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    Clinical Trial Results:
    An Open-Label Bosutinib Treatment Extension Study for Subjects With Chronic Myeloid Leukemia (CML) Who Have Previously Participated in Bosutinib Studies B1871006 or B1871008

    Summary
    EudraCT number
    		 2013-000691-15
    Trial protocol
    		 IT   HU   LT   LV   NL   FI   ES   GB   FR   BE   PL  
    Global end of trial date
    05 Jun 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Jun 2021
    First version publication date
    20 Jun 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    B1871040
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01903733
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pfizer Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    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
    05 Jun 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Jun 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Jun 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To allow long-term bosutinib treatment in subjects with chronic phase (CP) or advanced (ADV) phase Philadelphia chromosome-positive (Ph+) CML who received bosutinib in a previous Pfizer sponsored CML study (ie, studies B1871006 and B1871008) and who have the potential, as judged by the investigator, to derive clinical benefit from continued treatment with bosutinib.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council for Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Aug 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 10 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 24
    Country: Number of subjects enrolled
    Australia: 9
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    Brazil: 35
    Country: Number of subjects enrolled
    Canada: 21
    Country: Number of subjects enrolled
    Chile: 2
    Country: Number of subjects enrolled
    China: 51
    Country: Number of subjects enrolled
    Colombia: 8
    Country: Number of subjects enrolled
    Germany: 49
    Country: Number of subjects enrolled
    Spain: 19
    Country: Number of subjects enrolled
    Finland: 7
    Country: Number of subjects enrolled
    France: 10
    Country: Number of subjects enrolled
    United Kingdom: 12
    Country: Number of subjects enrolled
    Hong Kong: 10
    Country: Number of subjects enrolled
    Hungary: 14
    Country: Number of subjects enrolled
    India: 47
    Country: Number of subjects enrolled
    Italy: 61
    Country: Number of subjects enrolled
    Japan: 15
    Country: Number of subjects enrolled
    Korea, Republic of: 45
    Country: Number of subjects enrolled
    Lithuania: 7
    Country: Number of subjects enrolled
    Latvia: 2
    Country: Number of subjects enrolled
    Mexico: 5
    Country: Number of subjects enrolled
    Netherlands: 17
    Country: Number of subjects enrolled
    Norway: 3
    Country: Number of subjects enrolled
    Peru: 6
    Country: Number of subjects enrolled
    Poland: 13
    Country: Number of subjects enrolled
    Russian Federation: 94
    Country: Number of subjects enrolled
    Singapore: 15
    Country: Number of subjects enrolled
    Sweden: 1
    Country: Number of subjects enrolled
    Thailand: 4
    Country: Number of subjects enrolled
    Turkey: 6
    Country: Number of subjects enrolled
    Taiwan: 3
    Country: Number of subjects enrolled
    Ukraine: 25
    Country: Number of subjects enrolled
    United States: 165
    Country: Number of subjects enrolled
    South Africa: 9
    Worldwide total number of subjects
    820
    EEA total number of subjects
    209
    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)
    662
    From 65 to 84 years
    155
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study included subjects randomised to bosutinib arm in B1871008 or dosed with bosutinib in B1871006. Subjects enrolled were who in any parent study at time of protocol approval 1) receiving bosutinib, benefiting per investigator, 2) discontinued bosutinib, being followed-up, 3) completed parent study. 281 subjects were enrolled, 21 were from China.

    Pre-assignment
    Screening details
    		 Data from the 2 parent studies were combined with data from this study for all analyses. The B1871040 data from 21 subjects enrolled in China were not used in results as approval was not obtained to use the data per HGRAC regulations. Reporting arms were based on parent study, disease phase and line of therapy (CP1L, CP2L, CP3L/CP4L, ADV).

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Bosutinib, CP1L
    Arm description
    		 Subjects from B1871008 with Ph+ chronic phase 1st line (CP1L) CML who either continued to receive the same bosutinib dose as at the time of completion of B1871008 or continued to be followed for survival. Dose for bosutinib was 500 milligram (mg) orally once daily (adjusted dose varied from 200 mg to 600 mg once daily). Treatment continued until the end of the study, disease progression, unacceptable toxicity, death, withdrawal of consent or study discontinuation whichever occurred first. Follow-up continued till end of the study or death due to any cause whichever occurred first. Subjects remained in this study, either for treatment or for follow-up, until the last subject enrolled in 1 of the parent studies reached 10 years of follow-up, as calculated from the date of his/her first dose of bosutinib administered in parent study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bosutinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received bosutinib at a dose of 500 mg, orally once daily (adjusted dose varied from 200 mg to 600 mg once daily).

    Arm title
    		 Bosutinib, CP2L
    Arm description
    		 Subjects from B1871006 with Ph+ chronic phase 2nd line (CP2L) CML who were resistant or intolerant to imatinib either continued to receive the same bosutinib dose as at the time of completion of B1871006 or continued to be followed for survival. Dose for bosutinib was 500 mg orally once daily (adjusted dose varied from 200 mg to 600 mg once daily). Treatment continued until the end of the study, disease progression, unacceptable toxicity, death, withdrawal of consent or study discontinuation whichever occurred first. Follow-up continued till end of the study or death due to any cause whichever occurred first. Subjects remained in this study, either for treatment or for follow-up, until the last subject enrolled in 1 of the parent studies reached 10 years of follow-up, as calculated from the date of his/her first dose of bosutinib administered in parent study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bosutinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received bosutinib at a dose of 500 mg, orally once daily (adjusted dose varied from 200 mg to 600 mg once daily).

    Arm title
    		 Bosutinib, CP3L/CP4L
    Arm description
    		 Subjects from B1871006 with Ph+ chronic phase 3rd line (CP3L)/4th line (CP4L) CML who were resistant or intolerant to imatinib and resistant or intolerant to dasatinib and/or nilotinib either continued to receive the same bosutinib dose as at the time of completion of B1871006 or continued to be followed for survival. Dose for bosutinib was 500 mg orally once daily (adjusted dose varied from 200 mg to 600 mg once daily). Treatment continued until the end of the study, disease progression, unacceptable toxicity, death, withdrawal of consent or study discontinuation whichever occurred first. Follow-up continued till end of the study or death due to any cause whichever occurred first. Subjects remained in this study, either for treatment or for follow-up, until the last subject enrolled in 1 of the parent studies reached 10 years of follow-up, as calculated from the date of his/her first dose of bosutinib administered in parent study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bosutinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received bosutinib at a dose of 500 mg, orally once daily (adjusted dose varied from 200 mg to 600 mg once daily).

    Arm title
    		 Bosutinib, ADV
    Arm description
    		 ADV subjects from B1871006 with Ph+ accelerated phase(AP),blast phase(BP) CML, Ph+ acute lymphoblastic leukemia(ALL) and resistant or intolerant(R/I) to imatinib only or R/I to imatinib and at least 1 additional tyrosine kinase inhibitor(TKI) including dasatinib and/or nilotinib who either continued to receive same bosutinib dose as at time of completion of B1871008 or continued to be followed for survival. Dose for bosutinib was 500 mg orally once daily(od) (adjusted dose varied from 200 mg to 600 mg od). Treatment continued until end of study, disease progression,unacceptable toxicity,death,withdrawal of consent or study discontinuation whichever occurred first. Follow-up continued till end of study or death due to any cause whichever occurred first. Subjects remained in study, either for treatment or for follow-up,until last subject enrolled in 1 of parent studies reached 10 years of follow-up, as calculated from date of his/her first dose of bosutinib administered in parent study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bosutinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received bosutinib at a dose of 500 mg, orally once daily (adjusted dose varied from 200 mg to 600 mg once daily).

    Number of subjects in period 1
    		Bosutinib, CP1L Bosutinib, CP2L Bosutinib, CP3L/CP4L Bosutinib, ADV
    Started
    250
    284
    119
    167
    Full analysis set
    250
    284
    119
    167
    Safety analysis set
    248
    284
    119
    167
    Enrolled in B1871040
    124 [1]
    90 [2]
    28 [3]
    18 [4]
    Treated in B1871040
    98 [5]
    69 [6]
    13 [7]
    8 [8]
    Completed
    144
    158
    58
    48
    Not completed
    106
    126
    61
    119
         Adverse event, serious fatal
    23
    54
    30
    98
         Unspecified
    10
    15
    12
    3
         Subject refused further follow-up
    35
    38
    13
    9
         Lost to follow-up
    18
    19
    6
    9
         Missing
    2
    -
    -
    -
         Investigator request
    18
    -
    -
    -
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This milestone depicts number of subjects enrolled specifically in this study excluding subjects enrolled in China.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This milestone depicts number of subjects enrolled specifically in this study excluding subjects enrolled in China.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This milestone depicts number of subjects enrolled specifically in this study excluding subjects enrolled in China.
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This milestone depicts number of subjects enrolled specifically in this study excluding subjects enrolled in China.
    [5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This milestone depicts number of subjects enrolled specifically in this study excluding subjects enrolled in China.
    [6] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This milestone depicts number of subjects enrolled specifically in this study excluding subjects enrolled in China.
    [7] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This milestone depicts number of subjects enrolled specifically in this study excluding subjects enrolled in China.
    [8] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This milestone depicts number of subjects enrolled specifically in this study excluding subjects enrolled in China.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Bosutinib, CP1L
    Reporting group description
    		 Subjects from B1871008 with Ph+ chronic phase 1st line (CP1L) CML who either continued to receive the same bosutinib dose as at the time of completion of B1871008 or continued to be followed for survival. Dose for bosutinib was 500 milligram (mg) orally once daily (adjusted dose varied from 200 mg to 600 mg once daily). Treatment continued until the end of the study, disease progression, unacceptable toxicity, death, withdrawal of consent or study discontinuation whichever occurred first. Follow-up continued till end of the study or death due to any cause whichever occurred first. Subjects remained in this study, either for treatment or for follow-up, until the last subject enrolled in 1 of the parent studies reached 10 years of follow-up, as calculated from the date of his/her first dose of bosutinib administered in parent study.

