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    Clinical Trial Results:
    A Randomized, Double-blind, Placebo-controlled, Multi-center Phase 3 Study of Denosumab as Adjuvant Treatment for Women With Early-stage Breast Cancer at High Risk of Recurrence (D-CARE)

    Summary
    EudraCT number
    		 2009-011299-32
    Trial protocol
    		 PT   HU   GB   ES   CZ   LV   FR   BE   SK   NL   IE   DK   SI   GR   IT   BG   DE  
    Global end of trial date
    26 Mar 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Apr 2019
    First version publication date
    10 Apr 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    20060359
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01077154
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Amgen Inc.
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oaks, CA, United States, 91320
    Public contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Scientific contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    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
    26 Mar 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Mar 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to compare the treatment effect of denosumab with that of placebo on prolonging bone metastasis-free survival in subjects with early-stage breast cancer at high risk of disease recurrence.
    Protection of trial subjects
    This study was conducted in accordance with International Council for Harmonisation (ICH) Good Clinical Practice (GCP) and applicable federal and local regulations/guidelines. The protocol, proposed informed consent form (ICF), other written subject information, and any proposed advertising material was submitted to the Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for written approval before recruitment of subjects in the study and the shipment of investigational product. The investigator was responsible for obtaining written informed consent after the aims, methods, and potential hazards of the study were adequately explained. Informed consent was obtained before any protocol-specific screening procedures and before any investigational product was administered.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Jun 2010
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 373
    Country: Number of subjects enrolled
    Australia: 297
    Country: Number of subjects enrolled
    United Kingdom: 237
    Country: Number of subjects enrolled
    Belgium: 228
    Country: Number of subjects enrolled
    France: 170
    Country: Number of subjects enrolled
    Greece: 103
    Country: Number of subjects enrolled
    Ireland: 75
    Country: Number of subjects enrolled
    Netherlands: 67
    Country: Number of subjects enrolled
    Denmark: 55
    Country: Number of subjects enrolled
    Portugal: 51
    Country: Number of subjects enrolled
    Italy: 46
    Country: Number of subjects enrolled
    Germany: 41
    Country: Number of subjects enrolled
    Israel: 17
    Country: Number of subjects enrolled
    United States: 715
    Country: Number of subjects enrolled
    Canada: 287
    Country: Number of subjects enrolled
    Hungary: 232
    Country: Number of subjects enrolled
    Czech Republic: 121
    Country: Number of subjects enrolled
    Russian Federation: 118
    Country: Number of subjects enrolled
    Poland: 92
    Country: Number of subjects enrolled
    Latvia: 35
    Country: Number of subjects enrolled
    Bulgaria: 35
    Country: Number of subjects enrolled
    Slovakia: 29
    Country: Number of subjects enrolled
    Romania: 17
    Country: Number of subjects enrolled
    Slovenia: 9
    Country: Number of subjects enrolled
    Serbia: 4
    Country: Number of subjects enrolled
    Japan: 262
    Country: Number of subjects enrolled
    India: 174
    Country: Number of subjects enrolled
    Korea, Republic of: 78
    Country: Number of subjects enrolled
    Taiwan: 43
    Country: Number of subjects enrolled
    Philippines: 32
    Country: Number of subjects enrolled
    Hong Kong: 32
    Country: Number of subjects enrolled
    Malaysia: 15
    Country: Number of subjects enrolled
    Brazil: 200
    Country: Number of subjects enrolled
    South Africa: 63
    Country: Number of subjects enrolled
    Mexico: 53
    Country: Number of subjects enrolled
    Chile: 34
    Country: Number of subjects enrolled
    Peru: 28
    Country: Number of subjects enrolled
    Argentina: 22
    Country: Number of subjects enrolled
    Turkey: 19
    Worldwide total number of subjects
    4509
    EEA total number of subjects
    2016
    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)
    3919
    From 65 to 84 years
    588
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled at 407 centers in Australia, Western Europe, Eastern Europe, Israel, North America, Asia, South America, South Africa, and Turkey from 02 June 2010 to 24 August 2012.

    Pre-assignment
    Screening details
    		 Participants were randomized in a 1:1 ratio to 1 of 2 groups. Randomization was stratified based on breast cancer therapy/lymph node (LN) status, hormone receptor status, human epidermal growth factor receptor 2 (HER-2) status, age, and geographic region.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Participants were randomized to receive placebo subcutaneous injections once every 3 or 4 weeks for approximately 6 months followed by placebo subcutaneous injections once every 3 months for 4.5 years.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered subcutaneously for up to 5 years.

    Arm title
    		 Denosumab
    Arm description
    		 Participants were randomized to receive denosumab 120 mg subcutaneous injections once every 3 or 4 weeks for approximately 6 months followed by denosumab 120 mg subcutaneous injections once every 3 months for 4.5 years.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Denosumab
    Investigational medicinal product code
    AMG 162
    Other name
    XGEVA®
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered subcutaneously for up to 5 years.

    Number of subjects in period 1
    		Placebo Denosumab
    Started
    2253
    2256
    Received Study Drug
    2229
    2230
    Completed
    27
    28
    Not completed
    2226
    2228
         Consent withdrawn by subject
    369
    385
         Ineligibility Determined
    10
    14
         Protocol-specified Criteria (Study Ended)
    1524
    1514
         Adverse event, non-fatal
    9
    9
         Protocol Deviation
    1
    -
         Death
    215
    214
         Other
    14
    11
         Administrative Decision
    1
    6
         Lost to follow-up
    43
    35
         Disease Progression
    18
    20
         Noncompliance
    22
    20

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants were randomized to receive placebo subcutaneous injections once every 3 or 4 weeks for approximately 6 months followed by placebo subcutaneous injections once every 3 months for 4.5 years.

    Reporting group title
    Denosumab
    Reporting group description
    		 Participants were randomized to receive denosumab 120 mg subcutaneous injections once every 3 or 4 weeks for approximately 6 months followed by denosumab 120 mg subcutaneous injections once every 3 months for 4.5 years.

