Clinical Trial Results:
A randomized, open-label, multicenter Phase III study to evaluate the efficacy and safety of nilotinib versus imatinib in adult patients with unresectable or metastatic gastrointestinal stromal tumors (GIST) Due to EudraCT system limitations, which EMA is aware of, results of crossover studies are not accurately represented in this record. Please go to https://www.novctrd.com/CtrdWeb/home.nov for complete trial results.

Trial information Top of page
Trial identification
Sponsor protocol code	CAMN107G2301
Additional study identifiers
ISRCTN number	-
US NCT number	NCT00785785
WHO universal trial number (UTN)	-
Sponsors
Sponsor organisation name	Novartis Pharma AG
Sponsor organisation address	CH-4002, Basel, Switzerland,
Public contact	Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
Scientific contact	Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
Paediatric regulatory details
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
Results analysis stage
Analysis stage	Final
Date of interim/final analysis	23 Oct 2014
Is this the analysis of the primary completion data?	No
Global end of trial reached?	Yes
Global end of trial date	23 Oct 2014
Was the trial ended prematurely?	No
General information about the trial
Main objective of the trial	The primary objective of the study was to compare the progression free survival (PFS) of nilotinib and imatinib when used as initial therapy in adult patients with unresectable or metastatic gastrointestinal stromal tumors (GIST). This was summarized in the Core clinical study report (CSR) and is not repeated for the final analysis.
Protection of trial subjects	The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
Background therapy	-
Evidence for comparator	-
Actual start date of recruitment	16 Mar 2009
Long term follow-up planned	No
Independent data monitoring committee (IDMC) involvement?	Yes
Population of trial subjects
Number of subjects enrolled per country
Country: Number of subjects enrolled	Argentina: 8
Country: Number of subjects enrolled	Austria: 14
Country: Number of subjects enrolled	Brazil: 17
Country: Number of subjects enrolled	Bulgaria: 2
Country: Number of subjects enrolled	Canada: 22
Country: Number of subjects enrolled	China: 93
Country: Number of subjects enrolled	Czech Republic: 2
Country: Number of subjects enrolled	Denmark: 5
Country: Number of subjects enrolled	Egypt: 13
Country: Number of subjects enrolled	France: 32
Country: Number of subjects enrolled	Germany: 16
Country: Number of subjects enrolled	United Kingdom: 23
Country: Number of subjects enrolled	Hong Kong: 8
Country: Number of subjects enrolled	Hungary: 20
Country: Number of subjects enrolled	Israel: 5
Country: Number of subjects enrolled	Italy: 27
Country: Number of subjects enrolled	Japan: 51
Country: Number of subjects enrolled	Korea, Republic of: 22
Country: Number of subjects enrolled	Mexico: 4
Country: Number of subjects enrolled	Netherlands: 8
Country: Number of subjects enrolled	Norway: 5
Country: Number of subjects enrolled	Poland: 18
Country: Number of subjects enrolled	Romania: 13
Country: Number of subjects enrolled	Russian Federation: 33
Country: Number of subjects enrolled	Singapore: 12
Country: Number of subjects enrolled	Slovakia: 5
Country: Number of subjects enrolled	South Africa: 6
Country: Number of subjects enrolled	Spain: 10
Country: Number of subjects enrolled	Sweden: 20
Country: Number of subjects enrolled	Taiwan: 18
Country: Number of subjects enrolled	Thailand: 30
Country: Number of subjects enrolled	Turkey: 11
Country: Number of subjects enrolled	United States: 70
Country: Number of subjects enrolled	Venezuela, Bolivarian Republic of: 1
Worldwide total number of subjects	644
EEA total number of subjects	220
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)	453
From 65 to 84 years	189
85 years and over	2

Trial information Top of page

Subject disposition Top of page
Recruitment
Recruitment details	-
Pre-assignment
Screening details	Patients were on either: imatinib 400mg once daily or nilotinib 400 mg twice a day in the core phase and then crossed over to nilotinib 400 mg twice a day or imatinib 400mg once daily in the extension phase.