    Reporting group title
    Bosutinib, CP2L
    Reporting group description
    		 Subjects from B1871006 with Ph+ chronic phase 2nd line (CP2L) CML who were resistant or intolerant to imatinib either continued to receive the same bosutinib dose as at the time of completion of B1871006 or continued to be followed for survival. Dose for bosutinib was 500 mg orally once daily (adjusted dose varied from 200 mg to 600 mg once daily). Treatment continued until the end of the study, disease progression, unacceptable toxicity, death, withdrawal of consent or study discontinuation whichever occurred first. Follow-up continued till end of the study or death due to any cause whichever occurred first. Subjects remained in this study, either for treatment or for follow-up, until the last subject enrolled in 1 of the parent studies reached 10 years of follow-up, as calculated from the date of his/her first dose of bosutinib administered in parent study.

    Reporting group title
    Bosutinib, CP3L/CP4L
    Reporting group description
    		 Subjects from B1871006 with Ph+ chronic phase 3rd line (CP3L)/4th line (CP4L) CML who were resistant or intolerant to imatinib and resistant or intolerant to dasatinib and/or nilotinib either continued to receive the same bosutinib dose as at the time of completion of B1871006 or continued to be followed for survival. Dose for bosutinib was 500 mg orally once daily (adjusted dose varied from 200 mg to 600 mg once daily). Treatment continued until the end of the study, disease progression, unacceptable toxicity, death, withdrawal of consent or study discontinuation whichever occurred first. Follow-up continued till end of the study or death due to any cause whichever occurred first. Subjects remained in this study, either for treatment or for follow-up, until the last subject enrolled in 1 of the parent studies reached 10 years of follow-up, as calculated from the date of his/her first dose of bosutinib administered in parent study.

    Reporting group title
    Bosutinib, ADV
    Reporting group description
    		 ADV subjects from B1871006 with Ph+ accelerated phase(AP),blast phase(BP) CML, Ph+ acute lymphoblastic leukemia(ALL) and resistant or intolerant(R/I) to imatinib only or R/I to imatinib and at least 1 additional tyrosine kinase inhibitor(TKI) including dasatinib and/or nilotinib who either continued to receive same bosutinib dose as at time of completion of B1871008 or continued to be followed for survival. Dose for bosutinib was 500 mg orally once daily(od) (adjusted dose varied from 200 mg to 600 mg od). Treatment continued until end of study, disease progression,unacceptable toxicity,death,withdrawal of consent or study discontinuation whichever occurred first. Follow-up continued till end of study or death due to any cause whichever occurred first. Subjects remained in study, either for treatment or for follow-up,until last subject enrolled in 1 of parent studies reached 10 years of follow-up, as calculated from date of his/her first dose of bosutinib administered in parent study.

    Reporting group values
    		 Bosutinib, CP1L Bosutinib, CP2L Bosutinib, CP3L/CP4L Bosutinib, ADV Total
    Number of subjects
    		 250 284 119 167 820
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 220 217 91 134 662
        From 65-84 years
    		 29 65 28 33 155
        85 years and over
    		 1 2 0 0 3
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 47.9 ± 14.4 51.9 ± 15.1 55.1 ± 13.0 50.1 ± 15.4 -
    Sex: Female, Male
    Units: Subjects
        Female
    		 101 135 66 69 371
        Male
    		 149 149 53 98 449
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 1 0 0 1
        Asian
    		 83 61 15 37 196
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0
        Black or African American
    		 2 16 6 19 43
        White
    		 160 186 87 102 535
        More than one race
    		 0 0 0 0 0
        Unknown or Not Reported
    		 5 20 11 9 45

    End points

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    End points reporting groups
    Reporting group title
    Bosutinib, CP1L
    Reporting group description
    		 Subjects from B1871008 with Ph+ chronic phase 1st line (CP1L) CML who either continued to receive the same bosutinib dose as at the time of completion of B1871008 or continued to be followed for survival. Dose for bosutinib was 500 milligram (mg) orally once daily (adjusted dose varied from 200 mg to 600 mg once daily). Treatment continued until the end of the study, disease progression, unacceptable toxicity, death, withdrawal of consent or study discontinuation whichever occurred first. Follow-up continued till end of the study or death due to any cause whichever occurred first. Subjects remained in this study, either for treatment or for follow-up, until the last subject enrolled in 1 of the parent studies reached 10 years of follow-up, as calculated from the date of his/her first dose of bosutinib administered in parent study.

    Reporting group title
    Bosutinib, CP2L
    Reporting group description
    		 Subjects from B1871006 with Ph+ chronic phase 2nd line (CP2L) CML who were resistant or intolerant to imatinib either continued to receive the same bosutinib dose as at the time of completion of B1871006 or continued to be followed for survival. Dose for bosutinib was 500 mg orally once daily (adjusted dose varied from 200 mg to 600 mg once daily). Treatment continued until the end of the study, disease progression, unacceptable toxicity, death, withdrawal of consent or study discontinuation whichever occurred first. Follow-up continued till end of the study or death due to any cause whichever occurred first. Subjects remained in this study, either for treatment or for follow-up, until the last subject enrolled in 1 of the parent studies reached 10 years of follow-up, as calculated from the date of his/her first dose of bosutinib administered in parent study.

    Reporting group title
    Bosutinib, CP3L/CP4L
    Reporting group description
    		 Subjects from B1871006 with Ph+ chronic phase 3rd line (CP3L)/4th line (CP4L) CML who were resistant or intolerant to imatinib and resistant or intolerant to dasatinib and/or nilotinib either continued to receive the same bosutinib dose as at the time of completion of B1871006 or continued to be followed for survival. Dose for bosutinib was 500 mg orally once daily (adjusted dose varied from 200 mg to 600 mg once daily). Treatment continued until the end of the study, disease progression, unacceptable toxicity, death, withdrawal of consent or study discontinuation whichever occurred first. Follow-up continued till end of the study or death due to any cause whichever occurred first. Subjects remained in this study, either for treatment or for follow-up, until the last subject enrolled in 1 of the parent studies reached 10 years of follow-up, as calculated from the date of his/her first dose of bosutinib administered in parent study.

    Reporting group title
    Bosutinib, ADV
    Reporting group description
    		 ADV subjects from B1871006 with Ph+ accelerated phase(AP),blast phase(BP) CML, Ph+ acute lymphoblastic leukemia(ALL) and resistant or intolerant(R/I) to imatinib only or R/I to imatinib and at least 1 additional tyrosine kinase inhibitor(TKI) including dasatinib and/or nilotinib who either continued to receive same bosutinib dose as at time of completion of B1871008 or continued to be followed for survival. Dose for bosutinib was 500 mg orally once daily(od) (adjusted dose varied from 200 mg to 600 mg od). Treatment continued until end of study, disease progression,unacceptable toxicity,death,withdrawal of consent or study discontinuation whichever occurred first. Follow-up continued till end of study or death due to any cause whichever occurred first. Subjects remained in study, either for treatment or for follow-up,until last subject enrolled in 1 of parent studies reached 10 years of follow-up, as calculated from date of his/her first dose of bosutinib administered in parent study.

    Subject analysis set title
    Bosutinib 200 mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received uninterrupted once daily oral 200 mg dose of bosutinib for at least 2 weeks in study B1871040.

    Subject analysis set title
    Bosutinib 300 mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received uninterrupted once daily oral 300 mg dose of bosutinib for at least 2 weeks in study B1871040.

    Subject analysis set title
    Bosutinib 400 mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received uninterrupted once daily oral 400 mg dose of bosutinib for at least 2 weeks in study B1871040.

    Subject analysis set title
    Bosutinib 500 mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received uninterrupted once daily oral 500 mg dose of bosutinib for at least 2 weeks in study B1871040.

    Subject analysis set title
    Bosutinib 600 mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received uninterrupted once daily oral 600 mg dose of bosutinib for at least 2 weeks in study B1871040.

    Subject analysis set title
    Bosutinib, Total
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects from B1871008 CP1L cohort and B1871006 CP2L, CP3L/CP4L and ADV cohorts.