    Reporting group values
    		 Placebo Denosumab Total
    Number of subjects
    		 2253 2256 4509
    Age, Customized
    Units: Subjects
        18 - 64 years
    		 1960 1959 3919
        65 - 74 years
    		 259 260 519
        75 - 84 years
    		 33 36 69
        ≥ 85 years
    		 1 1 2
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 51.6 ( 10.6 ) 51.4 ( 10.7 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 2253 2256 4509
        Male
    		 0 0 0
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 1692 1676 3368
        Asian
    		 222 213 435
        Japanese
    		 134 135 269
        Hispanic/Latino
    		 112 135 247
        Black
    		 70 74 144
        Native Hawaiian or Other Pacific Islander
    		 4 3 7
        American Indian or Alaska Native
    		 1 0 1
        Other
    		 18 20 38
    Menopausal Status
    Units: Subjects
        Premenopausal
    		 1165 1195 2360
        Postmenopausal
    		 1088 1061 2149
    Eastern Cooperative Oncology Group (ECOG) Performance Status
    A scale to assess a patient's disease status. 0 = Fully active, able to carry out all pre-disease performance without restriction; 1 = Restricted in physically strenuous activity, ambulatory and able to carry out work of a light nature; 2 = Ambulatory and capable of all self-care, unable to carry out any work activities. Up and about > 50% of waking hours; 3 = Capable of only limited self-care, confined to bed or chair > 50% of waking hours; 4 = Completely disabled, confined to bed or chair; 5 = Dead.
    Units: Subjects
        0 (Fully active)
    		 1913 1922 3835
        1 (Restricted but ambulatory)
    		 340 329 669
        2 (Ambulatory, unable to work)
    		 0 3 3
        Missing
    		 0 2 2
    Breast Cancer Therapy / Lymph Node Status (Strata per Randomization)
    Breast cancer therapy / lymph node (LN) status: a. neo-adjuvant therapy / any LN status; b. adjuvant therapy / LN negative (based on axillary LN dissection, or based on sentinel node [SN] status); c. adjuvant therapy / LN positive
    Units: Subjects
        Neo-adjuvant therapy / any lymph node status
    		 550 552 1102
        Adjuvant therapy / lymph node negative
    		 68 65 133
        Adjuvant therapy / lymph node positive
    		 1635 1639 3274
    Hormone Receptor Status (Strata per Randomization)
    Hormone receptor (estrogen receptor [ER] / progesterone receptor [PR]) status a. ER and/or PR positive b. ER and PR negative
    Units: Subjects
        ER and/or PR positive
    		 1740 1747 3487
        ER and PR negative
    		 513 509 1022
    Human Epidermal Growth Factor Receptor 2 (HER-2) Status (Strata per Randomization)
    Units: Subjects
        HER-2 positive
    		 490 492 982
        HER-2 negative
    		 1763 1764 3527
    Age (Strata per Randomization)
    Units: Subjects
        < 50 years
    		 1026 1029 2055
        ≥ 50 years
    		 1227 1227 2454
    Geographic Region (Strata per Randomization)
    Units: Subjects
        Japan
    		 131 131 262
        Other
    		 2122 2125 4247
    Molecular Subtypes of Breast Cancer
    Hormone receptor (HR; estrogen receptor [ER] / progesterone receptor [PR]); HR positive = ER and/or PR positive; HR negative = ER and PR negative
    Units: Subjects
        HR positive and HER-2 positive
    		 288 286 574
        HR positive and HER-2 negative
    		 1460 1458 2918
        HR negative and HER-2 positive
    		 163 168 331
        HR negative and HER-2 negative
    		 341 343 684
        Missing
    		 1 1 2
    Lymph Node Status
    Clinical and pathologic regional lymph node (LN) status (by American Joint Committee on Cancer (AJCC)): N0 = no LN metastasis or pathologic (p) micrometastases <2.0 mm; N1 = Ipsilateral level I, II axillary (Ax) LN or p micrometastases >2.0mm or in internal mammary (IM) LN; N2 = fixed ipsilateral level I, II Ax LNs or clinically detected IM LNs only or pLN metastases in 4-9 Ax LNs; N3 = ipsilateral level III infraclavicular (IC) LNs or clinically detected IM LNs with other level I/II Ax LNs or supraclavicular (SC) LNs or pLN metastases in ≥10 Ax LNs; NX = LNs cannot be assessed.
    Units: Subjects
        N0
    		 130 131 261
        N1
    		 1369 1381 2750
        N2
    		 506 505 1011
        N3
    		 230 224 454
        Nx
    		 18 15 33
    Breast Cancer Histopathologic Grade
    Tumor grade was determined according to the Nottingham Combined Histological Grading System, based on morphological features (tubule formation, nuclear pleomorphism, and mitotic count), by assigning a value of 1 (favorable) to 3 (unfavorable) for each feature. Scores for the 3 categories were added to give a combined histopathologic grade score: Grade (G)1 (low grade; favorable) = total score of 3, 4, or 5; G2 (intermediate) = total score of 6 or 7; G3 (high; unfavorable) = total score of 8 or 9.
    Units: Subjects
        Grade 1 = Low
    		 222 209 431
        Grade 2 = Intermediate
    		 1015 1079 2094
        Grade 3 = High
    		 938 906 1844
        Not Evaluable/Missing
    		 78 62 140

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants were randomized to receive placebo subcutaneous injections once every 3 or 4 weeks for approximately 6 months followed by placebo subcutaneous injections once every 3 months for 4.5 years.

    Reporting group title
    Denosumab
    Reporting group description
    		 Participants were randomized to receive denosumab 120 mg subcutaneous injections once every 3 or 4 weeks for approximately 6 months followed by denosumab 120 mg subcutaneous injections once every 3 months for 4.5 years.

    Primary: Bone Metastasis-free Survival (BMFS)

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    End point title
    		 Bone Metastasis-free Survival (BMFS)
    End point description
    BMFS time was defined as the time interval from the randomization date to the first occurrence of bone metastasis or death from any cause, whichever came first. Participants last known to be alive with no bone metastasis were censored at their last assessment date, or at the primary analysis data cut-off date, whichever was first. Participants who had first occurrence of bone metastasis before randomization were censored at their randomization date. Bone metastasis must have been confirmed by central imaging analysis or by biopsy, Evidence of disseminated tumor cells in bone marrow was not sufficient for determination of disease recurrence. Development of new primary malignancy in bone was not considered as bone metastasis. Since the median BMSF time could not be estimated due to low number of events, the percentage of participants with an event (i.e., bone metastasis or death) is reported.
    End point type
    Primary
    End point timeframe
    From randomization until the primary analysis data cut-off date of 31 August 2017; median (minimum, maximum) time on study was 67.2 (0.0, 85.9) and 67.0 (0.0, 86.6) months in each treatment group respectively.
    End point values
    		 Placebo Denosumab
    Number of subjects analysed
    2253
    2256
    Units: percentage of participants
        number (confidence interval 95%)
    13.5 (12.1 to 15.0)
    12.9 (11.6 to 14.3)
    Statistical analysis title
    		 Analysis of Bone Metastasis-free Survival
    Statistical analysis description
    The hazard ratio of denosumab compared with placebo and its corresponding 2-sided 95% confidence interval was estimated using a Cox proportional hazards model with treatment groups as the independent variable and stratified by the randomization stratification factors. A hazard ratio < 1 favors denosumab.
    Comparison groups
    Placebo v Denosumab
    Number of subjects included in analysis
    4509
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7 [1]
    Method
    		 Stratified Log Rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.82
         upper limit
    		 1.14
    Notes
    [1] - Log rank test stratified by breast cancer therapy/LN status, hormone receptor status, HER-2 status, age, and geographic region.

