiated on tolvaptan at a split-dose of 45/15 mg with upward titration every 3 to 4 days to 60/30 mg or 90/30 mg per day according to tolerability.

Reporting group title

Tolvaptan (From Other: Placebo)

Reporting group description

Participants were previously treated with placebo in Other Trials (156-04-251 and 156-09-290). Participants initiated on tolvaptan at a split-dose of 45/15 mg with upward titration every 3 to 4 days to 60/30 mg or 90/30 mg per day according to tolerability.

Reporting group values	Tolvaptan (From 156-13-210: Tolvaptan)	Tolvaptan (From 156-13-210: Placebo)	Tolvaptan (From 156-08-271: Tolvaptan)	Tolvaptan (From Other: Tolvaptan)	Tolvaptan (From Other: Placebo)	Total
Number of subjects	506	570	718	6	3	1803
Age categorical
Units:
Age continuous
Units: Years
arithmetic mean (standard deviation)	48.9 ( 8.1 )	48.6 ( 8.0 )	45.5 ( 7.8 )	41.2 ( 11.4 )	47.0 ( 2.6 )	-
Gender categorical
Units: Subjects
Female	234	290	343	5	2	874
Male	272	280	375	1	1	929
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	3	0	0	0	0	3
Asian	16	16	10	0	0	42
Native Hawaiian or Other Pacific Islander	1	0	2	0	0	3
Black or African American	19	23	6	0	0	48
White	461	525	694	6	3	1689
More than one race	0	0	0	0	0	0
Unknown or Not Reported	6	6	6	0	0	18
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	27	25	49	1	0	102
Not Hispanic or Latino	479	545	669	5	3	1701
Unknown or Not Reported	0	0	0	0	0	0

End points

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Reporting group title

Tolvaptan (From 156-13-210: Tolvaptan)

Reporting group description

Participants were previously treated with tolvaptan in Trial 156-13-210. Participants initiated on tolvaptan at a split-dose of 45/15 milligrams (mg) with upward titration every 3 to 4 days to 60/30 mg or 90/30 mg per day according to tolerability.

Reporting group title

Tolvaptan (From 156-13-210: Placebo)

Reporting group description

Participants were previously treated with placebo in Trial 156-13-210. Participants initiated on tolvaptan at a split-dose of 45/15 mg with upward titration every 3 to 4 days to 60/30 mg or 90/30 mg per day according to tolerability.

Reporting group title

Tolvaptan (From 156-08-271: Tolvaptan)

Reporting group description

Participants were previously treated with tolvaptan in Trial 156-08-271. Participants retained the last dose level of tolvaptan received in the trial (45/15 mg, 60/30 mg, or 90/30 mg) and started at that same dose in Trial 156-13-211.

Reporting group title

Tolvaptan (From Other: Tolvaptan)

Reporting group description

Participants were previously treated with tolvaptan in Other Trials (156-04-251 and 156-09-290). Participants initiated on tolvaptan at a split-dose of 45/15 mg with upward titration every 3 to 4 days to 60/30 mg or 90/30 mg per day according to tolerability.

Reporting group title

Tolvaptan (From Other: Placebo)

Reporting group description

Participants were previously treated with placebo in Other Trials (156-04-251 and 156-09-290). Participants initiated on tolvaptan at a split-dose of 45/15 mg with upward titration every 3 to 4 days to 60/30 mg or 90/30 mg per day according to tolerability.

Primary: Number Of Participants Reporting Treatment-Emergent Adverse Events (TEAEs)

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End point title

Number Of Participants Reporting Treatment-Emergent Adverse Events (TEAEs) ^[1]

End point description

An adverse event (AE) was as any untoward medical occurrence associated with the use of an investigational medicinal product (IMP), whether or not considered IMP related. A TEAE was an AE that started after trial drug treatment; or if the event was continuous from baseline and was serious, related to IMP, or resulted in death, discontinuation, interruption or reduction of trial therapy. A serious TEAE included any event that resulted in: death, life-threatening, persistent or significant incapacity, substantial disruption of ability to conduct normal life functions, required inpatient hospitalization, prolonged hospitalization, congenital anomaly/birth defect, or other medically significant events as per medical judgment, that jeopardized the participant and that required medical or surgical intervention. A severe TEAE was an inability to work or perform normal daily activity. A summary of serious and all other non-serious TEAEs, regardless of causality, is located in the AE section.