    Primary: Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) Based on National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE) (Version 3.0)

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    End point title
    		 Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) Based on National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE) (Version 3.0) [1]
    End point description
    An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. SAE was any untoward medical occurrence at any dose that: resulted in death, was life threatening (immediate risk of death), required inpatient hospitalisation or prolongation of existing hospitalisation, resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions), resulted in congenital anomaly/birth defect. Treatment-emergent adverse events were defined as any event increasing in severity from baseline or any new event started during bosutinib therapy or within 30 days of the last dose of study drug. Safety analysis set included all dosed subjects for both B1871006 and B1871008.
    End point type
    Primary
    End point timeframe
    From first dose of drug up to 30 days after last dose (up to approximately 14 years)
    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: The endpoint reports data for B1871006 subjects.
    End point values
    		 Bosutinib, CP1L Bosutinib, CP2L Bosutinib, CP3L/CP4L Bosutinib, ADV Bosutinib, Total
    Number of subjects analysed
    248
    284
    119
    167
    818
    Units: subjects
        Treatment-Emergent AEs
    241
    283
    119
    165
    808
        Treatment-emergent SAEs
    102
    124
    44
    98
    368
    No statistical analyses for this end point

    Primary: Number of Subjects With Grade 3 or 4 Treatment-Emergent Adverse Events (AEs) Based on National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE) (Version 3.0)

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    End point title
    		 Number of Subjects With Grade 3 or 4 Treatment-Emergent Adverse Events (AEs) Based on National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE) (Version 3.0) [2]
    End point description
    An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. AEs were assessed according to severity grading based on NCI CTCAE version 3.0. Grade 1 =mild; Grade 2 =moderate; Grade 3 =severe or medically significant but not immediately life-threatening, hospitalisation or prolongation of hospitalisation indicated; Grade 4 =life-threatening or disabling, urgent intervention indicated; Grade 5 =death. Treatment-emergent adverse events were defined as any event increasing in severity from baseline or any new event started during bosutinib therapy or within 30 days of the last dose of study drug. Safety analysis set included all dosed subjects for both B1871006 and B1871008.
    End point type
    Primary
    End point timeframe
    From first dose of drug up to 30 days after last dose (up to approximately 14 years)
    Notes
    [2] - 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: The endpoint reports data for B1871006 subjects.
    End point values
    		 Bosutinib, CP1L Bosutinib, CP2L Bosutinib, CP3L/CP4L Bosutinib, ADV Bosutinib, Total
    Number of subjects analysed
    248
    284
    119
    167
    818
    Units: subjects
    191
    223
    84
    144
    642
    No statistical analyses for this end point

    Primary: Number of Subjects With Treatment-Emergent Treatment Related Adverse Events (AEs) Based on National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE) (Version 3.0)

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    End point title
    		 Number of Subjects With Treatment-Emergent Treatment Related Adverse Events (AEs) Based on National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE) (Version 3.0) [3]
    End point description
    An AE was any untoward medical occurrence in a subject who received study drug. Treatment-emergent adverse events were defined as any event increasing in severity from baseline or any new event started during bosutinib therapy or within 30 days of the last dose of study drug. Related TEAEs were those AEs who were related to the study treatment as judged by the investigator. Safety analysis set included all dosed subjects for both B1871006 and B1871008.
    End point type
    Primary
    End point timeframe
    From first dose of drug up to 30 days after last dose (up to approximately 14 years)
    Notes
    [3] - 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: The endpoint reports data for B1871006 subjects.
    End point values
    		 Bosutinib, CP1L Bosutinib, CP2L Bosutinib, CP3L/CP4L Bosutinib, ADV Bosutinib, Total
    Number of subjects analysed
    248
    284
    119
    167
    818
    Units: subjects
    235
    282
    119
    161
    797
    No statistical analyses for this end point

    Primary: Number of Subjects With Laboratory Test Abnormalities Based on National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE) (Version 4.03)

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    End point title
    		 Number of Subjects With Laboratory Test Abnormalities Based on National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE) (Version 4.03) [4]
    End point description
    Laboratory parameters were evaluated as per NCI CTCAE version 4.03 and included Chemistry: high alkaline phosphatase; high alanine aminotransferase; high aspartate aminotransferase; high blood bilirubin; high creatinine. Hematology: absolute neutrophils count decreased; anemia; platelet count decreased; WBC decreased. Safety analysis set included all dosed subjects for both B1871006 and B1871008.
    End point type
    Primary
    End point timeframe
    From first dose of drug up to 30 days after last dose (up to approximately 14 years)
    Notes
    [4] - 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: The endpoint reports data for B1871006 subjects.
    End point values
    		 Bosutinib, CP1L Bosutinib, CP2L Bosutinib, CP3L/CP4L Bosutinib, ADV Bosutinib, Total
    Number of subjects analysed
    248
    284
    119
    167
    818
    Units: subjects
        Grade 1
    45
    59
    28
    18
    150
        Grade 2
    86
    80
    39
    24
    229
        Grade 3
    84
    102
    27
    41
    254
        Grade 4
    33
    42
    23
    82
    180
    No statistical analyses for this end point

    Primary: Number of Subjects With Adverse Events as Reason for Treatment Discontinuation

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    End point title
    		 Number of Subjects With Adverse Events as Reason for Treatment Discontinuation [5]
    End point description
    An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. Safety analysis set included all dosed subjects for both B1871006 and B1871008.
    End point type
    Primary
    End point timeframe
    From first dose of drug up to 30 days after last dose (up to approximately 14 years)
    Notes
    [5] - 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: The endpoint reports data for B1871006 subjects.
    End point values
    		 Bosutinib, CP1L Bosutinib, CP2L Bosutinib, CP3L/CP4L Bosutinib, ADV Bosutinib, Total
    Number of subjects analysed
    248
    284
    119
    167
    818
    Units: subjects
    84
    79
    37
    32
    232
    No statistical analyses for this end point

    Primary: Number of Subjects With Diarrhea After Switch From Bosutinib Clinical Formulation to Bosutinib Commercial Formulation

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    End point title
    		 Number of Subjects With Diarrhea After Switch From Bosutinib Clinical Formulation to Bosutinib Commercial Formulation [6]
    End point description
    The incidence of diarrhea was collected and analysed before and after the switch from the clinical formulation of bosutinib to the commercial formulation of bosutinib. Safety analysis set included all dosed subjects for both B1871006 and B1871008. Here, ‘Overall number of subjects analysed (N)’= subjects evaluable for this endpoint who received commercial formulation.
    End point type
    Primary
    End point timeframe
    Last 6 months on clinical formulation and first 6 months on commercial formulation
    Notes
    [6] - 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: The endpoint reports data for B1871006 subjects.
    End point values
    		 Bosutinib, CP1L Bosutinib, CP2L Bosutinib, CP3L/CP4L Bosutinib, ADV Bosutinib, Total
    Number of subjects analysed
    119
    82
    13
    8
    222
    Units: subjects
        Clinical formulation (last 6 months)
    25
    22
    3
    5
    55
        Commercial formulation (first 6 months)
    34
    27
    4
    5
    70
    No statistical analyses for this end point

    Primary: Number of Subjects With Breakpoint Cluster Region Abelson Protooncogene (BCR-ABL) Mutations Present at Time of Bosutinib Treatment Discontinuation

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    End point title
    		 Number of Subjects With Breakpoint Cluster Region Abelson Protooncogene (BCR-ABL) Mutations Present at Time of Bosutinib Treatment Discontinuation [7]
    End point description
    BCR-ABL is a gene resulting from the 9:22 chromosomal translocation (Philadelphia chromosome). In this endpoint, the number of subjects who had emergent mutation or new BCR-ABL mutations (subjects who had a post-baseline mutation which was not present at baseline) were reported. The full analysis set included all subjects randomised to the bosutinib arm from B1871008 and all dosed subjects from B1871006.
    End point type
    Primary
    End point timeframe
    Post-baseline on Day 1 (maximum up to 14 years)
    Notes
    [7] - 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: The endpoint reports data for B1871006 subjects.
    End point values
    		 Bosutinib, CP1L Bosutinib, CP2L Bosutinib, CP3L/CP4L Bosutinib, ADV
    Number of subjects analysed
    250
    284
    119
    167
    Units: subjects
        Subjects with Emergent mutations
    7
    28
    13
    14
    No statistical analyses for this end point

    Primary: Overall Survival (OS) Rate at Year 10

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    End point title
    		 Overall Survival (OS) Rate at Year 10 [8]
    End point description
    OS was defined as the time from randomisation (B1871008) and time from first dose (B1871006) to the occurrence of death due to any cause or censoring. Kaplan-Meier analysis was used for determination of OS. Percentage of subjects who were alive were estimated in this endpoint. The full analysis set included all subjects randomised to the bosutinib arm from B1871008 and all dosed subjects from B1871006.
    End point type
    Primary
    End point timeframe
    Year 10
    Notes
    [8] - 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: The endpoint reports data for B1871006 subjects.
    End point values
    		 Bosutinib, CP1L Bosutinib, CP2L Bosutinib, CP3L/CP4L Bosutinib, ADV
    Number of subjects analysed
    250
    284
    119
    167
    Units: percentage of subjects
        number (confidence interval 95%)
    88.2 (83.3 to 93.2)
    71.5 (64.4 to 78.7)
    60.4 (47.2 to 73.7)
    34.2 (25.0 to 43.4)
    No statistical analyses for this end point

    Primary: Plasma Steady-State Trough Concentrations (Ctrough) of Bosutinib

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    End point title
    		 Plasma Steady-State Trough Concentrations (Ctrough) of Bosutinib [9]
    End point description
    Ctrough refers to plasma concentration of bosutinib observed just before treatment administration. The pharmacokinetic (PK) analysis set included subjects who received at least 1 dose of bosutinib and had 1 reported bosutinib concentration.
    End point type
    Primary
    End point timeframe
    One pre-dose sample was collected at the first scheduled visit (after approval and implementation of protocol amendment 1) following at least 2 weeks of uninterrupted dosing at the same dose level
    Notes
    [9] - 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: The endpoint reports data for B1871006 subjects.
    End point values
    		 Bosutinib 200 mg Bosutinib 300 mg Bosutinib 400 mg Bosutinib 500 mg Bosutinib 600 mg
    Number of subjects analysed
    6
    28
    23
    69
    8
    Units: nanogram per millilitre
        geometric mean (geometric coefficient of variation)
    62.2 ± 31.3
    62.0 ± 65.9
    82.2 ± 53.2
    93.3 ± 45.2
    99.4 ± 78.2
    No statistical analyses for this end point

    Primary: Kaplan-Meier Estimate of Probability of Maintaining Major Cytogenetic Response (MCyR) at Year 10: B1871006 Subjects