Period 1
Period 1 title	Core Phase up to 36 months (overall period)
Is this the baseline period?	Yes
Allocation method	Randomised - controlled
Blinding used	Double blind
Roles blinded	Investigator, Monitor, Carer, Data analyst, Subject, Assessor
Arms
Are arms mutually exclusive	Yes
Arm title	Imatinib first, then Nilotinib
Arm description	patients were on imatinib 400mg once daily in the core phase and then crossed over to nilotinib 400 mg twice a day in the extension phase
Arm type	Experimental
Investigational medicinal product name	Imatinib
Investigational medicinal product code	STI571
Other name
Pharmaceutical forms	Tablet
Routes of administration	Oral use
Dosage and administration details	Imatinib 400mg tablet orally once a day
Arm title	Nilotinib first, then Imatinib
Arm description	patients were on nilotinib 400 mg twice a day in the core phase and then crossed over to in the extension phase imatinib 400mg once daily
Arm type	Experimental
Investigational medicinal product name	Nilotinib
Investigational medicinal product code	AMN107
Other name
Pharmaceutical forms	Capsule, hard
Routes of administration	Oral use
Dosage and administration details	Nilotinib 400 mg capsule orally twice daily
Number of subjects in period 1 Imatinib first, then Nilotinib Nilotinib first, then Imatinib Started 324 320 Completed 0 0 Not completed 324 320      Patients didn't receive 1st line therapy 3 4      Adverse event, serious fatal 5 8      Consent withdrawn by subject 16 17      Disease progression 139 119      Adverse event, non-fatal 31 21      Protocol deviation 5 6      Administrative problems 3 3      Abnormal laboratory value 1 -      Study terminated by sponsor 116 133      Lost to follow-up 3 7      Abnormal test procedure result 2 2

Subject disposition Top of page

Baseline characteristics Top of page
Baseline characteristics reporting groups
Reporting group title	Imatinib first, then Nilotinib
Reporting group description	patients were on imatinib 400mg once daily in the core phase and then crossed over to nilotinib 400 mg twice a day in the extension phase
Reporting group title	Nilotinib first, then Imatinib
Reporting group description	patients were on nilotinib 400 mg twice a day in the core phase and then crossed over to in the extension phase imatinib 400mg once daily
Reporting group values Imatinib first, then Nilotinib Nilotinib first, then Imatinib Total Number of subjects 324 320 644 Age categorical Units: Subjects     In utero 0 0 0     Preterm newborn infants (gestational age < 37 wks) 0 0 0     Newborns (0-27 days) 0 0 0     Infants and toddlers (28 days-23 months) 0 0 0     Children (2-11 years) 0 0 0     Adolescents (12-17 years) 0 0 0     Adults (18-64 years) 225 228 453     From 65-84 years 99 90 189     85 years and over 0 2 2 Age Continuous Units: years     arithmetic mean (standard deviation) 57.4 ( 12.91 ) 57.3 ( 12.63 ) - Gender, Male/Female Units: participants     Male 179 187 366     Female 145 133 278
Subject analysis sets
Subject analysis set title	Nilotinib
Subject analysis set type	Full analysis
Subject analysis set description	nilotinib 400 mg twice aday
Subject analysis set title	Imatinib
Subject analysis set type	Full analysis
Subject analysis set description	imatinib 400 mg once daily
Subject analysis sets values Nilotinib Imatinib Number of subjects 324 320 Age categorical Units: Subjects     In utero 0 0     Preterm newborn infants (gestational age < 37 wks) 0 0     Newborns (0-27 days) 0 0     Infants and toddlers (28 days-23 months) 0 0     Children (2-11 years) 0 0     Adolescents (12-17 years) 0 0     Adults (18-64 years) 225 228     From 65-84 years 99 90     85 years and over 0 2 Age Continuous Units: years     arithmetic mean (standard deviation) 57.4 ( 12.91 ) 57.3 ( 12.63 ) Gender, Male/Female Units: participants     Male 179 187     Female 145 133

Baseline characteristics Top of page

End points Top of page
End points reporting groups
Reporting group title	Imatinib first, then Nilotinib
Reporting group description	patients were on imatinib 400mg once daily in the core phase and then crossed over to nilotinib 400 mg twice a day in the extension phase
Reporting group title	Nilotinib first, then Imatinib
Reporting group description	patients were on nilotinib 400 mg twice a day in the core phase and then crossed over to in the extension phase imatinib 400mg once daily
Subject analysis set title	Nilotinib
Subject analysis set type	Full analysis
Subject analysis set description	nilotinib 400 mg twice aday
Subject analysis set title	Imatinib
Subject analysis set type	Full analysis
Subject analysis set description	imatinib 400 mg once daily

End points Top of page

Primary: Time to Progression Free Survival (PFS) Top of page
End point title	Time to Progression Free Survival (PFS)
End point description	PFS was defined as the time from the date of start of treatment to the date of the first documented progression or death due to any cause. Progression is defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions
End point type	Primary
End point timeframe	up to month 37
End point values Nilotinib Imatinib Number of subjects analysed 324 320 Units: months     median (full range (min-max)) 25.9 (0 to 32.8) 29.7 (0 to 36.1)
Statistical analysis title	Time to Progression Free Survival (PFS)
Comparison groups	Imatinib v Nilotinib
Number of subjects included in analysis	644
Analysis specification	Pre-specified
Analysis type
P-value	= 0.0081
Method	Hazard Ratio
Parameter type	Hazard ratio (HR)
Point estimate	1.466
Confidence interval
level	95%
sides	2-sided
lower limit	1.104
upper limit	1.945

Primary: Time to Progression Free Survival (PFS) Top of page

Adverse events Top of page
Adverse events information
Timeframe for reporting adverse events	Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All adverse events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit
Adverse event reporting additional description	Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
Assessment type	Systematic
Dictionary used for adverse event reporting
Dictionary name	MedDRA
Dictionary version	17.1
Reporting groups
Reporting group title	First-line Nilotinib
Reporting group description	First-line Nilotinib
Reporting group title	First-line Imatinib
Reporting group description	First-line Imatinib
Reporting group title	Crossover Nilotinib
Reporting group description	Crossover Nilotinib
Reporting group title	Crossover Imatinib
Reporting group description	Crossover Imatinib