End point type

Primary

End point timeframe

Baseline through end of treatment (up to 42 months) and follow-up 7 days posttreatment (+ 7 days)

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 inferential statistical analyses were planned.

End point values	Tolvaptan (From 156-13-210: Tolvaptan)	Tolvaptan (From 156-13-210: Placebo)	Tolvaptan (From 156-08-271: Tolvaptan)	Tolvaptan (From Other: Tolvaptan)	Tolvaptan (From Other: Placebo)
Number of subjects analysed	505	569	717	6	3
Units: participants
number (not applicable)
Participants with TEAEs	473	531	640	6	3
Participants with serious TEAEs	87	96	103	1	2
Participants with severe TEAEs	74	78	83	2	1
Discontinued due to TEAEs	33	65	38	0	1
Deaths	1	5	3	0	0

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Baseline through end of treatment (up to 42 months) and follow-up 7 days posttreatment (+ 7 days)

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

21.0

Reporting group title

Tolvaptan (From 156-13-210: Tolvaptan)

Reporting group description

Participants were previously treated with tolvaptan in Trial 156-13-210. Participants initiated on tolvaptan at a split-dose of 45/15 milligrams (mg) with upward titration every 3 to 4 days to 60/30 mg or 90/30 mg per day according to tolerability.

Reporting group title

Tolvaptan (From 156-13-210: Placebo)

Reporting group description

Participants were previously treated with placebo in Trial 156-13-210. Participants initiated on tolvaptan at a split-dose of 45/15 mg with upward titration every 3 to 4 days to 60/30 mg or 90/30 mg per day according to tolerability.

Reporting group title

Tolvaptan (From 156-08-271: Tolvaptan)

Reporting group description

Participants were previously treated with tolvaptan in Trial 156-08-271. Participants retained the last dose level of tolvaptan received in the trial (45/15 mg, 60/30 mg, or 90/30 mg) and started at that same dose in Trial 156-13-211.

Reporting group title

Tolvaptan (From Other: Tolvaptan)

Reporting group description

Participants were previously treated with tolvaptan in Other Trials (156-04-251 and 156-09-290). Participants initiated on tolvaptan at a split-dose of 45/15 mg with upward titration every 3 to 4 days to 60/30 mg or 90/30 mg per day according to tolerability.

Reporting group title

Tolvaptan (From Other: Placebo)

Reporting group description

Participants were previously treated with placebo in Other Trials (156-04-251 and 156-09-290). Participants initiated on tolvaptan at a split-dose of 45/15 mg with upward titration every 3 to 4 days to 60/30 mg or 90/30 mg per day according to tolerability.