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    End point title
    		 Kaplan-Meier Estimate of Probability of Maintaining Major Cytogenetic Response (MCyR) at Year 10: B1871006 Subjects [10] [11]
    End point description
    Cytogenetic response(CyR) is based on prevalence of Ph+ cells.MCyR duration:time from first response to confirmed loss, progression of disease or on-treatment death due to any cause or censoring analysed for responders only.Confirmed loss:2 consecutive non-responses >=28 days apart. MCyR was grouped as complete CyR (CCyR) or partial CyR (PCyR).Response was achieved when there was 0% (CCyR) or 1-35% (PCyR) Ph+ cells analysed from conventional cytogenetics based on the analysis of 20 to 100 metaphases or <1% (CCyR) or 1-35% (PCyR) Ph+ cells analysed from FISH based on analysis of >=200 nuclei. CCyR may be imputed on specific date if MMR or better is achieved & denoted on CRF on that date for B1871040 study visits.Kaplan-Meier analysis was used.Evaluable analysis set for cytogenetic population: B1871006 dosed subjects with valid baseline efficacy assessment from B1871006 with >=20 metaphases or >=1 Ph+ metaphase from baseline BM cytogenetic assessment & who achieved MCyR(responders).
    End point type
    Primary
    End point timeframe
    Year 10
    Notes
    [10] - 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: The endpoint reports data for B1871006 subjects.
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint reports data for B1871006 subjects.
    End point values
    		 Bosutinib, CP2L Bosutinib, CP3L/CP4L Bosutinib, ADV
    Number of subjects analysed
    157
    47
    54
    Units: percentage of subjects
        number (confidence interval 95%)
    65.3 (56.6 to 74.0)
    55.3 (36.3 to 74.4)
    30.6 (16.4 to 44.7)
    No statistical analyses for this end point

    Primary: Kaplan-Meier Estimate of Probability of Maintaining Complete Cytogenetic Response (CCyR) at Year 10: B1871006 Subjects

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    End point title
    		 Kaplan-Meier Estimate of Probability of Maintaining Complete Cytogenetic Response (CCyR) at Year 10: B1871006 Subjects [12] [13]
    End point description
    Duration for CCyR was defined as time from first response to confirmed loss, progression of disease, or on-treatment death due to any cause, or censoring analysed for responders only. Confirmed loss was defined as 2 consecutive assessments with >0 Ph+ metaphases or >=1% positive cells from FISH at least 28 days apart or progression or death. CCyR was achieved when there was 0% Ph+ cells analysed from conventional cytogenetics with 20 to 100 metaphases or <1% Ph+ cells analysed from FISH with at least 200 nuclei. CCyR may be imputed on a specific date if MMR or better was achieved and denoted on the CRF on that date for B1871040 study visits. Kaplan-Meier analysis was used. Evaluable analysis set for cytogenetic population were those dosed subjects from B1871006 with a valid baseline efficacy assessment from B1871006 with at least 20 metaphases or at least 1 Ph+ metaphase from the baseline bone marrow cytogenetic assessment and who achieved CCyR (responders).
    End point type
    Primary
    End point timeframe
    Year 10
    Notes
    [12] - 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: The endpoint reports data for B1871006 subjects.
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint reports data for B1871006 subjects.
    End point values
    		 Bosutinib, CP2L Bosutinib, CP3L/CP4L Bosutinib, ADV
    Number of subjects analysed
    130
    36
    42
    Units: percentage of subjects
        number (confidence interval 95%)
    63.4 (54.0 to 72.8)
    40.8 (22.0 to 59.6)
    29.6 (14.6 to 44.7)
    No statistical analyses for this end point

    Primary: Kaplan-Meier Estimate of Probability of Maintaining Complete Hematologic Response (CHR) at Year 10: B1871006 Subjects

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    End point title
    		 Kaplan-Meier Estimate of Probability of Maintaining Complete Hematologic Response (CHR) at Year 10: B1871006 Subjects [14] [15]
    End point description
    Duration for CHR:time from first response to confirmed loss, progression of disease or on-treatment death due to any cause or censoring analysed for responders only. Confirmed loss:2 consecutive non-responses >=14 days apart. CHR considered when subjects met all criteria:WBC <=institutional ULN, no blasts or promyelocytes, <20% basophils, no extramedullary involvement (including hepatomegaly or splenomegaly), myelocytes, metamyelocytes <5% in blood, platelets <450*10^9/L. Following were applicable only to advanced phase: <=5% bone marrow blasts, absolute neutrophil count >=1.0*10^9/L, platelets >=100*10^9/L. Kaplan-Meier analysis used. Evaluable analysis set for hematologic population:B1871006 dosed subjects with valid baseline efficacy assessment from B1871006 & valid baseline hematologic assessment & who achieved CHR (responders). 99999=percentage & 95% CI not estimable since BM blasts were not always assessed in later years for ADV subjects.
    End point type
    Primary
    End point timeframe
    Year 10
    Notes
    [14] - 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: The endpoint reports data for B1871006 subjects.
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint reports data for B1871006 subjects.
    End point values
    		 Bosutinib, CP2L Bosutinib, CP3L/CP4L Bosutinib, ADV
    Number of subjects analysed
    245
    86
    36
    Units: percentage of subjects
        number (confidence interval 95%)
    44.1 (35.2 to 52.9)
    45.1 (29.3 to 60.9)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Primary: Cumulative Incidence of Progression/Death Events at Year 10: B1871006 Subjects

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    End point title
    		 Cumulative Incidence of Progression/Death Events at Year 10: B1871006 Subjects [16] [17]
    End point description
    PFS was defined as interval from date of first dose of bosutinib in parent study until earlier date of progression or death from any cause. Subjects without events censored at last evaluation date. PD evolution from: CP (or return to CP for ADV subjects) to AP or BP (on 2 consecutive assessments >=1 week apart), AP to BP (on 2 consecutive assessments >=1 week apart) and 1 of following conditions: for 2nd or later line, loss of MCyR (>=30% increase); for all lines of treatment: loss of CHR confirmed by 2 assessments >=2 weeks apart; increasing WBC defined as doubling of WBC over a period of >=1 month with second WBC >20*10^9/L confirmed >=1 week later. Percentage of subjects with PFS/death events based on cumulative incidence method adjusting for competing event of treatment discontinuation without event. The full analysis set from B1871006 included all dosed subjects from the study B1871006.
    End point type
    Primary
    End point timeframe
    Year 10
    Notes
    [16] - 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: The endpoint reports data for B1871006 subjects.
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint reports data for B1871006 subjects.
    End point values
    		 Bosutinib, CP2L Bosutinib, CP3L/CP4L Bosutinib, ADV
    Number of subjects analysed
    284
    119
    167
    Units: percentage of subjects
        number (confidence interval 95%)
    23.9 (19.5 to 29.5)
    26.9 (20.0 to 36.2)
    55.7 (48.6 to 63.8)
    No statistical analyses for this end point

    Primary: Cumulative Incidence of Rate of Transformation to Accelerated Phase (AP) or Blast Phase (BP) at Year 10: B1871006 Subjects

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    End point title
    		 Cumulative Incidence of Rate of Transformation to Accelerated Phase (AP) or Blast Phase (BP) at Year 10: B1871006 Subjects [18] [19]
    End point description
    Time to transformation was defined as the time from first dose in the parent study to the first date of confirmed transformation to AP or BP. Confirmed transformation was defined as 2 consecutive assessments at least 1 week apart or 1 assessment confirmed by progression of disease or death. For subjects without transformation, censorship was at the last evaluation date. Percentage of subjects with time to transformation to AP/BP was reported based on cumulative incidence method adjusting for the competing risk of treatment discontinuation without the event. The full analysis set from B1871006 included all dosed subjects from the study B1871006. For "Bosutinib ADV" reporting arm, data was analysed for subjects with AP who had BP transformation only.
    End point type
    Primary
    End point timeframe
    Year 10
    Notes
    [18] - 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: The endpoint reports data for B1871006 subjects.
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint reports data for B1871006 subjects.
    End point values
    		 Bosutinib, CP2L Bosutinib, CP3L/CP4L Bosutinib, ADV
    Number of subjects analysed
    284
    119
    79
    Units: percentage of subjects
        number (confidence interval 95%)
    5.3 (3.2 to 8.6)
    4.2 (1.8 to 9.9)
    3.8 (1.3 to 11.5)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug and up to 30 days after last dose (up to approximately 14 years)
    Adverse event reporting additional description
    The total number of deaths during study, from randomisation (B1871008)/first dose (B1871006) and up to end of the study are reported for all treated subjects and includes deaths which occurred after 30 days post last study drug dose. SAEs and other AEs: Analysis performed on safety set. Combined data from parent studies and this study reported.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Bosutinib, CP1L
    Reporting group description
    		 Subjects from B1871008 with Philadelphia chromosome-positive (Ph+) chronic phase 1st line (CP1L) chronic myeloid leukemia (CML).

    Reporting group title
    Bosutinib, CP2L
    Reporting group description
    		 Subjects from B1871006 with Ph+ chronic phase 2nd line (CP2L) CML who were resistant or intolerant to imatinib.

    Reporting group title
    Bosutinib, CP3L/CP4L
    Reporting group description
    		 Subjects from B1871006 with Ph+ chronic phase 3rd line (CP3L)/4th line (CP4L) CML who were resistant or intolerant to imatinib and resistant or intolerant to dasatinib and/or nilotinib.

    Reporting group title
    Bosutinib, ADV
    Reporting group description
    		 Subjects from B1871006 with Ph+ accelerated phase (AP), blast phase (BP) CML and Ph+ acute lymphoblastic leukemia (ALL) and resistant or intolerant to imatinib only or resistant and intolerant to imatinib and at least 1 additional tyrosine kinase inhibitor (TKI) including dasatinib and/or nilotinib.