Serious adverse events First-line Nilotinib First-line Imatinib Crossover Nilotinib Crossover Imatinib Total subjects affected by serious adverse events      subjects affected / exposed 80 / 321 (24.92%) 85 / 316 (26.90%) 15 / 39 (38.46%) 26 / 125 (20.80%)      number of deaths (all causes) 13 11 1 7      number of deaths resulting from adverse events 0 1 0 0 Neoplasms benign, malignant and unspecified (incl cysts and polyps) Adenoma benign      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Bladder cancer      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Colon cancer      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Gastric cancer      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Gastrointestinal stromal tumour      subjects affected / exposed 2 / 321 (0.62%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 2 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Hodgkin's disease      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Hepatic neoplasm      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Infected neoplasm      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 1 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Lip and/or oral cavity cancer      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 1 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Lung neoplasm malignant      subjects affected / exposed 1 / 321 (0.31%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 1 1 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Metastases to liver      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 1 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Metastases to peritoneum      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 1 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Neoplasm      subjects affected / exposed 0 / 321 (0.00%) 0 / 316 (0.00%) 0 / 39 (0.00%) 1 / 125 (0.80%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Pancreatic carcinoma metastatic      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Small intestine carcinoma      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Thyroid cancer      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Tumour haemorrhage      subjects affected / exposed 3 / 321 (0.93%) 2 / 316 (0.63%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 2 / 4 0 / 3 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Tumour necrosis      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 1 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Tumour perforation      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Tumour pain      subjects affected / exposed 0 / 321 (0.00%) 0 / 316 (0.00%) 0 / 39 (0.00%) 1 / 125 (0.80%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Urinary tract neoplasm      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Vascular disorders Deep vein thrombosis      subjects affected / exposed 1 / 321 (0.31%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Femoral artery occlusion      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Hypotension      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 1 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Peripheral arterial occlusive disease      subjects affected / exposed 2 / 321 (0.62%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 3 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Thrombosis      subjects affected / exposed 0 / 321 (0.00%) 0 / 316 (0.00%) 1 / 39 (2.56%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Vena cava thrombosis      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 1 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Venous thrombosis limb      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Surgical and medical procedures Gastrectomy      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Cytoreductive surgery      subjects affected / exposed 0 / 321 (0.00%) 0 / 316 (0.00%) 1 / 39 (2.56%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Tumour excision      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 General disorders and administration site conditions Asthenia      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Death      subjects affected / exposed 0 / 321 (0.00%) 0 / 316 (0.00%) 0 / 39 (0.00%) 1 / 125 (0.80%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1 Disease progression      subjects affected / exposed 0 / 321 (0.00%) 0 / 316 (0.00%) 1 / 39 (2.56%) 1 / 125 (0.80%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Face oedema      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 1 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Fatigue      subjects affected / exposed 0 / 321 (0.00%) 2 / 316 (0.63%) 0 / 39 (0.00%) 1 / 125 (0.80%)      occurrences causally related to treatment / all 0 / 0 0 / 2 0 / 0 1 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 General physical health deterioration      subjects affected / exposed 0 / 321 (0.00%) 0 / 316 (0.00%) 0 / 39 (0.00%) 1 / 125 (0.80%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Generalised oedema      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 1 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Multi-organ failure      subjects affected / exposed 1 / 321 (0.31%) 1 / 316 (0.32%) 0 / 39 (0.00%) 1 / 125 (0.80%)      occurrences causally related to treatment / all 0 / 1 0 / 1 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Oedema mucosal      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 1 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Oedema peripheral      subjects affected / exposed 1 / 321 (0.31%) 3 / 316 (0.95%) 1 / 39 (2.56%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 1 / 1 3 / 3 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Pain      subjects affected / exposed 0 / 321 (0.00%) 0 / 316 (0.00%) 2 / 39 (5.13%) 1 / 125 (0.80%)      occurrences causally related to treatment / all 0 / 0 0 / 0 1 / 2 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Performance status decreased      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 1 / 125 (0.80%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Pyrexia      subjects affected / exposed 2 / 321 (0.62%) 6 / 316 (1.90%) 0 / 39 (0.00%) 3 / 125 (2.40%)      occurrences causally related to treatment / all 1 / 2 1 / 6 0 / 0 0 / 3      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Immune system disorders Hypersensitivity      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Reproductive system and breast disorders Scrotal oedema      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 1 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Respiratory, thoracic