Serious adverse events	Tolvaptan (From 156-13-210: Tolvaptan)	Tolvaptan (From 156-13-210: Placebo)	Tolvaptan (From 156-08-271: Tolvaptan)	Tolvaptan (From Other: Tolvaptan)	Tolvaptan (From Other: Placebo)
Total subjects affected by serious adverse events
subjects affected / exposed	87 / 505 (17.23%)	96 / 569 (16.87%)	103 / 717 (14.37%)	1 / 6 (16.67%)	2 / 3 (66.67%)
number of deaths (all causes)	1	5	3	0	0
number of deaths resulting from adverse events	1	5	3	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastatic Squamous Cell Carcinoma
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Squamous Cell Carcinoma of Head and Neck
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Squamous Cell Carcinoma
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal Neoplasm
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Rectal Cancer
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Prostate Cancer
subjects affected / exposed ^[1]	1 / 272 (0.37%)	1 / 280 (0.36%)	0 / 375 (0.00%)	0 / 1 (0.00%)	0 / 1 (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
Papillary Thyroid Cancer
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ovarian Theca Cell Tumour
subjects affected / exposed ^[2]	0 / 234 (0.00%)	1 / 290 (0.34%)	0 / 343 (0.00%)	0 / 5 (0.00%)	0 / 2 (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
Metastases to Meninges
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Carcinoid Tumour
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Metastases to Adrenals
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Metastases to Liver
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Basal Cell Carcinoma
subjects affected / exposed	2 / 505 (0.40%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bone Cancer Metastatic
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
B-Cell Small Lymphocytic Lymphoma
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colon Cancer
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	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 / 505 (0.20%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Malignant Melanoma
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchial Carcinoma
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Breast Cancer
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Vascular disorders
Thrombophlebitis Superficial
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Shock
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Peripheral Ischaemia
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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 / 505 (0.00%)	2 / 569 (0.35%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Hypertensive Crisis
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Deep Vein Thrombosis
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhage
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arteritis
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aortic Dissection
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Aneurysm
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Hypertension
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	3 / 717 (0.42%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 3	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 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thirst
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Oedema Peripheral
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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 Pain
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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	1 / 505 (0.20%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Death
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Non-Cardiac Chest Pain
subjects affected / exposed	1 / 505 (0.20%)	2 / 569 (0.35%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Asthenia
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Immune system disorders
Drug Hypersensitivity
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Reproductive system and breast disorders
Rectocele
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Prostatitis
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Menorrhagia
subjects affected / exposed ^[3]	1 / 234 (0.43%)	0 / 290 (0.00%)	0 / 343 (0.00%)	0 / 5 (0.00%)	0 / 2 (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
Breast Enlargement
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Metrorrhagia
subjects affected / exposed ^[4]	0 / 234 (0.00%)	1 / 290 (0.34%)	0 / 343 (0.00%)	0 / 5 (0.00%)	0 / 2 (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
Respiratory, thoracic and mediastinal disorders
Sinus Polyp
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory Failure
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleuritic Pain
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Pulmonary Toxicity
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary Embolism
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	2 / 717 (0.28%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleural Effusion
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Epistaxis
subjects affected / exposed	1 / 505 (0.20%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Haemothorax
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute Respiratory Distress Syndrome
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Acute Respiratory Failure
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Acute Pulmonary Oedema
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Chronic Obstructive Pulmonary Disease
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Cough
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Bronchospasm
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Depression
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Panic Attack
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Suicidal Ideation
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Investigations
Weight Decreased
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Tumour Marker Increased
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Liver Function Test Increased
subjects affected / exposed	0 / 505 (0.00%)	3 / 569 (0.53%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 3	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
International Normalised Ratio Fluctuation
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic Enzyme Increased
subjects affected / exposed	2 / 505 (0.40%)	3 / 569 (0.53%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	1 / 2	2 / 3	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Glomerular Filtration Rate Decreased
subjects affected / exposed	2 / 505 (0.40%)	3 / 569 (0.53%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 3	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Transaminases Increased
subjects affected / exposed	2 / 505 (0.40%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	1 / 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
C-Reactive Protein Increased
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Gamma-Glutamyltransferase Increased
subjects affected / exposed	2 / 505 (0.40%)	2 / 569 (0.35%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	2 / 2	1 / 2	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Alanine Aminotransferase Increased
subjects affected / exposed	3 / 505 (0.59%)	5 / 569 (0.88%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	3 / 3	4 / 5	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aspartate Aminotransferase Increased
subjects affected / exposed	2 / 505 (0.40%)	1 / 569 (0.18%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	2 / 2	1 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Alanine Aminotransferase Abnormal
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Blood Creatinine Increased
subjects affected / exposed	1 / 505 (0.20%)	5 / 569 (0.88%)	3 / 717 (0.42%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 1	2 / 5	1 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood Glucose Increased