    Secondary: Disease-free Survival (DFS)

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    End point title
    		 Disease-free Survival (DFS)
    End point description
    DFS time was defined as the time interval from the randomization date to the date of first observation of disease recurrence or death from any cause, whichever was first. Participants last known to be alive with no disease recurrence were censored at their last assessment date, or at the primary analysis data cut-off date, whichever was first. Participants who had first disease recurrence before randomization were censored at their randomization date. Disease recurrence includes bone metastasis and extraosseous disease (EOD) confirmed by central imaging analysis or by biopsy/cytology. Development of non-breast cancer new primary malignancy was not considered as disease recurrence. Since the median DFS time could not be estimated due to low number of events, the percentage of participants with an event (i.e., disease recurrence or death) is reported.
    End point type
    Secondary
    End point timeframe
    From randomization until the primary analysis data cut-off date of 31 August 2017; median (minimum, maximum) time on study was 67.2 (0.0, 85.9) and 67.0 (0.0, 86.6) months in each treatment group respectively.
    End point values
    		 Placebo Denosumab
    Number of subjects analysed
    2253
    2256
    Units: percentage of participants
        number (confidence interval 95%)
    19.2 (17.6 to 20.8)
    19.6 (18.0 to 21.2)
    Statistical analysis title
    		 Analysis of Disease-free Survival
    Statistical analysis description
    The hazard ratio and its 2-sided 95% CI were estimated using a Cox proportional hazards model with treatment group as the independent variable and stratified by the randomization stratification factors; a hazard ratio < 1 favors denosumab.
    Comparison groups
    Placebo v Denosumab
    Number of subjects included in analysis
    4509
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.57 [2]
    Method
    		 Stratified Log Rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.91
         upper limit
    		 1.19
    Notes
    [2] - Log rank test stratified by breast cancer therapy/LN status, hormone receptor status, HER-2 status, age, and geographic region.

    Secondary: Disease-free Survival (DFS) in the Postmenopausal Subset

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    End point title
    		 Disease-free Survival (DFS) in the Postmenopausal Subset
    End point description
    DFS time was defined as the time interval from the randomization date to the date of first observation of disease recurrence or death from any cause, whichever was first. Participants last known to be alive with no disease recurrence were censored at their last assessment date, or at the primary analysis data cut-off date, whichever was first. Participants who had first disease recurrence before randomization were censored at their randomization date. Disease recurrence includes bone metastasis and extraosseous disease (EOD) confirmed by central imaging analysis or by biopsy/cytology. Development of non-breast cancer new primary malignancy was not considered as disease recurrence. Since the median DFS time in the postmenopausal subset could not be estimated due to low number of events, the percentage of participants with an event (i.e., disease recurrence or death) is reported.
    End point type
    Secondary
    End point timeframe
    From randomization until the primary analysis data cut-off date of 31 August 2017; median (minimum, maximum) time on study was 67.2 (0.0, 85.9) and 67.0 (0.0, 86.6) months in each treatment group respectively.
    End point values
    		 Placebo Denosumab
    Number of subjects analysed
    1088
    1061
    Units: percentage of participants
        number (confidence interval 95%)
    18.6 (16.3 to 20.9)
    20.3 (17.8 to 22.7)
    Statistical analysis title
    		 Analysis of DFS in Postmenopausal Subset
    Statistical analysis description
    The hazard ratio and its 2-sided 95% CI were estimated using a Cox proportional hazards model with treatment group as the independent variable and stratified by the randomization stratification factors; a hazard ratio < 1 favors denosumab.
    Comparison groups
    Placebo v Denosumab
    Number of subjects included in analysis
    2149
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.26 [3]
    Method
    		 Stratified Log Rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.92
         upper limit
    		 1.36
    Notes
    [3] - Log rank test stratified by breast cancer therapy/LN status, hormone receptor status, HER-2 status, age, and geographic region.

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Overall survival (OS) time was defined as the time interval from the randomization date to the date of death from any cause. Participants last known to be alive were censored at their last contact date. Since the median time to overall survival could not be estimated at the time of the final analysis due to low numbers of events, the percentage of participants with an event (i.e., death) is reported.
    End point type
    Secondary
    End point timeframe
    From randomization until the end of study; median (minimum, maximum) time on study was 72.7 (0, 92) and 72.3 (0, 92) months in each treatment group respectively.
    End point values
    		 Placebo Denosumab
    Number of subjects analysed
    2253
    2256
    Units: percentage of participants
        number (confidence interval 95%)
    9.5 (8.3 to 10.8)
    9.5 (8.3 to 10.7)
    Statistical analysis title
    		 Analysis of Overall Survival
    Statistical analysis description
    The hazard ratio and its 2-sided 95% CI were estimated using a Cox proportional hazards model with treatment group as the independent variable and stratified by the randomization stratification factors. A hazard ratio < 1 favors denosumab.
    Comparison groups
    Placebo v Denosumab
    Number of subjects included in analysis
    4509
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.94 [4]
    Method
    		 Stratified Log Rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 1.22
    Notes
    [4] - Log rank test stratified by breast cancer therapy/LN status, hormone receptor status, HER-2 status, age, and geographic region.

    Secondary: Distant Recurrence-free Survival

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    End point title
    		 Distant Recurrence-free Survival
    End point description
    Distant recurrence-free survival (DRFS) was defined as the time interval from the randomization date to the date of first observation of distant disease recurrence or death from any cause, whichever came first. Participants last known to be alive, who had not experienced distant disease recurrence, were censored at their last assessment date, or at the primary analysis data cut-off date, whichever was first. Participants who had first distant recurrence before randomization were censored at their randomization date. Distant disease recurrence includes confirmed bone metastasis and extraosseous disease other than local-regional disease recurrence. Development of non-breast cancer new primary malignancy was not considered as distant disease recurrence. Since the median time to DRFS could not be estimated due to the low number of events, the percentage of participants with an event (i.e., distant recurrence or death) is reported.
    End point type
    Secondary
    End point timeframe
    From randomization until the primary analysis data cut-off date of 31 August 2017; median (minimum, maximum) time on study was 67.2 (0.0, 85.9) and 67.0 (0.0, 86.6) months in each treatment group respectively.
    End point values
    		 Placebo Denosumab
    Number of subjects analysed
    2253
    2256
    Units: percentage of participants
        number (confidence interval 95%)
    18.0 (16.4 to 19.6)
    18.7 (17.1 to 20.3)
    Statistical analysis title
    		 Analysis of Distant Recurrence-free Survival
    Statistical analysis description
    The hazard ratio and its 2-sided 95% CI were estimated using Cox proportional hazards model with treatment group as the independent variable and stratified by the randomization stratification factors. A hazard ratio < 1 favors denosumab.
    Comparison groups
    Placebo v Denosumab
    Number of subjects included in analysis
    4509
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.41 [5]
    Method
    		 Stratified Log Rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.92
         upper limit
    		 1.21
    Notes
    [5] - Log rank test stratified by breast cancer therapy/LN status, hormone receptor status, HER-2 status, age, and geographic region.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug to 30 days after last dose; median time on treatment was 59 months in each arm. Total deaths includes deaths from first dose of study drug to the end of study date; median time on study was 72.5 months overall.
    Adverse event reporting additional description
    Data are reported for all randomized subjects who received ≥ 1 dose of investigational product. Subjects were analyzed according to their actual treatment received; eleven participants randomized to the placebo group received at least 1 dose of denosumab during the study and are counted in the denosumab group for safety analyses.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo subcutaneous injections once every 3 or 4 weeks for approximately 6 months followed by placebo subcutaneous injections once every 3 months for 4.5 years.