    Reporting group title
    Bosutinib, Total
    Reporting group description
    		 Subjects from B1871008 CP1L cohort and B1871006 CP2L, CP3L/CP4L and ADV cohorts.

    Serious adverse events
    		 Bosutinib, CP1L Bosutinib, CP2L Bosutinib, CP3L/CP4L Bosutinib, ADV Bosutinib, Total
    Total subjects affected by serious adverse events
         subjects affected / exposed
    102 / 248 (41.13%)
    124 / 284 (43.66%)
    44 / 119 (36.97%)
    98 / 167 (58.68%)
    368 / 818 (44.99%)
         number of deaths (all causes)
    23
    55
    30
    98
    206
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Blast cell crisis
         subjects affected / exposed
    1 / 248 (0.40%)
    3 / 284 (1.06%)
    0 / 119 (0.00%)
    2 / 167 (1.20%)
    6 / 818 (0.73%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
    0 / 0
    0 / 2
    1 / 7
         deaths causally related to treatment / all
    0 / 2
    1 / 1
    0 / 0
    0 / 1
    1 / 4
    Adenocarcinoma gastric
         subjects affected / exposed
    3 / 248 (1.21%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    3 / 818 (0.37%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Basal cell carcinoma
         subjects affected / exposed
    1 / 248 (0.40%)
    2 / 284 (0.70%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    3 / 818 (0.37%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
    0 / 0
    0 / 0
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blast crisis in myelogenous leukaemia
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    3 / 167 (1.80%)
    3 / 818 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 248 (0.00%)
    2 / 284 (0.70%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    3 / 818 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic myeloid leukaemia
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 2
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    1 / 119 (0.84%)
    0 / 167 (0.00%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angiomyolipoma
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anogenital warts
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder squamous cell carcinoma stage unspecified
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bowen's disease
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Central nervous system leukaemia
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chloroma
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholangiocarcinoma
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    1 / 119 (0.84%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Chronic myelomonocytic leukaemia
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colon cancer metastatic
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Follicle centre lymphoma, follicular grade I, II, III
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    1 / 119 (0.84%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Invasive ductal breast carcinoma
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Keratoacanthoma
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    1 / 119 (0.84%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laryngeal neoplasm
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukaemia
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Lipoma
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Melanocytic naevus
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasm prostate
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasm skin
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-small cell lung cancer
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    1 / 119 (0.84%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paraproteinaemia
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Uterine leiomyoma
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 248 (0.40%)
    2 / 284 (0.70%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    4 / 818 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    2 / 167 (1.20%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic stenosis
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    1 / 119 (0.84%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Allogenic bone marrow transplantation therapy
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cyst removal
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Knee arthroplasty
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Pregnancy
         subjects affected / exposed
    2 / 248 (0.81%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         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
    8 / 248 (3.23%)
    8 / 284 (2.82%)
    2 / 119 (1.68%)
    11 / 167 (6.59%)
    29 / 818 (3.55%)
         occurrences causally related to treatment / all
    1 / 8
    8 / 15
    0 / 3
    5 / 17
    14 / 43
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    0 / 248 (0.00%)
    3 / 284 (1.06%)
    1 / 119 (0.84%)
    8 / 167 (4.79%)
    12 / 818 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
    0 / 12
    0 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
    0 / 8
    0 / 12
    Chest pain
         subjects affected / exposed
    1 / 248 (0.40%)
    3 / 284 (1.06%)
    0 / 119 (0.00%)
    4 / 167 (2.40%)
    8 / 818 (0.98%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
    0 / 0
    0 / 4
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    6 / 167 (3.59%)
    7 / 818 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    1 / 9
    1 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 3
    Asthenia
         subjects affected / exposed
    0 / 248 (0.00%)
    4 / 284 (1.41%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    5 / 818 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
    1 / 1
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    2 / 167 (1.20%)
    3 / 818 (0.37%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 248 (0.40%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 3
    0 / 0
    0 / 0
    1 / 4
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    2 / 167 (1.20%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 3
    Oedema
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    1 / 119 (0.84%)
    1 / 167 (0.60%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adhesion
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adverse drug reaction
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    Swelling
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         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 / 248 (0.40%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    3 / 818 (0.37%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    1 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaphylactic shock
         subjects affected / exposed
    2 / 248 (0.81%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Social circumstances
    Pregnancy of partner
         subjects affected / exposed
    2 / 248 (0.81%)
    0 / 284 (0.00%)
    1 / 119 (0.84%)
    0 / 167 (0.00%)
    3 / 818 (0.37%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Menorrhagia
         subjects affected / exposed
    0 / 248 (0.00%)
    2 / 284 (0.70%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast hyperplasia
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervical dysplasia
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysfunctional uterine bleeding
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metrorrhagia
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic pain
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    12 / 248 (4.84%)
    15 / 284 (5.28%)
    8 / 119 (6.72%)
    8 / 167 (4.79%)
    43 / 818 (5.26%)
         occurrences causally related to treatment / all
    13 / 16
    7 / 22
    6 / 10
    9 / 11
    35 / 59
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Dyspnoea
         subjects affected / exposed
    1 / 248 (0.40%)
    7 / 284 (2.46%)
    3 / 119 (2.52%)
    5 / 167 (2.99%)
    16 / 818 (1.96%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 13
    4 / 5
    1 / 6
    6 / 25
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 248 (0.40%)
    2 / 284 (0.70%)
    1 / 119 (0.84%)
    2 / 167 (1.20%)
    6 / 818 (0.73%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
    1 / 1
    0 / 2
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    5 / 167 (2.99%)
    6 / 818 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    1 / 6
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 3
    Pulmonary hypertension
         subjects affected / exposed
    3 / 248 (1.21%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    4 / 818 (0.49%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
    0 / 0
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    1 / 119 (0.84%)
    1 / 167 (0.60%)
    3 / 818 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Acute pulmonary oedema
         subjects affected / exposed
    2 / 248 (0.81%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Asthma
         subjects affected / exposed
    0 / 248 (0.00%)
    2 / 284 (0.70%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 248 (0.40%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    2 / 248 (0.81%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    1 / 248 (0.40%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    1 / 248 (0.40%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    1 / 119 (0.84%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchiectasis
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis chronic
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung infiltration
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    1 / 119 (0.84%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Organising pneumonia
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vocal cord polyp
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Confusional state
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disorientation
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dissociative disorder
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hallucination
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hallucination, visual
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    2 / 248 (0.81%)
    4 / 284 (1.41%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    7 / 818 (0.86%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 6
    0 / 0
    0 / 1
    2 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    1 / 119 (0.84%)
    1 / 167 (0.60%)
    3 / 818 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    2 / 167 (1.20%)
    3 / 818 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gallbladder disorder
         subjects affected / exposed
    0 / 248 (0.00%)
    2 / 284 (0.70%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bile duct stone
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
    0 / 0
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gallbladder polyp
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
    0 / 0
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Perforation bile duct
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    8 / 248 (3.23%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    9 / 818 (1.10%)
         occurrences causally related to treatment / all
    12 / 14
    1 / 1
    0 / 0
    0 / 0
    13 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 248 (1.61%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    5 / 818 (0.61%)
         occurrences causally related to treatment / all
    4 / 4
    1 / 1
    0 / 0
    0 / 0
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 248 (0.40%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    1 / 248 (0.40%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 3
    0 / 0
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Amylase increased
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood glucose increased
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood pressure increased
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intraocular pressure increased
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver function test increased
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
    0 / 0
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 248 (0.40%)
    2 / 284 (0.70%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    3 / 818 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 2
    Upper limb fracture
         subjects affected / exposed
    0 / 248 (0.00%)
    2 / 284 (0.70%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal injury
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervical vertebral fracture
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Exposure during pregnancy
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    1 / 119 (0.84%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Failure to anastomose