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood Alkaline Phosphatase Increased
subjects affected / exposed	1 / 505 (0.20%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	1 / 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
Blood Urine Present
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Injury, poisoning and procedural complications
Radius Fracture
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	2 / 717 (0.28%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	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	2 / 505 (0.40%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tendon Rupture
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Subdural Haematoma
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Subarachnoid Haemorrhage
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Spinal Fracture
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Perirenal Haematoma
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Traumatic Haemothorax
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	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	1 / 505 (0.20%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Humerus Fracture
subjects affected / exposed	2 / 505 (0.40%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fibula Fracture
subjects affected / exposed	2 / 505 (0.40%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Brain Contusion
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arteriovenous Fistula Site Haematoma
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ankle Fracture
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	1 / 3 (33.33%)
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
Anastomotic Complication
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	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 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Accidental Overdose
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	2 / 717 (0.28%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Congenital, familial and genetic disorders
Polycystic Liver Disease
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urachal Abnormality
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Ventricular Tachycardia
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Pericarditis
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Pericardial Effusion
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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	1 / 505 (0.20%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mitral Valve Prolapse
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Left Ventricular Dysfunction
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Coronary Artery Stenosis
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Coronary Artery Disease
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Cardiogenic Shock
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Cardiac Failure
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac Arrest
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Atrial Fibrillation
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	3 / 717 (0.42%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aortic Valve Incompetence
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Angina Unstable
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Angina Pectoris
subjects affected / exposed	1 / 505 (0.20%)	2 / 569 (0.35%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute Myocardial Infarction
subjects affected / exposed	1 / 505 (0.20%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Acute Left Ventricular Failure
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Acute Coronary Syndrome
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Paraesthesia
subjects affected / exposed	1 / 505 (0.20%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Tremor
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	1 / 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
Transient Ischaemic Attack
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	1 / 505 (0.20%)	2 / 569 (0.35%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Sciatica
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Ruptured Cerebral Aneurysm
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Presyncope
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	1 / 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
Vith Nerve Paralysis
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Headache
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	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	1 / 505 (0.20%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Basilar Artery Aneurysm
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Cerebellar Ischaemia
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemic Stroke
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Cerebrovascular Accident
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Encephalopathy
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Cerebral Ischaemia
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Epilepsy
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	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	2 / 505 (0.40%)	1 / 569 (0.18%)	2 / 717 (0.28%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhagic Anaemia
subjects affected / exposed	1 / 505 (0.20%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Leukocytosis
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Pancytopenia
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Ear and labyrinth disorders
Deafness
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Retinal Detachment
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	2 / 717 (0.28%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Borderline Glaucoma
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	1 / 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
Diplopia
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Endocrine Ophthalmopathy
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Gastrointestinal Disorder
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Upper Gastrointestinal Haemorrhage
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Umbilical Hernia
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	3 / 717 (0.42%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Small Intestinal Obstruction
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Pancreatitis Acute
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	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 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lower Gastrointestinal Haemorrhage
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal Obstruction
subjects affected / exposed	2 / 505 (0.40%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Inguinal Hernia, Obstructive
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Inguinal Hernia
subjects affected / exposed	1 / 505 (0.20%)	1 / 569 (0.18%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Incarcerated Umbilical Hernia
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Ileus
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	3 / 717 (0.42%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 3	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	1 / 505 (0.20%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Gastrooesophageal Reflux Disease
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Gastric Ulcer Haemorrhage
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Duodenal Perforation
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Diverticulum
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	1 / 505 (0.20%)	3 / 569 (0.53%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 3	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	1 / 505 (0.20%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Haematemesis
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Ascites
subjects affected / exposed	1 / 505 (0.20%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal Pain Upper