    Reporting group title
    Denosumab
    Reporting group description
    		 Participants received denosumab 120 mg subcutaneous injections once every 3 or 4 weeks for approximately 6 months followed by denosumab 120 mg subcutaneous injections once every 3 months for 4.5 years.

    Serious adverse events
    		 Placebo Denosumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    675 / 2218 (30.43%)
    702 / 2241 (31.33%)
         number of deaths (all causes)
    215
    215
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acrochordon
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute leukaemia
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myeloid leukaemia
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Adenocarcinoma
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Adenocarcinoma gastric
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    2 / 2218 (0.09%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenolipoma
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendix cancer
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    B-cell lymphoma
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    B-cell small lymphocytic lymphoma
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    0 / 2218 (0.00%)
    4 / 2241 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign neoplasm of thymus
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign neoplasm of thyroid gland
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder transitional cell carcinoma
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder transitional cell carcinoma stage III
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone neoplasm
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bowen's disease
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain cancer metastatic
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    3 / 2218 (0.14%)
    8 / 2241 (0.36%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 8
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    Breast cancer metastatic
         subjects affected / exposed
    3 / 2218 (0.14%)
    4 / 2241 (0.18%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Breast cancer recurrent
         subjects affected / exposed
    2 / 2218 (0.09%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    0 / 2218 (0.00%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest wall tumour
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic myeloid leukaemia
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    5 / 2218 (0.23%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Colorectal adenocarcinoma
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial adenocarcinoma
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial adenoma
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial cancer
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial cancer stage I
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial stromal sarcoma
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extranodal marginal zone B-cell lymphoma (MALT type)
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fallopian tube cancer
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastric neoplasm
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic cancer
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatocellular carcinoma
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal metastasis
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intraductal proliferative breast lesion
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine benign neoplasm
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leiomyoma
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leiomyosarcoma
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leiomyosarcoma metastatic
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    3 / 2218 (0.14%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Lung adenocarcinoma stage IV
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lung cancer metastatic
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphangiosis carcinomatosa
         subjects affected / exposed
    2 / 2218 (0.09%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    2 / 2218 (0.09%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma stage III
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant neoplasm of thorax
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Malignant neoplasm progression
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant pleural effusion
         subjects affected / exposed
    3 / 2218 (0.14%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningioma
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to breast
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    17 / 2218 (0.77%)
    15 / 2241 (0.67%)
         occurrences causally related to treatment / all
    0 / 20
    0 / 17
         deaths causally related to treatment / all
    0 / 4
    0 / 4
    Metastases to liver
         subjects affected / exposed
    4 / 2218 (0.18%)
    3 / 2241 (0.13%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to lung
         subjects affected / exposed
    4 / 2218 (0.18%)
    7 / 2241 (0.31%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 7
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metastases to lymph nodes
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to meninges
         subjects affected / exposed
    3 / 2218 (0.14%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Metastases to ovary
         subjects affected / exposed
    2 / 2218 (0.09%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to peritoneum
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metastases to skin
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic neoplasm
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuroendocrine carcinoma
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-small cell lung cancer stage I
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal neoplasm
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian adenoma
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cancer
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cancer stage III
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ovarian epithelial cancer
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian neoplasm
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paget's disease of the vulva
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Papillary thyroid cancer
         subjects affected / exposed
    2 / 2218 (0.09%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraneoplastic syndrome
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Parathyroid tumour benign
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal adenocarcinoma
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal cancer
         subjects affected / exposed
    1 / 2218 (0.05%)
    3 / 2241 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cancer
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cancer stage I
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    0 / 2218 (0.00%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retro-orbital neoplasm
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestine carcinoma
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of the cervix
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thymoma
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroid cancer
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroid neoplasm
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    5 / 2218 (0.23%)
    5 / 2241 (0.22%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Astrocytoma
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Papilloma
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic stenosis
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteritis
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brachiocephalic vein thrombosis
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    12 / 2218 (0.54%)
    9 / 2241 (0.40%)
         occurrences causally related to treatment / all
    0 / 12
    1 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism arterial
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism venous
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    3 / 2218 (0.14%)
    3 / 2241 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    6 / 2218 (0.27%)
    7 / 2241 (0.31%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intermittent claudication
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphocele
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphoedema
         subjects affected / exposed
    2 / 2218 (0.09%)
    5 / 2241 (0.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery stenosis
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery thrombosis
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral vascular disorder
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Phlebitis
         subjects affected / exposed
    2 / 2218 (0.09%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subclavian artery thrombosis
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subclavian vein thrombosis
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superior vena cava syndrome
         subjects affected / exposed
    1 / 2218 (0.05%)
    3 / 2241 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis superficial
         subjects affected / exposed
    3 / 2218 (0.14%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    2 / 2218 (0.09%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varicose vein
         subjects affected / exposed
    1 / 2218 (0.05%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vena cava thrombosis
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Ankle arthroplasty
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast conserving surgery
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast operation
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast reconstruction
         subjects affected / exposed
    2 / 2218 (0.09%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cancer surgery
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter removal
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervical polypectomy
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystectomy
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hysterectomy
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incisional drainage
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mammoplasty
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oophorectomy bilateral
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salpingo-oophorectomy bilateral
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine dilation and curettage
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mastectomy
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Foetal death
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Adverse drug reaction
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Application site pain
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    3 / 2218 (0.14%)
    3 / 2241 (0.13%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRCA2 gene mutation
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast complication associated with device
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Capsular contracture associated with breast implant
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site haematoma
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    1 / 2218 (0.05%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    6 / 2218 (0.27%)
    5 / 2241 (0.22%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    2 / 2218 (0.09%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Complication associated with device
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Disease progression
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Drug intolerance