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal stoma complication
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscle injury
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    1 / 119 (0.84%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural complication
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural haematoma
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural haematuria
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    1 / 119 (0.84%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural swelling
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Procedural haemorrhage
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seroma
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    1 / 119 (0.84%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin laceration
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skull fracture
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Subdural haemorrhage
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tooth fracture
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transfusion reaction
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Traumatic lung injury
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular pseudoaneurysm
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound haematoma
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Cytogenetic abnormality
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    1 / 119 (0.84%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydrocele
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    1 / 119 (0.84%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Pericardial effusion
         subjects affected / exposed
    6 / 248 (2.42%)
    5 / 284 (1.76%)
    2 / 119 (1.68%)
    2 / 167 (1.20%)
    15 / 818 (1.83%)
         occurrences causally related to treatment / all
    4 / 8
    4 / 6
    2 / 2
    3 / 3
    13 / 19
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Cardiac failure congestive
         subjects affected / exposed
    2 / 248 (0.81%)
    6 / 284 (2.11%)
    1 / 119 (0.84%)
    1 / 167 (0.60%)
    10 / 818 (1.22%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 11
    1 / 1
    0 / 2
    3 / 18
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 1
    0 / 4
    Atrial fibrillation
         subjects affected / exposed
    1 / 248 (0.40%)
    4 / 284 (1.41%)
    3 / 119 (2.52%)
    1 / 167 (0.60%)
    9 / 818 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
    1 / 3
    0 / 1
    1 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    3 / 248 (1.21%)
    2 / 284 (0.70%)
    2 / 119 (1.68%)
    1 / 167 (0.60%)
    8 / 818 (0.98%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 2
    1 / 2
    0 / 2
    2 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Acute myocardial infarction
         subjects affected / exposed
    1 / 248 (0.40%)
    3 / 284 (1.06%)
    1 / 119 (0.84%)
    2 / 167 (1.20%)
    7 / 818 (0.86%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 1
    0 / 2
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 2
    Cardiac failure
         subjects affected / exposed
    0 / 248 (0.00%)
    4 / 284 (1.41%)
    1 / 119 (0.84%)
    1 / 167 (0.60%)
    6 / 818 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 8
    1 / 1
    0 / 1
    2 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Pericarditis
         subjects affected / exposed
    2 / 248 (0.81%)
    1 / 284 (0.35%)
    1 / 119 (0.84%)
    1 / 167 (0.60%)
    5 / 818 (0.61%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
    1 / 1
    1 / 1
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 248 (0.00%)
    3 / 284 (1.06%)
    1 / 119 (0.84%)
    0 / 167 (0.00%)
    4 / 818 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    1 / 1
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    3 / 119 (2.52%)
    1 / 167 (0.60%)
    4 / 818 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 4
    1 / 1
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    1 / 1
    1 / 3
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 248 (0.00%)
    2 / 284 (0.70%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    3 / 818 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 248 (0.00%)
    2 / 284 (0.70%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericardial haemorrhage
         subjects affected / exposed
    0 / 248 (0.00%)
    2 / 284 (0.70%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    2 / 167 (1.20%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic valve stenosis
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Arteriosclerosis coronary artery
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bundle branch block right
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorder
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Cardiorenal syndrome
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    3 / 248 (1.21%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    4 / 818 (0.49%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
    0 / 0
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
    0 / 0
    1 / 3
    Extrasystoles
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive cardiomyopathy
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Palpitations
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    1 / 119 (0.84%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleuropericarditis
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 248 (1.21%)
    0 / 284 (0.00%)
    2 / 119 (1.68%)
    8 / 167 (4.79%)
    13 / 818 (1.59%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
    0 / 2
    0 / 9
    2 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 248 (0.40%)
    4 / 284 (1.41%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    5 / 818 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
    0 / 0
    0 / 0
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 248 (0.81%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    4 / 818 (0.49%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 0
    0 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 248 (0.00%)
    2 / 284 (0.70%)
    0 / 119 (0.00%)
    2 / 167 (1.20%)
    4 / 818 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 2
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    2 / 167 (1.20%)
    3 / 818 (0.37%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 3
    Cerebral infarction
         subjects affected / exposed
    0 / 248 (0.00%)
    2 / 284 (0.70%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    3 / 818 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Cerebellar infarction
         subjects affected / exposed
    0 / 248 (0.00%)
    2 / 284 (0.70%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    2 / 167 (1.20%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    1 / 119 (0.84%)
    1 / 167 (0.60%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    2 / 248 (0.81%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Carotid arteriosclerosis
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Carpal tunnel syndrome
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalitis post varicella
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intraventricular haemorrhage
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Ischaemic stroke
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Monoparesis
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Parkinson's disease
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Partial seizures
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radiculopathy
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Speech disorder
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    1 / 119 (0.84%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Trigeminal neuralgia
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    6 / 248 (2.42%)
    5 / 284 (1.76%)
    1 / 119 (0.84%)
    8 / 167 (4.79%)
    20 / 818 (2.44%)
         occurrences causally related to treatment / all
    9 / 9
    5 / 10
    1 / 1
    17 / 24
    32 / 44
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    6 / 248 (2.42%)
    3 / 284 (1.06%)
    0 / 119 (0.00%)
    6 / 167 (3.59%)
    15 / 818 (1.83%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 6
    0 / 0
    0 / 7
    2 / 19
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    1 / 119 (0.84%)
    8 / 167 (4.79%)
    9 / 818 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 10
    2 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 248 (0.81%)
    0 / 284 (0.00%)
    4 / 119 (3.36%)
    2 / 167 (1.20%)
    8 / 818 (0.98%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    3 / 4
    1 / 2
    5 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    3 / 167 (1.80%)
    4 / 818 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperleukocytosis
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    2 / 167 (1.20%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Granulocytopenia
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukostasis syndrome
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Lymphadenopathy
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Splenomegaly
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    1 / 119 (0.84%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness unilateral
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vestibular disorder
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Glaucoma
         subjects affected / exposed
    1 / 248 (0.40%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    3 / 818 (0.37%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cataract
         subjects affected / exposed
    1 / 248 (0.40%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Visual impairment
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diplopia
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retinopathy
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retinopathy hypertensive
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    1 / 119 (0.84%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vitreous haemorrhage
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    9 / 248 (3.63%)
    8 / 284 (2.82%)
    1 / 119 (0.84%)
    4 / 167 (2.40%)
    22 / 818 (2.69%)
         occurrences causally related to treatment / all
    11 / 12
    7 / 9
    1 / 1
    2 / 4
    21 / 26
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    3 / 248 (1.21%)
    3 / 284 (1.06%)
    0 / 119 (0.00%)
    5 / 167 (2.99%)
    11 / 818 (1.34%)
         occurrences causally related to treatment / all
    2 / 3
    2 / 4
    0 / 0
    1 / 7
    5 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 248 (1.21%)
    2 / 284 (0.70%)
    0 / 119 (0.00%)
    5 / 167 (2.99%)
    10 / 818 (1.22%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 2
    0 / 0
    3 / 5
    5 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    1 / 119 (0.84%)
    6 / 167 (3.59%)
    8 / 818 (0.98%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    3 / 6
    3 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    3 / 248 (1.21%)
    1 / 284 (0.35%)
    1 / 119 (0.84%)
    1 / 167 (0.60%)
    6 / 818 (0.73%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
    0 / 1
    2 / 2
    3 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 248 (0.40%)
    3 / 284 (1.06%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    5 / 818 (0.61%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
    0 / 0
    0 / 2
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    3 / 167 (1.80%)
    4 / 818 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Inguinal hernia
         subjects affected / exposed
    0 / 248 (0.00%)
    3 / 284 (1.06%)
    1 / 119 (0.84%)
    0 / 167 (0.00%)
    4 / 818 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    2 / 248 (0.81%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    4 / 818 (0.49%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 0
    0 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Colitis
         subjects affected / exposed
    0 / 248 (0.00%)
    2 / 284 (0.70%)
    1 / 119 (0.84%)
    0 / 167 (0.00%)
    3 / 818 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 1
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    1 / 119 (0.84%)
    1 / 167 (0.60%)
    3 / 818 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    2 / 248 (0.81%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorder
         subjects affected / exposed
    2 / 248 (0.81%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 248 (0.00%)
    2 / 284 (0.70%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toothache
         subjects affected / exposed
    0 / 248 (0.00%)
    2 / 284 (0.70%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal adhesions