and mediastinal disorders Atelectasis      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 1 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Chronic obstructive pulmonary disease      subjects affected / exposed 2 / 321 (0.62%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 2 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Cough      subjects affected / exposed 1 / 321 (0.31%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Dyspnoea      subjects affected / exposed 2 / 321 (0.62%) 1 / 316 (0.32%) 1 / 39 (2.56%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 1 / 2 1 / 1 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Interstitial lung disease      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 1 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Laryngeal oedema      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Pleural effusion      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 1 / 125 (0.80%)      occurrences causally related to treatment / all 1 / 1 0 / 0 0 / 0 2 / 2      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Pneumothorax      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Pulmonary embolism      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Pulmonary fibrosis      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Pulmonary infarction      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 1 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Pulmonary oedema      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 1 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Respiratory failure      subjects affected / exposed 2 / 321 (0.62%) 0 / 316 (0.00%) 0 / 39 (0.00%) 1 / 125 (0.80%)      occurrences causally related to treatment / all 0 / 2 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Upper respiratory tract congestion      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Respiratory tract haemorrhage      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Psychiatric disorders Mental status changes      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Confusional state      subjects affected / exposed 0 / 321 (0.00%) 2 / 316 (0.63%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 2 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Investigations Alanine aminotransferase increased      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 1 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Aspartate aminotransferase increased      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 1 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Bilirubin conjugated increased      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Blood bilirubin increased      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Blood creatinine increased      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Blood potassium decreased      subjects affected / exposed 0 / 321 (0.00%) 0 / 316 (0.00%) 0 / 39 (0.00%) 1 / 125 (0.80%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Lipase increased      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 1 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Haemoglobin decreased      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 1 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Weight decreased      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Injury, poisoning and procedural complications Accidental overdose      subjects affected / exposed 0 / 321 (0.00%) 0 / 316 (0.00%) 0 / 39 (0.00%) 1 / 125 (0.80%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 1 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Fall      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Femur fracture      subjects affected / exposed 0 / 321 (0.00%) 0 / 316 (0.00%) 0 / 39 (0.00%) 1 / 125 (0.80%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Fracture      subjects affected / exposed 0 / 321 (0.00%) 2 / 316 (0.63%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 2 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Multiple fractures      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Overdose      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Post procedural bile leak      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Procedural pain      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Thermal burn      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Transfusion reaction      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0 Congenital, familial and genetic disorders Dermoid cyst      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Cardiac disorders Angina unstable      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 2 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Acute myocardial infarction      subjects affected / exposed 2 / 321 (0.62%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 1 / 3 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Angina pectoris      subjects affected / exposed 2 / 321 (0.62%) 0 / 316 (0.00%) 0 / 39 (0.00%) 1 / 125 (0.80%)      occurrences causally related to treatment / all 1 / 2 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Cardiac arrest      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0 Arrhythmia      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 1 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Atrial fibrillation      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Cardiac failure      subjects affected / exposed 0 / 321 (0.00%) 0 / 316 (0.00%) 0 / 39 (0.00%) 1 / 125 (0.80%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Cardiac failure congestive      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Cardio-respiratory arrest      subjects affected / exposed 0 / 321 (0.00%) 2 / 316 (0.63%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 2 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0 Myocardial infarction      subjects affected / exposed 1 / 321 (0.31%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 1 1 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Mitral valve stenosis      subjects affected / exposed 0 / 321 (0.00%) 0 / 316 (0.00%) 0 / 39 (0.00%) 1 / 125 (0.80%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Supraventricular tachycardia      subjects affected / exposed 0 / 321 (0.00%) 2 / 316 (0.63%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 2 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Pericardial effusion      subjects affected / exposed 2 / 321 (0.62%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 