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extravasation
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    4 / 2218 (0.18%)
    4 / 2241 (0.18%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    3 / 2218 (0.14%)
    3 / 2241 (0.13%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Generalised oedema
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Granuloma
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Idiosyncratic drug reaction
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired healing
         subjects affected / exposed
    3 / 2218 (0.14%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incarcerated hernia
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inflammation
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    0 / 2218 (0.00%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion site extravasation
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 2218 (0.05%)
    7 / 2241 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    4 / 2218 (0.18%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    4 / 2218 (0.18%)
    6 / 2241 (0.27%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    2 / 2218 (0.09%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 2218 (0.05%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral swelling
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudocyst
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    33 / 2218 (1.49%)
    37 / 2241 (1.65%)
         occurrences causally related to treatment / all
    1 / 40
    4 / 42
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    3 / 2218 (0.14%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Allergy to vaccine
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    2 / 2218 (0.09%)
    3 / 2241 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reaction to preservatives
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Bartholin's cyst
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast haematoma
         subjects affected / exposed
    1 / 2218 (0.05%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast inflammation
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast mass
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast necrosis
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast pain
         subjects affected / exposed
    2 / 2218 (0.09%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervical dysplasia
         subjects affected / exposed
    2 / 2218 (0.09%)
    3 / 2241 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystocele
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysfunctional uterine bleeding
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial disorder
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial hyperplasia
         subjects affected / exposed
    4 / 2218 (0.18%)
    7 / 2241 (0.31%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometriosis
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Genital haemorrhage
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Genital prolapse
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic ovarian cyst
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Menometrorrhagia
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Menopausal symptoms
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Menorrhagia
         subjects affected / exposed
    2 / 2218 (0.09%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metrorrhagia
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    7 / 2218 (0.32%)
    3 / 2241 (0.13%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian enlargement
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic pain
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postmenopausal haemorrhage
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine polyp
         subjects affected / exposed
    2 / 2218 (0.09%)
    3 / 2241 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine prolapse
         subjects affected / exposed
    4 / 2218 (0.18%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    3 / 2218 (0.14%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Asthma
         subjects affected / exposed
    4 / 2218 (0.18%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    0 / 2218 (0.00%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 2218 (0.00%)
    3 / 2241 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    1 / 2218 (0.05%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    10 / 2218 (0.45%)
    13 / 2241 (0.58%)
         occurrences causally related to treatment / all
    0 / 11
    1 / 13
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    Dyspnoea at rest
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    2 / 2218 (0.09%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperventilation
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    2 / 2218 (0.09%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngospasm
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infiltration
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstructive airways disorder
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Organising pneumonia
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    5 / 2218 (0.23%)
    4 / 2241 (0.18%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    2 / 2218 (0.09%)
    6 / 2241 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    2 / 2218 (0.09%)
    3 / 2241 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Productive cough
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    20 / 2218 (0.90%)
    17 / 2241 (0.76%)
         occurrences causally related to treatment / all
    0 / 21
    2 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary mass
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    7 / 2218 (0.32%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    1 / 8
    0 / 2
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    Vocal cord polyp
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Alcoholism
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    0 / 2218 (0.00%)
    7 / 2241 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anxiety disorder
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Confusional state
         subjects affected / exposed
    3 / 2218 (0.14%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depressed mood
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    2 / 2218 (0.09%)
    8 / 2241 (0.36%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypomania
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Insomnia
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mania
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Persistent depressive disorder
         subjects affected / exposed
    2 / 2218 (0.09%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychomotor retardation
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Restlessness
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    1 / 2218 (0.05%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device expulsion
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device failure
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary colic
         subjects affected / exposed
    2 / 2218 (0.09%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    3 / 2218 (0.14%)
    6 / 2241 (0.27%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    4 / 2218 (0.18%)
    3 / 2241 (0.13%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    4 / 2218 (0.18%)
    5 / 2241 (0.22%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gallbladder non-functioning
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    2 / 2218 (0.09%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Hepatic function abnormal
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic steatosis
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatocellular injury
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatomegaly
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperplastic cholecystopathy
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Body temperature increased
         subjects affected / exposed
    2 / 2218 (0.09%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone scan abnormal
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac murmur
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    2 / 2218 (0.09%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibrin D dimer increased
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    2 / 2218 (0.09%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    International normalised ratio increased
         subjects affected / exposed
    0 / 2218 (0.00%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    0 / 2218 (0.00%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count abnormal
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    2 / 2218 (0.09%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oestradiol increased
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oxygen saturation decreased
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stroke volume increased
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Abdominal wound dehiscence
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Accidental overdose
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acetabulum fracture
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alcohol poisoning
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cartilage injury
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    2 / 2218 (0.09%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Exposure to radiation
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    2 / 2218 (0.09%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    3 / 2218 (0.14%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 2218 (0.00%)
    3 / 2241 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    6 / 2218 (0.27%)
    3 / 2241 (0.13%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    0 / 2218 (0.00%)
    3 / 2241 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    0 / 2218 (0.00%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Graft complication
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    2 / 2218 (0.09%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incision site pain
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intentional overdose
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament sprain
         subjects affected / exposed
    2 / 2218 (0.09%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle strain
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax traumatic
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Poisoning
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural complication
         subjects affected / exposed
    2 / 2218 (0.09%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haematoma
         subjects affected / exposed
    0 / 2218 (0.00%)
    3 / 2241 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural inflammation
         subjects affected / exposed
    0 / 2218 (0.00%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postmastectomy lymphoedema syndrome
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative renal failure
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative thrombosis
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound complication
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural complication
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pubis fracture
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiation injury
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiation mastitis
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiation pneumonitis
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    6 / 2218 (0.27%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 2218 (0.00%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Scapula fracture