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal distension
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dental caries
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    1 / 119 (0.84%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epigastric discomfort
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Food poisoning
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis haemorrhagic
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal necrosis
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal haemorrhage
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    1 / 119 (0.84%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    1 / 119 (0.84%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Large intestinal stenosis
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    1 / 119 (0.84%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    Melaena
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mesenteric artery embolism
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal perforation
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Proctitis
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    1 / 119 (0.84%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal polyp
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retroperitoneal haemorrhage
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 248 (0.40%)
    8 / 284 (2.82%)
    1 / 119 (0.84%)
    1 / 167 (0.60%)
    11 / 818 (1.34%)
         occurrences causally related to treatment / all
    1 / 1
    8 / 8
    1 / 1
    0 / 1
    10 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    2 / 119 (1.68%)
    1 / 167 (0.60%)
    4 / 818 (0.49%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    2 / 2
    1 / 1
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angioedema
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    1 / 119 (0.84%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Circumoral oedema
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dermatitis
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erythema multiforme
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    1 / 119 (0.84%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin disorder
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin lesion
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    5 / 248 (2.02%)
    6 / 284 (2.11%)
    1 / 119 (0.84%)
    3 / 167 (1.80%)
    15 / 818 (1.83%)
         occurrences causally related to treatment / all
    0 / 5
    1 / 10
    0 / 1
    0 / 3
    1 / 19
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 2
    Renal failure
         subjects affected / exposed
    1 / 248 (0.40%)
    2 / 284 (0.70%)
    1 / 119 (0.84%)
    1 / 167 (0.60%)
    5 / 818 (0.61%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 3
    1 / 1
    0 / 1
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 248 (0.40%)
    2 / 284 (0.70%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    3 / 818 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Calculus urinary
         subjects affected / exposed
    2 / 248 (0.81%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Calculus bladder
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    1 / 119 (0.84%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystitis haemorrhagic
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    End stage renal disease
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prerenal failure
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal artery stenosis
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal disorder
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tubulointerstitial nephritis
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Goitre
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thyroid mass
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 248 (0.81%)
    2 / 284 (0.70%)
    2 / 119 (1.68%)
    0 / 167 (0.00%)
    6 / 818 (0.73%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 2
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gouty arthritis
         subjects affected / exposed
    1 / 248 (0.40%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc disorder
         subjects affected / exposed
    2 / 248 (0.81%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    1 / 119 (0.84%)
    1 / 167 (0.60%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    1 / 248 (0.40%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone cyst
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Groin pain
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    1 / 119 (0.84%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint range of motion decreased
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    1 / 119 (0.84%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mandibular mass
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal stiffness
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteochondrosis
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    1 / 119 (0.84%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal stenosis
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Synovitis
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    10 / 248 (4.03%)
    15 / 284 (5.28%)
    0 / 119 (0.00%)
    19 / 167 (11.38%)
    44 / 818 (5.38%)
         occurrences causally related to treatment / all
    2 / 14
    3 / 18
    0 / 0
    2 / 26
    7 / 58
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 3
    0 / 7
    Sepsis
         subjects affected / exposed
    1 / 248 (0.40%)
    4 / 284 (1.41%)
    1 / 119 (0.84%)
    6 / 167 (3.59%)
    12 / 818 (1.47%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 1
    1 / 8
    1 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 3
    0 / 4
    Cellulitis
         subjects affected / exposed
    3 / 248 (1.21%)
    3 / 284 (1.06%)
    1 / 119 (0.84%)
    1 / 167 (0.60%)
    8 / 818 (0.98%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
    0 / 1
    0 / 1
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 248 (0.81%)
    4 / 284 (1.41%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    7 / 818 (0.86%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 0
    0 / 1
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    2 / 248 (0.81%)
    3 / 284 (1.06%)
    1 / 119 (0.84%)
    0 / 167 (0.00%)
    6 / 818 (0.73%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
    0 / 1
    0 / 0
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    3 / 248 (1.21%)
    3 / 284 (1.06%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    6 / 818 (0.73%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 3
    0 / 0
    0 / 0
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 248 (0.00%)
    4 / 284 (1.41%)
    1 / 119 (0.84%)
    1 / 167 (0.60%)
    6 / 818 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 1
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 248 (0.40%)
    2 / 284 (0.70%)
    1 / 119 (0.84%)
    0 / 167 (0.00%)
    4 / 818 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 1
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 248 (0.40%)
    1 / 284 (0.35%)
    1 / 119 (0.84%)
    0 / 167 (0.00%)
    3 / 818 (0.37%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    1 / 248 (0.40%)
    2 / 284 (0.70%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    3 / 818 (0.37%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
    0 / 0
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    3 / 167 (1.80%)
    3 / 818 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 248 (0.00%)
    2 / 284 (0.70%)
    1 / 119 (0.84%)
    0 / 167 (0.00%)
    3 / 818 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 248 (0.40%)
    2 / 284 (0.70%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    3 / 818 (0.37%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 248 (0.00%)
    2 / 284 (0.70%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
    0 / 0
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 248 (0.00%)
    2 / 284 (0.70%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    1 / 248 (0.40%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine infection
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 248 (0.40%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 248 (0.00%)
    2 / 284 (0.70%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Sinusitis
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    1 / 248 (0.40%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tooth infection
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    2 / 167 (1.20%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis infective
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain abscess
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Catheter bacteraemia
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis of male external genital organ
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dengue fever
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    1 / 119 (0.84%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dermatitis infected
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eczema infected
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterococcal sepsis
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Enterocolitis infectious
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fungal infection
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Gastrointestinal infection
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gingival abscess
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis A
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infected dermal cyst
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Kidney infection
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malaria
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Orchitis
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Perirectal abscess
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngotonsillitis
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia fungal
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Pneumonia necrotising
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pseudomembranous colitis
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pseudomonal sepsis
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary mycosis
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Pyelonephritis
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Salmonella bacteraemia
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Salmonellosis
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Streptococcal sepsis
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 248 (0.81%)
    2 / 284 (0.70%)
    1 / 119 (0.84%)
    3 / 167 (1.80%)
    8 / 818 (0.98%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 1
    1 / 3
    1 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    3 / 167 (1.80%)
    3 / 818 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Gout
         subjects affected / exposed
    1 / 248 (0.40%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    3 / 818 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fluid retention
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    1 / 119 (0.84%)
    0 / 167 (0.00%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    2 / 2
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 248 (0.00%)
    2 / 284 (0.70%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    2 / 818 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acidosis
         subjects affected / exposed
    0 / 248 (0.00%)
    0 / 284 (0.00%)
    0 / 119 (0.00%)
    1 / 167 (0.60%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    Decreased appetite
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 284 (0.35%)
    0 / 119 (0.00%)
    0 / 167 (0.00%)
    1 / 818 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Bosutinib, CP1L Bosutinib, CP2L Bosutinib, CP3L/CP4L Bosutinib, ADV Bosutinib, Total
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    239 / 248 (96.37%)
    283 / 284 (99.65%)
    119 / 119 (100.00%)
    164 / 167 (98.20%)
    805 / 818 (98.41%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    90 / 248 (36.29%)
    67 / 284 (23.59%)
    19 / 119 (15.97%)
    17 / 167 (10.18%)
    193 / 818 (23.59%)
         occurrences all number
    309
    168
    44
    53
    574
    Aspartate aminotransferase increased
         subjects affected / exposed
    74 / 248 (29.84%)
    59 / 284 (20.77%)
    10 / 119 (8.40%)
    17 / 167 (10.18%)
    160 / 818 (19.56%)
         occurrences all number
    183
    124
    14
    42
    363
    Lipase increased
         subjects affected / exposed
    52 / 248 (20.97%)
    29 / 284 (10.21%)
    8 / 119 (6.72%)
    9 / 167 (5.39%)
    98 / 818 (11.98%)
         occurrences all number
    128
    62