1 / 2 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Palpitations      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Nervous system disorders Altered state of consciousness      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 1 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Cerebral haemorrhage      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Cerebral infarction      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 1 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Cerebral ischaemia      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Cerebrovascular accident      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Cognitive disorder      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 1 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Complex partial seizures      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Convulsion      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Dizziness      subjects affected / exposed 0 / 321 (0.00%) 0 / 316 (0.00%) 2 / 39 (5.13%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 1 / 2 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Epilepsy      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Haemorrhage intracranial      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0 Haemorrhagic stroke      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Hemiparesis      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Headache      subjects affected / exposed 1 / 321 (0.31%) 2 / 316 (0.63%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 1 / 1 0 / 2 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Ischaemic stroke      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 IIIrd nerve paralysis      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 2 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Loss of consciousness      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Migraine      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Peripheral motor neuropathy      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Myelitis transverse      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Peripheral sensory neuropathy      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Radiculopathy      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Sciatica      subjects affected / exposed 2 / 321 (0.62%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 1 / 2 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Status epilepticus      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Syncope      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Blood and lymphatic system disorders Anaemia      subjects affected / exposed 6 / 321 (1.87%) 3 / 316 (0.95%) 2 / 39 (5.13%) 3 / 125 (2.40%)      occurrences causally related to treatment / all 1 / 7 1 / 4 0 / 2 1 / 3      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Febrile neutropenia      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 1 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Neutropenia      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 1 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Thrombocytopenia      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Gastrointestinal disorders Abdominal distension      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 1 / 125 (0.80%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Abdominal mass      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Abdominal hernia      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Anal fissure      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 3 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Abdominal pain      subjects affected / exposed 15 / 321 (4.67%) 12 / 316 (3.80%) 4 / 39 (10.26%) 3 / 125 (2.40%)      occurrences causally related to treatment / all 1 / 15 5 / 14 2 / 5 1 / 3      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Abdominal pain upper      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Ascites      subjects affected / exposed 2 / 321 (0.62%) 1 / 316 (0.32%) 0 / 39 (0.00%) 2 / 125 (1.60%)      occurrences causally related to treatment / all 1 / 2 1 / 1 0 / 0 0 / 2      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Anal fistula      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Diarrhoea      subjects affected / exposed 1 / 321 (0.31%) 4 / 316 (1.27%) 0 / 39 (0.00%) 2 / 125 (1.60%)      occurrences causally related to treatment / all 0 / 1 1 / 4 0 / 0 2 / 3      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Colonic fistula      subjects affected / exposed 0 / 321 (0.00%) 0 / 316 (0.00%) 1 / 39 (2.56%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Constipation      subjects affected / exposed 3 / 321 (0.93%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 2 / 3 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Gastric ulcer      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Faecaloma      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 1 / 125 (0.80%)      occurrences causally related to treatment / all 0 / 0 1 / 1 0 / 0 1 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Gastritis haemorrhagic      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 1 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Gastritis      subjects affected / exposed 2 / 321 (0.62%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 2 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Gastric ulcer haemorrhage      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Gastrooesophageal reflux disease      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Gastrointestinal obstruction      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Gastrointestinal haemorrhage      subjects affected / exposed 5 / 321 (1.56%) 5 / 316 (1.58%) 1 / 39 (2.56%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 1 / 5 5 / 7 0 / 2 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Haematemesis      subjects affected / exposed 1 / 321 (0.31%) 2 / 316 (0.63%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 2 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Haematochezia      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 1 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Ileus      subjects affected / exposed 2 / 321 (0.62%) 2 / 316 (0.63%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 3 0 / 3 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Haemorrhoids      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Intestinal obstruction      