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seroma
         subjects affected / exposed
    6 / 2218 (0.27%)
    5 / 2241 (0.22%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin flap necrosis
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Synovial rupture
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thermal burn
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    2 / 2218 (0.09%)
    3 / 2241 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    1 / 2218 (0.05%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    4 / 2218 (0.18%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrong drug administered
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    3 / 2218 (0.14%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriospasm coronary
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    6 / 2218 (0.27%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial thrombosis
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac aneurysm
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    4 / 2218 (0.18%)
    4 / 2241 (0.18%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 2218 (0.00%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Cardiogenic shock
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 2218 (0.00%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic cardiomyopathy
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    4 / 2218 (0.18%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    1 / 2218 (0.05%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis constrictive
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 2218 (0.00%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    2 / 2218 (0.09%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachyarrhythmia
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    5 / 2218 (0.23%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    2 / 2218 (0.09%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ataxia
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    1 / 2218 (0.05%)
    3 / 2241 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carpal tunnel syndrome
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebellar ataxia
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebellar infarction
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral disorder
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    3 / 2218 (0.14%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrospinal fistula
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    6 / 2218 (0.27%)
    5 / 2241 (0.22%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cervical radiculopathy
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coma hepatic
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dementia
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dementia with Lewy bodies
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    1 / 2218 (0.05%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Dizziness
         subjects affected / exposed
    4 / 2218 (0.18%)
    3 / 2241 (0.13%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dystonia
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 2218 (0.00%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial neuralgia
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial paralysis
         subjects affected / exposed
    2 / 2218 (0.09%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    3 / 2218 (0.14%)
    10 / 2241 (0.45%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 2218 (0.00%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Intracranial aneurysm
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 2218 (0.00%)
    3 / 2241 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myoclonus
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurological symptom
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Occipital neuralgia
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychomotor hyperactivity
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ruptured cerebral aneurysm
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    4 / 2218 (0.18%)
    5 / 2241 (0.22%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superior sagittal sinus thrombosis
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    9 / 2218 (0.41%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombotic stroke
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    4 / 2218 (0.18%)
    3 / 2241 (0.13%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Trigeminal nerve disorder
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Visual field defect
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    IIIrd nerve paralysis
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nerve root compression
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Agranulocytosis
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    12 / 2218 (0.54%)
    17 / 2241 (0.76%)
         occurrences causally related to treatment / all
    1 / 13
    0 / 19
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Anaemia megaloblastic
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone marrow failure
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    114 / 2218 (5.14%)
    83 / 2241 (3.70%)
         occurrences causally related to treatment / all
    4 / 128
    1 / 98
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune thrombocytopenic purpura
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    3 / 2218 (0.14%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    5 / 2218 (0.23%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    36 / 2218 (1.62%)
    35 / 2241 (1.56%)
         occurrences causally related to treatment / all
    3 / 43
    1 / 39
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    4 / 2218 (0.18%)
    3 / 2241 (0.13%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    5 / 2218 (0.23%)
    6 / 2241 (0.27%)
         occurrences causally related to treatment / all
    0 / 5
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear pain
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    External ear disorder
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tinnitus
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertigo
         subjects affected / exposed
    0 / 2218 (0.00%)
    5 / 2241 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertigo positional
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Angle closure glaucoma
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blindness
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cataract
         subjects affected / exposed
    5 / 2218 (0.23%)
    5 / 2241 (0.22%)
         occurrences causally related to treatment / all
    3 / 5
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diplopia
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Macular hole
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal artery occlusion
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    0 / 2218 (0.00%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinopathy proliferative
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vision blurred
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vitreous haematoma
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vitreous haemorrhage
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal incarcerated hernia
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    2 / 2218 (0.09%)
    6 / 2241 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    3 / 2218 (0.14%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 2218 (0.00%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fissure
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal prolapse
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 2218 (0.00%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic gastritis
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 2218 (0.05%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 2218 (0.09%)
    4 / 2241 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Crohn's disease
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dental caries
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    24 / 2218 (1.08%)
    15 / 2241 (0.67%)
         occurrences causally related to treatment / all
    0 / 25
    2 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulum intestinal
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal obstruction
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis haemorrhagic
         subjects affected / exposed
    2 / 2218 (0.09%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral hernia
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric disorder
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric polyps
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 2218 (0.00%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    2 / 2218 (0.09%)
    3 / 2241 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorder
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 2218 (0.05%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gingival pain
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids thrombosed
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hiatus hernia
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal haemorrhage
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal haemorrhage
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mouth ulceration
         subjects affected / exposed
    0 / 2218 (0.00%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    10 / 2218 (0.45%)
    18 / 2241 (0.80%)
         occurrences causally related to treatment / all
    0 / 10
    2 / 24
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Necrotising colitis
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Obstructive pancreatitis
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal spasm
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal stenosis
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 2218 (0.05%)
    3 / 2241 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis chronic
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal prolapse
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    2 / 2218 (0.09%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 2218 (0.05%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    13 / 2218 (0.59%)
    24 / 2241 (1.07%)
         occurrences causally related to treatment / all
    0 / 14
    2 / 31
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erythema
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lichen sclerosus
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Onycholysis
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain of skin
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash papular
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Segmented hyalinising vasculitis
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    0 / 2218 (0.00%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxic skin eruption
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    3 / 2218 (0.14%)
    6 / 2241 (0.27%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder perforation
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus bladder
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysuria
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 2218 (0.00%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrocalcinosis
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    3 / 2218 (0.14%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteric stenosis
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary incontinence
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroiditis acute
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 2218 (0.05%)
    6 / 2241 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    6 / 2218 (0.27%)
    3 / 2241 (0.13%)
         occurrences causally related to treatment / all