subjects affected / exposed	1 / 505 (0.20%)	1 / 569 (0.18%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal Pain Lower
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal Pain
subjects affected / exposed	3 / 505 (0.59%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal Hernia
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Hepatobiliary disorders
Bile Duct Stone
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Cholecystitis
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Hepatic Cyst
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Hepatic Pain
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemic Hepatitis
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Skin and subcutaneous tissue disorders
Angioedema
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rash Vesicular
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin Laxity
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Skin Lesion
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Renal Pain
subjects affected / exposed	2 / 505 (0.40%)	5 / 569 (0.88%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 7	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal Impairment
subjects affected / exposed	6 / 505 (1.19%)	2 / 569 (0.35%)	3 / 717 (0.42%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	3 / 6	0 / 2	1 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal Haemorrhage
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Renal Failure
subjects affected / exposed	2 / 505 (0.40%)	1 / 569 (0.18%)	2 / 717 (0.28%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal Cyst Haemorrhage
subjects affected / exposed	3 / 505 (0.59%)	4 / 569 (0.70%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 6	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal Cyst
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal Colic
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal Cyst Ruptured
subjects affected / exposed	1 / 505 (0.20%)	1 / 569 (0.18%)	2 / 717 (0.28%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pollakiuria
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Nephropathy
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute Kidney Injury
subjects affected / exposed	5 / 505 (0.99%)	8 / 569 (1.41%)	7 / 717 (0.98%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	1 / 5	3 / 9	3 / 7	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	1 / 505 (0.20%)	1 / 569 (0.18%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Kidney Enlargement
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haematuria
subjects affected / exposed	1 / 505 (0.20%)	2 / 569 (0.35%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
End Stage Renal Disease
subjects affected / exposed	3 / 505 (0.59%)	0 / 569 (0.00%)	8 / 717 (1.12%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 8	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chronic Kidney Disease
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Polyuria
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Musculoskeletal and connective tissue disorders
Spinal Osteoarthritis
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Arthritis
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Foot Deformity
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Arthralgia
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Pain In Extremity
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Infections and infestations
Pulmonary Tuberculosis
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	3 / 505 (0.59%)	1 / 569 (0.18%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 1	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 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Renal Abscess
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Renal Cyst Infection
subjects affected / exposed	5 / 505 (0.99%)	8 / 569 (1.41%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	1 / 7	0 / 10	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Salmonellosis
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Sepsis
subjects affected / exposed	0 / 505 (0.00%)	2 / 569 (0.35%)	2 / 717 (0.28%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2	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	3 / 505 (0.59%)	2 / 569 (0.35%)	5 / 717 (0.70%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 2	0 / 5	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sinusitis
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Staphylococcal Infection
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Superinfection
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tonsillitis
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Urosepsis
subjects affected / exposed	1 / 505 (0.20%)	1 / 569 (0.18%)	2 / 717 (0.28%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Viral Infection
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia Staphylococcal
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Septic Shock
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Pneumonia
subjects affected / exposed	4 / 505 (0.79%)	5 / 569 (0.88%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 5	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal Wall Abscess
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ophthalmic Herpes Zoster
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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 Perforated
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cat Scratch Disease
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Clostridium Difficile Infection
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Peritonitis Bacterial
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Diarrhoea Infectious
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Diverticulitis
subjects affected / exposed	2 / 505 (0.40%)	1 / 569 (0.18%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cytomegalovirus
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Escherichia Bacteraemia
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Escherichia Urinary Tract Infection
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Gastroenteritis
subjects affected / exposed	2 / 505 (0.40%)	3 / 569 (0.53%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic Cyst Infection
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Herpes Zoster
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Herpes Zoster Oticus
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Infected Cyst
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infection
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Endocarditis
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	2 / 505 (0.40%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diabetes Mellitus
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Hyperkalaemia
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypernatraemia
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Hypoglycaemia
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Hypokalaemia
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Hyponatraemia
subjects affected / exposed	1 / 505 (0.20%)	2 / 569 (0.35%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 2	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypophosphataemia
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Metabolic Acidosis
subjects affected / exposed	0 / 505 (0.00%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
Obesity
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	1 / 717 (0.14%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Notes
[1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The adverse event occurs in only male participants.
[2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The adverse event occurs in only female participants.
[3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The adverse event occurs in only female participants.
[4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: The adverse event occurs in only female participants.