    20
    19
    229
    Blood creatinine increased
         subjects affected / exposed
    23 / 248 (9.27%)
    36 / 284 (12.68%)
    16 / 119 (13.45%)
    10 / 167 (5.99%)
    85 / 818 (10.39%)
         occurrences all number
    59
    60
    26
    16
    161
    Weight decreased
         subjects affected / exposed
    16 / 248 (6.45%)
    36 / 284 (12.68%)
    7 / 119 (5.88%)
    9 / 167 (5.39%)
    68 / 818 (8.31%)
         occurrences all number
    27
    42
    7
    11
    87
    Amylase increased
         subjects affected / exposed
    30 / 248 (12.10%)
    18 / 284 (6.34%)
    6 / 119 (5.04%)
    5 / 167 (2.99%)
    59 / 818 (7.21%)
         occurrences all number
    82
    35
    7
    10
    134
    Blood creatine phosphokinase increased
         subjects affected / exposed
    23 / 248 (9.27%)
    18 / 284 (6.34%)
    2 / 119 (1.68%)
    3 / 167 (1.80%)
    46 / 818 (5.62%)
         occurrences all number
    44
    28
    14
    4
    90
    Blood alkaline phosphatase increased
         subjects affected / exposed
    20 / 248 (8.06%)
    10 / 284 (3.52%)
    6 / 119 (5.04%)
    9 / 167 (5.39%)
    45 / 818 (5.50%)
         occurrences all number
    34
    13
    8
    20
    75
    Vascular disorders
    Hypertension
         subjects affected / exposed
    24 / 248 (9.68%)
    30 / 284 (10.56%)
    10 / 119 (8.40%)
    11 / 167 (6.59%)
    75 / 818 (9.17%)
         occurrences all number
    34
    57
    15
    13
    119
    Nervous system disorders
    Headache
         subjects affected / exposed
    41 / 248 (16.53%)
    54 / 284 (19.01%)
    31 / 119 (26.05%)
    30 / 167 (17.96%)
    156 / 818 (19.07%)
         occurrences all number
    68
    140
    55
    44
    307
    Dizziness
         subjects affected / exposed
    25 / 248 (10.08%)
    26 / 284 (9.15%)
    18 / 119 (15.13%)
    21 / 167 (12.57%)
    90 / 818 (11.00%)
         occurrences all number
    37
    43
    26
    21
    127
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    80 / 248 (32.26%)
    117 / 284 (41.20%)
    45 / 119 (37.82%)
    69 / 167 (41.32%)
    311 / 818 (38.02%)
         occurrences all number
    239
    551
    192
    333
    1315
    Anaemia
         subjects affected / exposed
    72 / 248 (29.03%)
    87 / 284 (30.63%)
    28 / 119 (23.53%)
    64 / 167 (38.32%)
    251 / 818 (30.68%)
         occurrences all number
    178
    290
    56
    204
    728
    Neutropenia
         subjects affected / exposed
    35 / 248 (14.11%)
    46 / 284 (16.20%)
    23 / 119 (19.33%)
    35 / 167 (20.96%)
    139 / 818 (16.99%)
         occurrences all number
    87
    154
    67
    117
    425
    Leukopenia
         subjects affected / exposed
    25 / 248 (10.08%)
    37 / 284 (13.03%)
    5 / 119 (4.20%)
    25 / 167 (14.97%)
    92 / 818 (11.25%)
         occurrences all number
    49
    106
    14
    63
    232
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    50 / 248 (20.16%)
    79 / 284 (27.82%)
    17 / 119 (14.29%)
    59 / 167 (35.33%)
    205 / 818 (25.06%)
         occurrences all number
    74
    156
    30
    85
    345
    Fatigue
         subjects affected / exposed
    42 / 248 (16.94%)
    73 / 284 (25.70%)
    27 / 119 (22.69%)
    35 / 167 (20.96%)
    177 / 818 (21.64%)
         occurrences all number
    78
    184
    39
    46
    347
    Asthenia
         subjects affected / exposed
    26 / 248 (10.48%)
    45 / 284 (15.85%)
    10 / 119 (8.40%)
    19 / 167 (11.38%)
    100 / 818 (12.22%)
         occurrences all number
    65
    122
    17
    37
    241
    Oedema peripheral
         subjects affected / exposed
    17 / 248 (6.85%)
    32 / 284 (11.27%)
    13 / 119 (10.92%)
    18 / 167 (10.78%)
    80 / 818 (9.78%)
         occurrences all number
    32
    53
    20
    29
    134
    Pain
         subjects affected / exposed
    7 / 248 (2.82%)
    22 / 284 (7.75%)
    7 / 119 (5.88%)
    12 / 167 (7.19%)
    48 / 818 (5.87%)
         occurrences all number
    10
    34
    16
    17
    77
    Oedema
         subjects affected / exposed
    15 / 248 (6.05%)
    16 / 284 (5.63%)
    4 / 119 (3.36%)
    9 / 167 (5.39%)
    44 / 818 (5.38%)
         occurrences all number
    21
    17
    10
    9
    57
    Chest pain
         subjects affected / exposed
    7 / 248 (2.82%)
    21 / 284 (7.39%)
    4 / 119 (3.36%)
    11 / 167 (6.59%)
    43 / 818 (5.26%)
         occurrences all number
    9
    29
    5
    15
    58
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    177 / 248 (71.37%)
    244 / 284 (85.92%)
    99 / 119 (83.19%)
    124 / 167 (74.25%)
    644 / 818 (78.73%)
         occurrences all number
    786
    2275
    729
    414
    4204
    Nausea
         subjects affected / exposed
    89 / 248 (35.89%)
    132 / 284 (46.48%)
    58 / 119 (48.74%)
    78 / 167 (46.71%)
    357 / 818 (43.64%)
         occurrences all number
    174
    394
    152
    176
    896
    Vomiting
         subjects affected / exposed
    88 / 248 (35.48%)
    106 / 284 (37.32%)
    47 / 119 (39.50%)
    72 / 167 (43.11%)
    313 / 818 (38.26%)
         occurrences all number
    172
    293
    90
    139
    694
    Abdominal pain
         subjects affected / exposed
    39 / 248 (15.73%)
    77 / 284 (27.11%)
    28 / 119 (23.53%)
    34 / 167 (20.36%)
    178 / 818 (21.76%)
         occurrences all number
    72
    168
    70
    56
    366
    Abdominal pain upper
         subjects affected / exposed
    40 / 248 (16.13%)
    59 / 284 (20.77%)
    21 / 119 (17.65%)
    16 / 167 (9.58%)
    136 / 818 (16.63%)
         occurrences all number
    59
    157
    97
    31
    344
    Constipation
         subjects affected / exposed
    18 / 248 (7.26%)
    44 / 284 (15.49%)
    16 / 119 (13.45%)
    28 / 167 (16.77%)
    106 / 818 (12.96%)
         occurrences all number
    25
    73
    29
    42
    169
    Dyspepsia
         subjects affected / exposed
    22 / 248 (8.87%)
    29 / 284 (10.21%)
    12 / 119 (10.08%)
    12 / 167 (7.19%)
    75 / 818 (9.17%)
         occurrences all number
    31
    66
    38
    16
    151
    Toothache
         subjects affected / exposed
    14 / 248 (5.65%)
    19 / 284 (6.69%)
    5 / 119 (4.20%)
    3 / 167 (1.80%)
    41 / 818 (5.01%)
         occurrences all number
    18
    27
    7
    3
    55
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    32 / 248 (12.90%)
    70 / 284 (24.65%)
    26 / 119 (21.85%)
    33 / 167 (19.76%)
    161 / 818 (19.68%)
         occurrences all number
    59
    108
    43
    56
    266
    Dyspnoea
         subjects affected / exposed
    25 / 248 (10.08%)
    34 / 284 (11.97%)
    13 / 119 (10.92%)
    30 / 167 (17.96%)
    102 / 818 (12.47%)
         occurrences all number
    57
    52
    39
    43
    191
    Pleural effusion
         subjects affected / exposed
    26 / 248 (10.48%)
    32 / 284 (11.27%)
    20 / 119 (16.81%)
    14 / 167 (8.38%)
    92 / 818 (11.25%)
         occurrences all number
    58
    67
    58
    25
    208
    Oropharyngeal pain
         subjects affected / exposed
    15 / 248 (6.05%)
    37 / 284 (13.03%)
    11 / 119 (9.24%)
    13 / 167 (7.78%)
    76 / 818 (9.29%)
         occurrences all number
    17
    47
    20
    21
    105
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    65 / 248 (26.21%)
    105 / 284 (36.97%)
    34 / 119 (28.57%)
    52 / 167 (31.14%)
    256 / 818 (31.30%)
         occurrences all number
    140
    217
    61
    86
    504
    Pruritus
         subjects affected / exposed
    20 / 248 (8.06%)
    29 / 284 (10.21%)
    20 / 119 (16.81%)
    10 / 167 (5.99%)
    79 / 818 (9.66%)
         occurrences all number
    25
    51
    31
    23
    130
    Dry skin
         subjects affected / exposed
    10 / 248 (4.03%)
    22 / 284 (7.75%)
    8 / 119 (6.72%)
    4 / 167 (2.40%)
    44 / 818 (5.38%)
         occurrences all number
    12
    33
    12
    4
    61
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    12 / 248 (4.84%)
    10 / 284 (3.52%)
    10 / 119 (8.40%)
    15 / 167 (8.98%)
    47 / 818 (5.75%)
         occurrences all number
    16
    11
    14
    22
    63
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    32 / 248 (12.90%)
    55 / 284 (19.37%)
    21 / 119 (17.65%)
    24 / 167 (14.37%)
    132 / 818 (16.14%)
         occurrences all number
    43
    76
    48
    40
    207
    Back pain
         subjects affected / exposed
    26 / 248 (10.48%)
    43 / 284 (15.14%)
    15 / 119 (12.61%)
    16 / 167 (9.58%)
    100 / 818 (12.22%)
         occurrences all number
    34
    64
    36
    24
    158
    Pain in extremity
         subjects affected / exposed
    23 / 248 (9.27%)
    35 / 284 (12.32%)
    10 / 119 (8.40%)
    19 / 167 (11.38%)
    87 / 818 (10.64%)
         occurrences all number
    35
    59
    24
    31
    149
    Myalgia
         subjects affected / exposed
    16 / 248 (6.45%)
    26 / 284 (9.15%)
    6 / 119 (5.04%)
    14 / 167 (8.38%)
    62 / 818 (7.58%)
         occurrences all number
    19
    37
    7
    17
    80
    Bone pain
         subjects affected / exposed
    11 / 248 (4.44%)
    20 / 284 (7.04%)
    9 / 119 (7.56%)
    11 / 167 (6.59%)
    51 / 818 (6.23%)
         occurrences all number
    14
    25
    12
    13
    64
    Musculoskeletal pain
         subjects affected / exposed
    12 / 248 (4.84%)
    11 / 284 (3.87%)
    12 / 119 (10.08%)
    9 / 167 (5.39%)
    44 / 818 (5.38%)
         occurrences all number
    13
    16
    16
    14
    59
    Muscle spasms
         subjects affected / exposed
    14 / 248 (5.65%)
    14 / 284 (4.93%)
    8 / 119 (6.72%)
    7 / 167 (4.19%)
    43 / 818 (5.26%)
         occurrences all number
    18
    25
    20
    11
    74
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    30 / 248 (12.10%)
    40 / 284 (14.08%)
    14 / 119 (11.76%)
    9 / 167 (5.39%)
    93 / 818 (11.37%)
         occurrences all number
    78
    56
    19
    11
    164
    Upper respiratory tract infection
         subjects affected / exposed
    39 / 248 (15.73%)
    32 / 284 (11.27%)
    12 / 119 (10.08%)
    10 / 167 (5.99%)
    93 / 818 (11.37%)
         occurrences all number
    73
    55
    25
    22
    175
    Influenza
         subjects affected / exposed
    26 / 248 (10.48%)
    30 / 284 (10.56%)
    13 / 119 (10.92%)
    6 / 167 (3.59%)
    75 / 818 (9.17%)
         occurrences all number
    37
    50
    18
    10
    115
    Urinary tract infection
         subjects affected / exposed
    15 / 248 (6.05%)
    31 / 284 (10.92%)
    7 / 119 (5.88%)
    2 / 167 (1.20%)
    55 / 818 (6.72%)
         occurrences all number
    28
    52
    7
    7
    94
    Bronchitis
         subjects affected / exposed
    17 / 248 (6.85%)
    16 / 284 (5.63%)
    7 / 119 (5.88%)
    6 / 167 (3.59%)
    46 / 818 (5.62%)
         occurrences all number
    31
    17
    10
    8
    66
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    23 / 248 (9.27%)
    41 / 284 (14.44%)
    15 / 119 (12.61%)
    21 / 167 (12.57%)
    100 / 818 (12.22%)
         occurrences all number
    34
    61
    22
    32
    149
    Hypophosphataemia
         subjects affected / exposed
    26 / 248 (10.48%)
    12 / 284 (4.23%)
    3 / 119 (2.52%)
    10 / 167 (5.99%)
    51 / 818 (6.23%)
         occurrences all number
    69
    23
    5
    20
    117
    Hypokalaemia
         subjects affected / exposed
    10 / 248 (4.03%)
    16 / 284 (5.63%)
    5 / 119 (4.20%)
    10 / 167 (5.99%)
    41 / 818 (5.01%)
         occurrences all number
    18
    23
    12
    22
    75

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Aug 2016
    Study objectives updated to fulfill a European Medicines Agency (EMA) post-approval requirement for the collection and analysis of the pharmacokinetics (PK) of bosutinib; Extension of bosutinib dosing of all eligible subjects to be studied for at least 10 years; Updated contraception language per current standard operating procedures (SOPs); Study procedures and efficacy assessment sections updated for consistency and allowance for local assessment of molecular response; Updated study conduct plans requiring mutational analysis of the BCR-ABL kinase domain to be performed by a central laboratory; Adverse event and exposure definitions updated per new protocol SOPs: Update to data analysis and statistical methods sections to define diarrhea and PK analyses.
    07 Nov 2016
    Update to exclude subjects from China from the pharmacokinetic (PK) analysis and the centralised testing for mutational analysis of the BCR-ABL kinase domain; Lifestyle guidelines and requirements for contraception updated throughout the protocol for consistency with updated Pfizer SOPs; Adverse event reporting and reporting requirements updated per Pfizer SOPs.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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