subjects affected / exposed 4 / 321 (1.25%) 2 / 316 (0.63%) 1 / 39 (2.56%) 3 / 125 (2.40%)      occurrences causally related to treatment / all 1 / 5 0 / 2 0 / 1 1 / 5      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Intestinal perforation      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 1 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Intra-abdominal haemorrhage      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Jejunal perforation      subjects affected / exposed 0 / 321 (0.00%) 2 / 316 (0.63%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 1 / 2 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0 Large intestinal stenosis      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Mechanical ileus      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 1 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Nausea      subjects affected / exposed 2 / 321 (0.62%) 2 / 316 (0.63%) 0 / 39 (0.00%) 1 / 125 (0.80%)      occurrences causally related to treatment / all 1 / 2 2 / 2 0 / 0 1 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Peptic ulcer      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Small intestinal haemorrhage      subjects affected / exposed 0 / 321 (0.00%) 0 / 316 (0.00%) 1 / 39 (2.56%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 1 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Upper gastrointestinal haemorrhage      subjects affected / exposed 1 / 321 (0.31%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Subileus      subjects affected / exposed 2 / 321 (0.62%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 2 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Vomiting      subjects affected / exposed 5 / 321 (1.56%) 3 / 316 (0.95%) 1 / 39 (2.56%) 4 / 125 (3.20%)      occurrences causally related to treatment / all 2 / 5 2 / 3 2 / 3 1 / 4      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Hepatobiliary disorders Bile duct obstruction      subjects affected / exposed 1 / 321 (0.31%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Hepatic failure      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 1 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Cholangitis      subjects affected / exposed 2 / 321 (0.62%) 2 / 316 (0.63%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 4 0 / 2 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Hepatic pain      subjects affected / exposed 0 / 321 (0.00%) 0 / 316 (0.00%) 1 / 39 (2.56%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Hyperbilirubinaemia      subjects affected / exposed 0 / 321 (0.00%) 0 / 316 (0.00%) 0 / 39 (0.00%) 1 / 125 (0.80%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 1 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Hepatic function abnormal      subjects affected / exposed 1 / 321 (0.31%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 1 1 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Jaundice      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 1 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Jaundice cholestatic      subjects affected / exposed 1 / 321 (0.31%) 2 / 316 (0.63%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 2 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Portal hypertension      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Skin and subcutaneous tissue disorders Dermatitis      subjects affected / exposed 0 / 321 (0.00%) 0 / 316 (0.00%) 0 / 39 (0.00%) 1 / 125 (0.80%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 2 / 2      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Exfoliative rash      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 1 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Erythema multiforme      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 2 / 2 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Pityriasis rosea      subjects affected / exposed 0 / 321 (0.00%) 0 / 316 (0.00%) 0 / 39 (0.00%) 1 / 125 (0.80%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 1 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Rash      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 1 / 39 (2.56%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 1 / 1 1 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Rash generalised      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 1 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Renal and urinary disorders Anuria      subjects affected / exposed 0 / 321 (0.00%) 0 / 316 (0.00%) 0 / 39 (0.00%) 1 / 125 (0.80%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1 Haematuria      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Renal failure      subjects affected / exposed 0 / 321 (0.00%) 0 / 316 (0.00%) 1 / 39 (2.56%) 1 / 125 (0.80%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1 Pollakiuria      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Renal failure acute      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Renal impairment      subjects affected / exposed 0 / 321 (0.00%) 0 / 316 (0.00%) 0 / 39 (0.00%) 1 / 125 (0.80%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Urinary tract obstruction      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Musculoskeletal and connective tissue disorders Back pain      subjects affected / exposed 3 / 321 (0.93%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 1 / 3 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Fibromyalgia      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 2 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Joint swelling      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Osteoporosis      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Osteoarthritis      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Pain in extremity      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Tenosynovitis      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Infections and infestations Abdominal infection      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 1 / 125 (0.80%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Abdominal wall abscess      subjects affected / exposed 0 / 321 (0.00%) 0 / 316 (0.00%) 0 / 39 (0.00%) 1 / 125 (0.80%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 1 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Appendicitis      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Bacterial sepsis      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 1 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Bronchitis      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 