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

Non-serious adverse events	Tolvaptan (From 156-13-210: Tolvaptan)	Tolvaptan (From 156-13-210: Placebo)	Tolvaptan (From 156-08-271: Tolvaptan)	Tolvaptan (From Other: Tolvaptan)	Tolvaptan (From Other: Placebo)
Total subjects affected by non serious adverse events
subjects affected / exposed	469 / 505 (92.87%)	525 / 569 (92.27%)	633 / 717 (88.28%)	6 / 6 (100.00%)	3 / 3 (100.00%)
Vascular disorders
Hypertension
subjects affected / exposed	87 / 505 (17.23%)	77 / 569 (13.53%)	139 / 717 (19.39%)	4 / 6 (66.67%)	1 / 3 (33.33%)
occurrences all number	116	97	163	4	1
Lymphoedema
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	1
Orthostatic Hypotension
subjects affected / exposed	1 / 505 (0.20%)	2 / 569 (0.35%)	3 / 717 (0.42%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	1	2	3	1	0
General disorders and administration site conditions
Chest Discomfort
subjects affected / exposed	1 / 505 (0.20%)	1 / 569 (0.18%)	1 / 717 (0.14%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	1	1	1	1	0
Fatigue
subjects affected / exposed	47 / 505 (9.31%)	74 / 569 (13.01%)	34 / 717 (4.74%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	55	85	37	0	0
Non-Cardiac Chest Pain
subjects affected / exposed	5 / 505 (0.99%)	5 / 569 (0.88%)	4 / 717 (0.56%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	5	5	4	1	0
Oedema Peripheral
subjects affected / exposed	32 / 505 (6.34%)	39 / 569 (6.85%)	42 / 717 (5.86%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	37	46	49	0	0
Pain
subjects affected / exposed	6 / 505 (1.19%)	1 / 569 (0.18%)	3 / 717 (0.42%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	9	1	3	1	0
Thirst
subjects affected / exposed	139 / 505 (27.52%)	183 / 569 (32.16%)	91 / 717 (12.69%)	4 / 6 (66.67%)	0 / 3 (0.00%)
occurrences all number	176	213	99	4	0
Immune system disorders
Type I Hypersensitivity
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	1
Reproductive system and breast disorders
Vaginal Haemorrhage
subjects affected / exposed ^[5]	0 / 234 (0.00%)	1 / 290 (0.34%)	3 / 343 (0.87%)	0 / 5 (0.00%)	1 / 2 (50.00%)
occurrences all number	0	1	3	0	1
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	27 / 505 (5.35%)	27 / 569 (4.75%)	28 / 717 (3.91%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	30	31	31	0	0
Wheezing
subjects affected / exposed	2 / 505 (0.40%)	0 / 569 (0.00%)	1 / 717 (0.14%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	2	0	1	1	0
Psychiatric disorders
Anxiety
subjects affected / exposed	9 / 505 (1.78%)	9 / 569 (1.58%)	13 / 717 (1.81%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	9	9	15	1	0
Stress
subjects affected / exposed	2 / 505 (0.40%)	4 / 569 (0.70%)	1 / 717 (0.14%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	2	4	1	1	0
Investigations
Alanine Aminotransferase Increased
subjects affected / exposed	7 / 505 (1.39%)	19 / 569 (3.34%)	17 / 717 (2.37%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	9	26	21	1	0
Blood Calcium Increased
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	0	0	1	1	0
Blood Creatinine Increased
subjects affected / exposed	77 / 505 (15.25%)	87 / 569 (15.29%)	69 / 717 (9.62%)	0 / 6 (0.00%)	1 / 3 (33.33%)
occurrences all number	104	129	87	0	1
Kidney Palpable
subjects affected / exposed	1 / 505 (0.20%)	0 / 569 (0.00%)	0 / 717 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	1	0	0	1	0
Weight Decreased
subjects affected / exposed	4 / 505 (0.79%)	5 / 569 (0.88%)	2 / 717 (0.28%)	0 / 6 (0.00%)	1 / 3 (33.33%)
occurrences all number	4	6	3	0	1
Weight Increased
subjects affected / exposed	1 / 505 (0.20%)	3 / 569 (0.53%)	4 / 717 (0.56%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	1	3	5	1	0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	8 / 505 (1.58%)	9 / 569 (1.58%)	11 / 717 (1.53%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	10	10	11	1	0
Cardiac disorders
Left Ventricular Hypertrophy
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	0 / 717 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0
Palpitations
subjects affected / exposed	5 / 505 (0.99%)	6 / 569 (1.05%)	14 / 717 (1.95%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	5	6	15	1	0