    1 / 7
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot deformity
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    2 / 2218 (0.09%)
    6 / 2241 (0.27%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaw disorder
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint instability
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle haemorrhage
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle spasms
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 2218 (0.05%)
    3 / 2241 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 2218 (0.05%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    4 / 2218 (0.18%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteitis
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    4 / 2218 (0.18%)
    6 / 2241 (0.27%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteochondritis
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteochondrosis
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    0 / 2218 (0.00%)
    30 / 2241 (1.34%)
         occurrences causally related to treatment / all
    0 / 0
    29 / 31
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 2218 (0.05%)
    3 / 2241 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in jaw
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periarthritis
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periostitis
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue necrosis
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Synovial cyst
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Synovitis
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon disorder
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tenosynovitis stenosans
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    2 / 2218 (0.09%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendiceal abscess
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    3 / 2218 (0.14%)
    7 / 2241 (0.31%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    0 / 2218 (0.00%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 2218 (0.05%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    1 / 2218 (0.05%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bartholinitis
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast abscess
         subjects affected / exposed
    3 / 2218 (0.14%)
    5 / 2241 (0.22%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cellulitis
         subjects affected / exposed
    18 / 2218 (0.81%)
    20 / 2241 (0.89%)
         occurrences causally related to treatment / all
    2 / 20
    0 / 22
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    3 / 2218 (0.14%)
    4 / 2241 (0.18%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bursitis infective
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Campylobacter gastroenteritis
         subjects affected / exposed
    0 / 2218 (0.00%)
    3 / 2241 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site infection
         subjects affected / exposed
    2 / 2218 (0.09%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    30 / 2218 (1.35%)
    34 / 2241 (1.52%)
         occurrences causally related to treatment / all
    0 / 33
    2 / 42
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis staphylococcal
         subjects affected / exposed
    2 / 2218 (0.09%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis streptococcal
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest wall abscess
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridial infection
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium colitis
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    2 / 2218 (0.09%)
    3 / 2241 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    2 / 2218 (0.09%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colonic abscess
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    2 / 2218 (0.09%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dengue fever
         subjects affected / exposed
    0 / 2218 (0.00%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    10 / 2218 (0.45%)
    3 / 2241 (0.13%)
         occurrences causally related to treatment / all
    1 / 11
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    8 / 2218 (0.36%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    4 / 2218 (0.18%)
    14 / 2241 (0.62%)
         occurrences causally related to treatment / all
    1 / 5
    1 / 19
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelothrix infection
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    2 / 2218 (0.09%)
    4 / 2241 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fungal skin infection
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    3 / 2218 (0.14%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis salmonella
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Genital herpes simplex
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    H1N1 influenza
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemophilus infection
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis B
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis C
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    2 / 2218 (0.09%)
    4 / 2241 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected fistula
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected seroma
         subjects affected / exposed
    0 / 2218 (0.00%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    2 / 2218 (0.09%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious colitis
         subjects affected / exposed
    0 / 2218 (0.00%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    5 / 2218 (0.23%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral discitis
         subjects affected / exposed
    0 / 2218 (0.00%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Labyrinthitis
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    3 / 2218 (0.14%)
    6 / 2241 (0.27%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection bacterial
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphangitis
         subjects affected / exposed
    3 / 2218 (0.14%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mastitis
         subjects affected / exposed
    8 / 2218 (0.36%)
    12 / 2241 (0.54%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mastitis bacterial
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis aseptic
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mycobacterial infection
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Necrotising fasciitis
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic infection
         subjects affected / exposed
    2 / 2218 (0.09%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    14 / 2218 (0.63%)
    15 / 2241 (0.67%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal candidiasis
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ophthalmic herpes zoster
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    2 / 2218 (0.09%)
    3 / 2241 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis chronic
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic inflammatory disease
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericoronitis
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perirectal abscess
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritoneal abscess
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periumbilical abscess
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngeal abscess
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    2 / 2218 (0.09%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis streptococcal
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    30 / 2218 (1.35%)
    27 / 2241 (1.20%)
         occurrences causally related to treatment / all
    0 / 32
    2 / 29
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 2218 (0.00%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia haemophilus
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia klebsiella
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia staphylococcal
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia streptococcal
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural cellulitis
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    1 / 2218 (0.05%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative abscess
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    9 / 2218 (0.41%)
    7 / 2241 (0.31%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonal sepsis
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 2218 (0.00%)
    5 / 2241 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 2218 (0.05%)
    4 / 2241 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 2218 (0.05%)
    3 / 2241 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sebaceous gland infection
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    11 / 2218 (0.50%)
    3 / 2241 (0.13%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Septic shock
         subjects affected / exposed
    2 / 2218 (0.09%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sinusitis
         subjects affected / exposed
    1 / 2218 (0.05%)
    3 / 2241 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    2 / 2218 (0.09%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    2 / 2218 (0.09%)
    4 / 2241 (0.18%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal skin infection
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal sepsis
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    1 / 2218 (0.05%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth infection
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    9 / 2218 (0.41%)
    7 / 2241 (0.31%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection bacterial
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    13 / 2218 (0.59%)
    6 / 2241 (0.27%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    2 / 2218 (0.09%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection pseudomonal
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    3 / 2218 (0.14%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vestibular neuronitis
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    2 / 2218 (0.09%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    3 / 2218 (0.14%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vulval abscess
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vulvovaginal candidiasis
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    2 / 2218 (0.09%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection bacterial
         subjects affected / exposed
    3 / 2218 (0.14%)
    6 / 2241 (0.27%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection staphylococcal
         subjects affected / exposed
    3 / 2218 (0.14%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis escherichia
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 2218 (0.05%)
    3 / 2241 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    8 / 2218 (0.36%)
    16 / 2241 (0.71%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 2218 (0.05%)
    2 / 2241 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid overload
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    2 / 2218 (0.09%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    3 / 2218 (0.14%)
    5 / 2241 (0.22%)
         occurrences causally related to treatment / all
    2 / 3
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 2218 (0.05%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 2218 (0.05%)
    6 / 2241 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 2218 (0.05%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    2 / 2218 (0.09%)
    0 / 2241 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vitamin D deficiency
         subjects affected / exposed
    0 / 2218 (0.00%)
    1 / 2241 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Denosumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2123 / 2218 (95.72%)