1 / 39 (2.56%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 1 / 2 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Cellulitis      subjects affected / exposed 1 / 321 (0.31%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Ear infection      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Eye infection      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Gastroenteritis      subjects affected / exposed 2 / 321 (0.62%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 2 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Helicobacter gastritis      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Infection      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Infectious pleural effusion      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Lung infection      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Periodontitis      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Peritonitis      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Pneumonia      subjects affected / exposed 3 / 321 (0.93%) 4 / 316 (1.27%) 1 / 39 (2.56%) 1 / 125 (0.80%)      occurrences causally related to treatment / all 1 / 3 1 / 4 0 / 1 1 / 1      deaths causally related to treatment / all 0 / 0 1 / 1 0 / 0 0 / 0 Post procedural infection      subjects affected / exposed 0 / 321 (0.00%) 2 / 316 (0.63%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 2 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Postoperative wound infection      subjects affected / exposed 0 / 321 (0.00%) 0 / 316 (0.00%) 1 / 39 (2.56%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Respiratory tract infection      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Sepsis      subjects affected / exposed 2 / 321 (0.62%) 2 / 316 (0.63%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 2 0 / 2 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0 Septic shock      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0 Upper respiratory tract infection      subjects affected / exposed 1 / 321 (0.31%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Urinary tract infection      subjects affected / exposed 4 / 321 (1.25%) 2 / 316 (0.63%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 4 0 / 3 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Viral infection      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Metabolism and nutrition disorders Decreased appetite      subjects affected / exposed 4 / 321 (1.25%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 3 / 4 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Dehydration      subjects affected / exposed 0 / 321 (0.00%) 0 / 316 (0.00%) 0 / 39 (0.00%) 3 / 125 (2.40%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 3      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Diabetes mellitus      subjects affected / exposed 2 / 321 (0.62%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 1 / 2 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Fluid overload      subjects affected / exposed 1 / 321 (0.31%) 0 / 316 (0.00%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Hypokalaemia      subjects affected / exposed 1 / 321 (0.31%) 3 / 316 (0.95%) 1 / 39 (2.56%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 1 1 / 4 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Hypoglycaemia      subjects affected / exposed 3 / 321 (0.93%) 0 / 316 (0.00%) 0 / 39 (0.00%) 1 / 125 (0.80%)      occurrences causally related to treatment / all 0 / 3 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Hypomagnesaemia      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 2 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Hyponatraemia      subjects affected / exposed 0 / 321 (0.00%) 2 / 316 (0.63%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 2 / 2 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Hypophosphataemia      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 2 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Hypovolaemia      subjects affected / exposed 0 / 321 (0.00%) 1 / 316 (0.32%) 0 / 39 (0.00%) 0 / 125 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0
Frequency threshold for reporting non-serious adverse events: 5%
Non-serious adverse events First-line Nilotinib First-line Imatinib Crossover Nilotinib Crossover Imatinib Total subjects affected by non serious adverse events      subjects affected / exposed 291 / 321 (90.65%) 289 / 316 (91.46%) 28 / 39 (71.79%) 89 / 125 (71.20%) General disorders and administration site conditions Asthenia      subjects affected / exposed 27 / 321 (8.41%) 29 / 316 (9.18%) 0 / 39 (0.00%) 6 / 125 (4.80%)      occurrences all number 35 41 0 10 Face oedema      subjects affected / exposed 5 / 321 (1.56%) 43 / 316 (13.61%) 0 / 39 (0.00%) 13 / 125 (10.40%)      occurrences all number 9 60 0 13 Fatigue      subjects affected / exposed 66 / 321 (20.56%) 65 / 316 (20.57%) 7 / 39 (17.95%) 12 / 125 (9.60%)      occurrences all number 104 99 8 14 Oedema peripheral      subjects affected / exposed 29 / 321 (9.03%) 68 / 316 (21.52%) 2 / 39 (5.13%) 17 / 125 (13.60%)      occurrences all number 38 94 2 20 Pyrexia      subjects affected / exposed 23 / 321 (7.17%) 30 / 316 (9.49%) 3 / 39 (7.69%) 4 / 125 (3.20%)      occurrences all number 32 40 4 8 Respiratory, thoracic and mediastinal disorders Cough      subjects affected / exposed 28 / 321 (8.72%) 21 / 316 (6.65%) 1 / 39 (2.56%) 3 / 125 (2.40%)      occurrences all number 37 31 3 3 Dyspnoea      subjects affected / exposed 17 / 321 (5.30%) 21 / 316 (6.65%) 2 / 39 (5.13%) 5 / 125 (4.00%)      occurrences all number 22 24 2 5 Psychiatric disorders Insomnia      subjects affected / exposed 21 / 321 (6.54%) 20 / 316 (6.33%) 1 / 39 (2.56%) 2 / 125 (1.60%)      occurrences all number 27 23 2 2 Investigations Alanine aminotransferase increased      subjects affected / exposed 45 / 321 (14.02%) 18 / 316 (5.70%) 5 / 39 (12.82%) 3 / 125 (2.40%)      occurrences all number 63 22 7 3 Aspartate aminotransferase increased      subjects affected / exposed 23 / 321 (7.17%) 15 / 316 (4.75%) 2 / 39 (5.13%) 2 / 125 (1.60%)      occurrences all number 30 17 2 5 Amylase increased      subjects affected / exposed 8 / 321 (2.49%) 13 / 316 (4.11%) 2 / 39 (5.13%) 2 / 125 (1.60%)      occurrences all number 14 20 4 2 Blood alkaline phosphatase increased      subjects affected / exposed 7 / 321 (2.18%) 3 / 316 (0.95%) 3 / 39 (7.69%) 2 / 125 (1.60%)      occurrences all number 8 3 3 2 Blood bilirubin increased      subjects affected / exposed 32 / 321 (9.97%) 4 / 316 (1.27%) 2 / 39 (5.13%) 