Nervous system disorders
Dizziness
subjects affected / exposed	18 / 505 (3.56%)	31 / 569 (5.45%)	31 / 717 (4.32%)	0 / 6 (0.00%)	1 / 3 (33.33%)
occurrences all number	20	37	37	0	1
Headache
subjects affected / exposed	51 / 505 (10.10%)	72 / 569 (12.65%)	51 / 717 (7.11%)	2 / 6 (33.33%)	0 / 3 (0.00%)
occurrences all number	61	83	68	2	0
Tremor
subjects affected / exposed	1 / 505 (0.20%)	1 / 569 (0.18%)	2 / 717 (0.28%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	1	1	2	1	0
Ear and labyrinth disorders
Hypoacusis
subjects affected / exposed	3 / 505 (0.59%)	0 / 569 (0.00%)	1 / 717 (0.14%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	3	0	1	1	0
Motion Sickness
subjects affected / exposed	1 / 505 (0.20%)	1 / 569 (0.18%)	0 / 717 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)
occurrences all number	1	1	0	0	1
Gastrointestinal disorders
Abdominal Discomfort
subjects affected / exposed	9 / 505 (1.78%)	14 / 569 (2.46%)	4 / 717 (0.56%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	10	16	5	1	0
Abdominal Hernia
subjects affected / exposed	7 / 505 (1.39%)	1 / 569 (0.18%)	6 / 717 (0.84%)	0 / 6 (0.00%)	1 / 3 (33.33%)
occurrences all number	7	1	6	0	1
Abdominal Pain Lower
subjects affected / exposed	6 / 505 (1.19%)	6 / 569 (1.05%)	6 / 717 (0.84%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	6	7	6	1	0
Abdominal Pain Upper
subjects affected / exposed	20 / 505 (3.96%)	19 / 569 (3.34%)	12 / 717 (1.67%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	24	24	12	1	0
Constipation
subjects affected / exposed	16 / 505 (3.17%)	28 / 569 (4.92%)	10 / 717 (1.39%)	0 / 6 (0.00%)	1 / 3 (33.33%)
occurrences all number	17	34	11	0	1
Diarrhoea
subjects affected / exposed	37 / 505 (7.33%)	38 / 569 (6.68%)	33 / 717 (4.60%)	0 / 6 (0.00%)	1 / 3 (33.33%)
occurrences all number	41	43	39	0	1
Dry Mouth
subjects affected / exposed	22 / 505 (4.36%)	38 / 569 (6.68%)	3 / 717 (0.42%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	24	41	4	0	0
Dyspepsia
subjects affected / exposed	17 / 505 (3.37%)	27 / 569 (4.75%)	10 / 717 (1.39%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	19	28	10	1	0
Gastrooesophageal Reflux Disease
subjects affected / exposed	11 / 505 (2.18%)	19 / 569 (3.34%)	17 / 717 (2.37%)	0 / 6 (0.00%)	1 / 3 (33.33%)
occurrences all number	11	22	17	0	1
Gingival Pain
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	1 / 717 (0.14%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	0	0	1	1	0
Nausea
subjects affected / exposed	37 / 505 (7.33%)	51 / 569 (8.96%)	38 / 717 (5.30%)	0 / 6 (0.00%)	1 / 3 (33.33%)
occurrences all number	40	59	40	0	1
Vomiting
subjects affected / exposed	24 / 505 (4.75%)	38 / 569 (6.68%)	32 / 717 (4.46%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	27	41	36	0	0
Skin and subcutaneous tissue disorders
Dermatitis Contact
subjects affected / exposed	7 / 505 (1.39%)	4 / 569 (0.70%)	3 / 717 (0.42%)	0 / 6 (0.00%)	1 / 3 (33.33%)
occurrences all number	9	5	3	0	1
Renal and urinary disorders
Chronic Kidney Disease
subjects affected / exposed	4 / 505 (0.79%)	6 / 569 (1.05%)	7 / 717 (0.98%)	0 / 6 (0.00%)	1 / 3 (33.33%)
occurrences all number	4	6	7	0	1
Haematuria
subjects affected / exposed	27 / 505 (5.35%)	52 / 569 (9.14%)	48 / 717 (6.69%)	0 / 6 (0.00%)	2 / 3 (66.67%)
occurrences all number	34	63	53	0	2
Nocturia
subjects affected / exposed	77 / 505 (15.25%)	124 / 569 (21.79%)	58 / 717 (8.09%)	3 / 6 (50.00%)	1 / 3 (33.33%)
occurrences all number	105	150	63	4	2
Pollakiuria
subjects affected / exposed	27 / 505 (5.35%)	34 / 569 (5.98%)	12 / 717 (1.67%)	2 / 6 (33.33%)	0 / 3 (0.00%)
occurrences all number	36	38	18	2	0
Polyuria
subjects affected / exposed	117 / 505 (23.17%)	180 / 569 (31.63%)	53 / 717 (7.39%)	2 / 6 (33.33%)	0 / 3 (0.00%)
occurrences all number	141	203	56	2	0
Renal Cyst Ruptured
subjects affected / exposed	4 / 505 (0.79%)	9 / 569 (1.58%)	7 / 717 (0.98%)	0 / 6 (0.00%)	1 / 3 (33.33%)
occurrences all number	4	12	8	0	1
Renal Impairment
subjects affected / exposed	12 / 505 (2.38%)	29 / 569 (5.10%)	14 / 717 (1.95%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	12	31	16	0	0
Renal Pain
subjects affected / exposed	98 / 505 (19.41%)	110 / 569 (19.33%)	141 / 717 (19.67%)	3 / 6 (50.00%)	2 / 3 (66.67%)
occurrences all number	139	179	209	4	3
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	33 / 505 (6.53%)	25 / 569 (4.39%)	26 / 717 (3.63%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	42	26	36	0	0
Back Pain
subjects affected / exposed	53 / 505 (10.50%)	57 / 569 (10.02%)	51 / 717 (7.11%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	59	71	55	1	0
Infections and infestations
Bronchitis
subjects affected / exposed	23 / 505 (4.55%)	29 / 569 (5.10%)	31 / 717 (4.32%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	25	34	35	1	0
Ear Infection
subjects affected / exposed	8 / 505 (1.58%)	9 / 569 (1.58%)	5 / 717 (0.70%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	9	9	8	1	0
Gastroenteritis
subjects affected / exposed	14 / 505 (2.77%)	22 / 569 (3.87%)	41 / 717 (5.72%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	15	24	44	1	0
Gingivitis
subjects affected / exposed	2 / 505 (0.40%)	3 / 569 (0.53%)	2 / 717 (0.28%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	2	3	2	2	0
Influenza
subjects affected / exposed	34 / 505 (6.73%)	43 / 569 (7.56%)	39 / 717 (5.44%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	38	49	52	0	0
Nasopharyngitis
subjects affected / exposed	92 / 505 (18.22%)	100 / 569 (17.57%)	94 / 717 (13.11%)	0 / 6 (0.00%)	1 / 3 (33.33%)
occurrences all number	129	143	123	0	1
Sinusitis
subjects affected / exposed	22 / 505 (4.36%)	31 / 569 (5.45%)	35 / 717 (4.88%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	30	37	47	1	0
Upper Respiratory Tract Infection
subjects affected / exposed	58 / 505 (11.49%)	53 / 569 (9.31%)	86 / 717 (11.99%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	64	83	129	1	0
Urinary Tract Infection
subjects affected / exposed	52 / 505 (10.30%)	58 / 569 (10.19%)	65 / 717 (9.07%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	86	79	117	1	0
Vulvovaginal Mycotic Infection
subjects affected / exposed ^[6]	3 / 234 (1.28%)	1 / 290 (0.34%)	6 / 343 (1.75%)	0 / 5 (0.00%)	1 / 2 (50.00%)
occurrences all number	3	1	7	0	1
Zika Virus Infection
subjects affected / exposed	0 / 505 (0.00%)	0 / 569 (0.00%)	0 / 717 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	1
Metabolism and nutrition disorders
Decreased Appetite
subjects affected / exposed	8 / 505 (1.58%)	18 / 569 (3.16%)	4 / 717 (0.56%)	0 / 6 (0.00%)	1 / 3 (33.33%)
occurrences all number	9	19	4	0	1
Gout
subjects affected / exposed	28 / 505 (5.54%)	25 / 569 (4.39%)	30 / 717 (4.18%)	0 / 6 (0.00%)	1 / 3 (33.33%)
occurrences all number	49	46	42	0	1
Hyperlipidaemia
subjects affected / exposed	4 / 505 (0.79%)	5 / 569 (0.88%)	7 / 717 (0.98%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	5	5	7	1	0
Polydipsia
subjects affected / exposed	27 / 505 (5.35%)	53 / 569 (9.31%)	14 / 717 (1.95%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	29	54	14	0	0

Notes
[5] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The adverse event occurs in only female participants.
[6] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The adverse event occurs in only female participants.

More information

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Were there any global substantial amendments to the protocol? Yes

14 Jul 2014

Protocol procedures were revised to accommodate the treatment and monitoring of participants enrolling into the protocol from additional tolvaptan trials. The sample size was increased, the inclusion criteria were slightly modified, schedules for initiation of treatment and liver function testing were further defined, and pharmacokinetic sampling was included to assess compliance.

06 Mar 2015

The window was increased from 30 days to up to 3 months to allow use of historical laboratory values for screening, to add flexibility and allow combining of screening and baseline visits in the trial, and to provide clarification on trial discontinuation.

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

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