1 / 125 (0.80%)      occurrences all number 48 4 3 1 Gamma-glutamyltransferase increased      subjects affected / exposed 9 / 321 (2.80%) 2 / 316 (0.63%) 4 / 39 (10.26%) 1 / 125 (0.80%)      occurrences all number 16 3 6 1 Haemoglobin decreased      subjects affected / exposed 10 / 321 (3.12%) 20 / 316 (6.33%) 3 / 39 (7.69%) 5 / 125 (4.00%)      occurrences all number 17 25 3 8 Lipase increased      subjects affected / exposed 27 / 321 (8.41%) 23 / 316 (7.28%) 1 / 39 (2.56%) 6 / 125 (4.80%)      occurrences all number 35 34 1 7 Neutrophil count decreased      subjects affected / exposed 2 / 321 (0.62%) 24 / 316 (7.59%) 1 / 39 (2.56%) 7 / 125 (5.60%)      occurrences all number 2 40 1 9 Weight decreased      subjects affected / exposed 27 / 321 (8.41%) 20 / 316 (6.33%) 3 / 39 (7.69%) 3 / 125 (2.40%)      occurrences all number 38 25 3 3 White blood cell count decreased      subjects affected / exposed 3 / 321 (0.93%) 21 / 316 (6.65%) 0 / 39 (0.00%) 11 / 125 (8.80%)      occurrences all number 3 36 0 16 Nervous system disorders Dizziness      subjects affected / exposed 22 / 321 (6.85%) 19 / 316 (6.01%) 2 / 39 (5.13%) 4 / 125 (3.20%)      occurrences all number 31 28 2 4 Dysgeusia      subjects affected / exposed 10 / 321 (3.12%) 9 / 316 (2.85%) 2 / 39 (5.13%) 3 / 125 (2.40%)      occurrences all number 13 12 2 4 Headache      subjects affected / exposed 54 / 321 (16.82%) 24 / 316 (7.59%) 5 / 39 (12.82%) 2 / 125 (1.60%)      occurrences all number 76 35 6 2 Blood and lymphatic system disorders Anaemia      subjects affected / exposed 38 / 321 (11.84%) 61 / 316 (19.30%) 7 / 39 (17.95%) 20 / 125 (16.00%)      occurrences all number 60 92 9 22 Neutropenia      subjects affected / exposed 4 / 321 (1.25%) 42 / 316 (13.29%) 1 / 39 (2.56%) 11 / 125 (8.80%)      occurrences all number 7 72 1 12 Thrombocytopenia      subjects affected / exposed 2 / 321 (0.62%) 5 / 316 (1.58%) 2 / 39 (5.13%) 1 / 125 (0.80%)      occurrences all number 2 11 2 1 Leukopenia      subjects affected / exposed 4 / 321 (1.25%) 35 / 316 (11.08%) 1 / 39 (2.56%) 10 / 125 (8.00%)      occurrences all number 6 70 1 11 Eye disorders Eyelid oedema      subjects affected / exposed 5 / 321 (1.56%) 55 / 316 (17.41%) 0 / 39 (0.00%) 19 / 125 (15.20%)      occurrences all number 8 87 0 23 Lacrimation increased      subjects affected / exposed 3 / 321 (0.93%) 21 / 316 (6.65%) 0 / 39 (0.00%) 3 / 125 (2.40%)      occurrences all number 5 31 0 4 Periorbital oedema      subjects affected / exposed 2 / 321 (0.62%) 58 / 316 (18.35%) 0 / 39 (0.00%) 9 / 125 (7.20%)      occurrences all number 2 89 0 10 Gastrointestinal disorders Abdominal distension      subjects affected / exposed 17 / 321 (5.30%) 12 / 316 (3.80%) 1 / 39 (2.56%) 1 / 125 (0.80%)      occurrences all number 18 14 1 1 Abdominal pain      subjects affected / exposed 63 / 321 (19.63%) 61 / 316 (19.30%) 6 / 39 (15.38%) 18 / 125 (14.40%)      occurrences all number 94 86 11 19 Constipation      subjects affected / exposed 49 / 321 (15.26%) 24 / 316 (7.59%) 3 / 39 (7.69%) 3 / 125 (2.40%)      occurrences all number 68 31 4 3 Abdominal pain upper      subjects affected / exposed 38 / 321 (11.84%) 15 / 316 (4.75%) 1 / 39 (2.56%) 5 / 125 (4.00%)      occurrences all number 47 16 1 10 Diarrhoea      subjects affected / exposed 46 / 321 (14.33%) 106 / 316 (33.54%) 2 / 39 (5.13%) 17 / 125 (13.60%)      occurrences all number 65 170 3 27 Nausea      subjects affected / exposed 73 / 321 (22.74%) 105 / 316 (33.23%) 12 / 39 (30.77%) 20 / 125 (16.00%)      occurrences all number 102 163 14 25 Stomatitis      subjects affected / exposed 10 / 321 (3.12%) 14 / 316 (4.43%) 2 / 39 (5.13%) 1 / 125 (0.80%)      occurrences all number 11 19 2 1 Vomiting      subjects affected / exposed 51 / 321 (15.89%) 65 / 316 (20.57%) 5 / 39 (12.82%) 10 / 125 (8.00%)      occurrences all number 69 105 6 24 Hepatobiliary disorders Hyperbilirubinaemia      subjects affected / exposed 63 / 321 (19.63%) 11 / 316 (3.48%) 3 / 39 (7.69%) 3 / 125 (2.40%)      occurrences all number 128 16 5 3 Skin and subcutaneous tissue disorders Alopecia      subjects affected / exposed 33 / 321 (10.28%) 13 / 316 (4.11%) 1 / 39 (2.56%) 3 / 125 (2.40%)      occurrences all number 40 20 1 3 Pruritus      subjects affected / exposed 39 / 321 (12.15%) 25 / 316 (7.91%) 4 / 39 (10.26%) 2 / 125 (1.60%)      occurrences all number 62 42 5 2 Dry skin      subjects affected / exposed 19 / 321 (5.92%) 21 / 316 (6.65%) 0 / 39 (0.00%) 3 / 125 (2.40%)      occurrences all number 29 25 0 3 Rash      subjects affected / exposed 89 / 321 (27.73%) 46 / 316 (14.56%) 4 / 39 (10.26%) 12 / 125 (9.60%)      occurrences all number 139 85 4 16 Musculoskeletal and connective tissue disorders Arthralgia      subjects affected / exposed 20 / 321 (6.23%) 15 / 316 (4.75%) 2 / 39 (5.13%) 3 / 125 (2.40%)      occurrences all number 28 22 2 3 Back pain      subjects affected / exposed 32 / 321 (9.97%) 18 / 316 (5.70%) 3 / 39 (7.69%) 3 / 125 (2.40%)      occurrences all number 46 23 5 3 Pain in extremity      subjects affected / exposed 22 / 321 (6.85%) 16 / 316 (5.06%) 2 / 39 (5.13%) 3 / 125 (2.40%)      occurrences all number 26 22 4 3 Myalgia      subjects affected / exposed 39 / 321 (12.15%) 17 / 316 (5.38%) 2 / 39 (5.13%) 2 / 125 (1.60%)      occurrences all number 49 22 3 2 Muscle spasms      subjects affected / exposed 18 / 321 (5.61%) 47 / 316 (14.87%) 1 / 39 (2.56%) 2 / 125 (1.60%)      occurrences all number 25 81 1 2 Infections and infestations Nasopharyngitis      subjects affected / exposed 25 / 321 (7.79%) 19 / 316 (6.01%) 1 / 39 (2.56%) 1 / 125 (0.80%)      occurrences all number 42 24 1 3 Upper respiratory tract infection      subjects affected / exposed 8 / 321 (2.49%) 17 / 316 (5.38%) 0 / 39 (0.00%) 1 / 125 (0.80%)      occurrences all number 15 21 0 1 Metabolism and nutrition disorders Hyperglycaemia      subjects affected / exposed 15 / 321 (4.67%) 7 / 316 (2.22%) 2 / 39 (5.13%) 2 / 125 (1.60%)      occurrences all number 23 12 2 2 Decreased appetite      subjects affected / exposed 40 / 321 (12.46%) 50 / 316 (15.82%) 5 / 39 (12.82%) 5 / 125 (4.00%)      occurrences all number 53 68 5 5 Hyperuricaemia      subjects affected / exposed 2 / 321 (0.62%) 5 / 316 (1.58%) 2 / 39 (5.13%) 1 / 125 (0.80%)      occurrences all number 3 8 2 1 Hypophosphataemia      subjects affected / exposed 20 / 321 (6.23%) 53 / 316 (16.77%) 3 / 39 (7.69%) 10 / 125 (8.00%)      occurrences all number 36 85 5 12 Hypokalaemia      subjects affected / exposed 9 / 321 (2.80%) 19 / 316 (6.01%) 0 / 39 (0.00%) 8 / 125 (6.40%)      occurrences all number 9 31 0 9