    2149 / 2241 (95.89%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    645 / 2218 (29.08%)
    669 / 2241 (29.85%)
         occurrences all number
    859
    929
    Hypertension
         subjects affected / exposed
    209 / 2218 (9.42%)
    195 / 2241 (8.70%)
         occurrences all number
    275
    267
    Lymphoedema
         subjects affected / exposed
    350 / 2218 (15.78%)
    392 / 2241 (17.49%)
         occurrences all number
    443
    498
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    404 / 2218 (18.21%)
    407 / 2241 (18.16%)
         occurrences all number
    806
    796
    Fatigue
         subjects affected / exposed
    893 / 2218 (40.26%)
    901 / 2241 (40.21%)
         occurrences all number
    1638
    1724
    Influenza like illness
         subjects affected / exposed
    145 / 2218 (6.54%)
    154 / 2241 (6.87%)
         occurrences all number
    220
    284
    Mucosal inflammation
         subjects affected / exposed
    278 / 2218 (12.53%)
    281 / 2241 (12.54%)
         occurrences all number
    372
    373
    Oedema
         subjects affected / exposed
    112 / 2218 (5.05%)
    106 / 2241 (4.73%)
         occurrences all number
    131
    113
    Oedema peripheral
         subjects affected / exposed
    397 / 2218 (17.90%)
    380 / 2241 (16.96%)
         occurrences all number
    534
    498
    Pain
         subjects affected / exposed
    178 / 2218 (8.03%)
    156 / 2241 (6.96%)
         occurrences all number
    210
    190
    Pyrexia
         subjects affected / exposed
    342 / 2218 (15.42%)
    338 / 2241 (15.08%)
         occurrences all number
    474
    458
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    189 / 2218 (8.52%)
    178 / 2241 (7.94%)
         occurrences all number
    218
    236
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    426 / 2218 (19.21%)
    410 / 2241 (18.30%)
         occurrences all number
    549
    557
    Dyspnoea
         subjects affected / exposed
    268 / 2218 (12.08%)
    280 / 2241 (12.49%)
         occurrences all number
    363
    369
    Epistaxis
         subjects affected / exposed
    151 / 2218 (6.81%)
    168 / 2241 (7.50%)
         occurrences all number
    176
    192
    Oropharyngeal pain
         subjects affected / exposed
    176 / 2218 (7.94%)
    157 / 2241 (7.01%)
         occurrences all number
    199
    186
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    207 / 2218 (9.33%)
    220 / 2241 (9.82%)
         occurrences all number
    248
    277
    Depression
         subjects affected / exposed
    202 / 2218 (9.11%)
    195 / 2241 (8.70%)
         occurrences all number
    245
    236
    Insomnia
         subjects affected / exposed
    432 / 2218 (19.48%)
    429 / 2241 (19.14%)
         occurrences all number
    531
    538
    Investigations
    Weight increased
         subjects affected / exposed
    151 / 2218 (6.81%)
    167 / 2241 (7.45%)
         occurrences all number
    236
    296
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    161 / 2218 (7.26%)
    170 / 2241 (7.59%)
         occurrences all number
    237
    231
    Radiation skin injury
         subjects affected / exposed
    351 / 2218 (15.83%)
    361 / 2241 (16.11%)
         occurrences all number
    419
    432
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    255 / 2218 (11.50%)
    273 / 2241 (12.18%)
         occurrences all number
    336
    367
    Dysgeusia
         subjects affected / exposed
    344 / 2218 (15.51%)
    351 / 2241 (15.66%)
         occurrences all number
    460
    473
    Headache
         subjects affected / exposed
    567 / 2218 (25.56%)
    527 / 2241 (23.52%)
         occurrences all number
    957
    844
    Hypoaesthesia
         subjects affected / exposed
    112 / 2218 (5.05%)
    112 / 2241 (5.00%)
         occurrences all number
    137
    156
    Neuropathy peripheral
         subjects affected / exposed
    421 / 2218 (18.98%)
    417 / 2241 (18.61%)
         occurrences all number
    576
    584
    Paraesthesia
         subjects affected / exposed
    197 / 2218 (8.88%)
    216 / 2241 (9.64%)
         occurrences all number
    254
    271
    Peripheral sensory neuropathy
         subjects affected / exposed
    177 / 2218 (7.98%)
    198 / 2241 (8.84%)
         occurrences all number
    249
    289
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    349 / 2218 (15.73%)
    354 / 2241 (15.80%)
         occurrences all number
    677
    664
    Leukopenia
         subjects affected / exposed
    154 / 2218 (6.94%)
    145 / 2241 (6.47%)
         occurrences all number
    338
    319
    Neutropenia
         subjects affected / exposed
    461 / 2218 (20.78%)
    441 / 2241 (19.68%)
         occurrences all number
    826
    920
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    243 / 2218 (10.96%)
    195 / 2241 (8.70%)
         occurrences all number
    276
    218
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    242 / 2218 (10.91%)
    232 / 2241 (10.35%)
         occurrences all number
    320
    296
    Abdominal pain upper
         subjects affected / exposed
    199 / 2218 (8.97%)
    179 / 2241 (7.99%)
         occurrences all number
    248
    218
    Constipation
         subjects affected / exposed
    635 / 2218 (28.63%)
    626 / 2241 (27.93%)
         occurrences all number
    958
    903
    Diarrhoea
         subjects affected / exposed
    638 / 2218 (28.76%)
    660 / 2241 (29.45%)
         occurrences all number
    1011
    1112
    Dyspepsia
         subjects affected / exposed
    245 / 2218 (11.05%)
    273 / 2241 (12.18%)
         occurrences all number
    317
    367
    Nausea
         subjects affected / exposed
    1095 / 2218 (49.37%)
    1145 / 2241 (51.09%)
         occurrences all number
    2210
    2327
    Stomatitis
         subjects affected / exposed
    398 / 2218 (17.94%)
    399 / 2241 (17.80%)
         occurrences all number
    596
    624
    Toothache
         subjects affected / exposed
    159 / 2218 (7.17%)
    198 / 2241 (8.84%)
         occurrences all number
    184
    236
    Vomiting
         subjects affected / exposed
    536 / 2218 (24.17%)
    536 / 2241 (23.92%)
         occurrences all number
    865
    882
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    923 / 2218 (41.61%)
    938 / 2241 (41.86%)
         occurrences all number
    1129
    1158
    Dermatitis
         subjects affected / exposed
    112 / 2218 (5.05%)
    107 / 2241 (4.77%)
         occurrences all number
    132
    134
    Dry skin
         subjects affected / exposed
    133 / 2218 (6.00%)
    125 / 2241 (5.58%)
         occurrences all number
    143
    145
    Erythema
         subjects affected / exposed
    226 / 2218 (10.19%)
    260 / 2241 (11.60%)
         occurrences all number
    255
    315
    Nail disorder
         subjects affected / exposed
    264 / 2218 (11.90%)
    275 / 2241 (12.27%)
         occurrences all number
    303
    328
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    114 / 2218 (5.14%)
    138 / 2241 (6.16%)
         occurrences all number
    152
    201
    Pruritus
         subjects affected / exposed
    181 / 2218 (8.16%)
    144 / 2241 (6.43%)
         occurrences all number
    223
    159
    Rash
         subjects affected / exposed
    372 / 2218 (16.77%)
    392 / 2241 (17.49%)
         occurrences all number
    514
    540
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    974 / 2218 (43.91%)
    973 / 2241 (43.42%)
         occurrences all number
    1799
    1787
    Back pain
         subjects affected / exposed
    486 / 2218 (21.91%)
    563 / 2241 (25.12%)
         occurrences all number
    657
    823
    Bone pain
         subjects affected / exposed
    256 / 2218 (11.54%)
    288 / 2241 (12.85%)
         occurrences all number
    342
    422
    Muscle spasms
         subjects affected / exposed
    204 / 2218 (9.20%)
    201 / 2241 (8.97%)
         occurrences all number
    247
    253
    Musculoskeletal chest pain
         subjects affected / exposed
    143 / 2218 (6.45%)
    129 / 2241 (5.76%)
         occurrences all number
    179
    154
    Musculoskeletal pain
         subjects affected / exposed
    308 / 2218 (13.89%)
    337 / 2241 (15.04%)
         occurrences all number
    431
    444
    Myalgia
         subjects affected / exposed
    539 / 2218 (24.30%)
    553 / 2241 (24.68%)
         occurrences all number
    838
    910
    Neck pain
         subjects affected / exposed
    112 / 2218 (5.05%)
    106 / 2241 (4.73%)
         occurrences all number
    132
    118
    Pain in extremity
         subjects affected / exposed
    545 / 2218 (24.57%)
    570 / 2241 (25.44%)
         occurrences all number
    815
    871
    Pain in jaw
         subjects affected / exposed
    124 / 2218 (5.59%)
    150 / 2241 (6.69%)
         occurrences all number
    146
    182
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    112 / 2218 (5.05%)
    86 / 2241 (3.84%)
         occurrences all number
    134
    112
    Influenza
         subjects affected / exposed
    117 / 2218 (5.28%)
    117 / 2241 (5.22%)
         occurrences all number
    143
    138
    Nasopharyngitis
         subjects affected / exposed
    290 / 2218 (13.07%)
    292 / 2241 (13.03%)
         occurrences all number
    521
    486
    Sinusitis
         subjects affected / exposed
    101 / 2218 (4.55%)
    113 / 2241 (5.04%)
         occurrences all number
    136
    149
    Upper respiratory tract infection
         subjects affected / exposed
    195 / 2218 (8.79%)
    206 / 2241 (9.19%)
         occurrences all number
    265
    283
    Urinary tract infection
         subjects affected / exposed
    149 / 2218 (6.72%)
    177 / 2241 (7.90%)
         occurrences all number
    211
    252
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    289 / 2218 (13.03%)
    330 / 2241 (14.73%)
         occurrences all number
    427
    486
    Hypocalcaemia
         subjects affected / exposed
    73 / 2218 (3.29%)
    135 / 2241 (6.02%)
         occurrences all number
    95
    181

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 May 2011
    - window for screening imaging assessments to document disease extent was increased from 12 to 24 weeks - a second formal interim analysis was added in consideration of the length of time anticipated to reach the primary analysis date - amount of time expected to reach the primary analysis data cutoff date was modified - number of centers was increased from 400 to 500 centers globally - breast density measurements were included as an exploratory outcome (objective and endpoint) for the study
    15 Aug 2012
    - collection of skeletal-related event information was extended through the long-term follow-up - objectives and endpoints for skeletal-related events and bone metastasis were modified - fasting requirement from the urine collection for urinary N-telopeptide of type I collagen was removed
    18 Mar 2015
    - disease-free survival in the postmenopausal subset as a secondary endpoint was added - hazard ratio of denosumab compared with placebo was added for the postmenopausal subset - pathological variables in tumor tissue from neoadjuvant subjects after surgery was added as an exploratory objective - numbers of subjects with events (any disease recurrence or died, whichever comes last) required for the interim and final analyses was updated - period of time for which subjects must not become pregnant or breastfeed after the end of treatment was updated - duration of the study was changed based on the change in the expected/projected time to primary analysis - atypical femoral fracture was included as an adverse event of interest with adjudication by an independent panel of experts - covariates explored in relation to the primary and secondary efficacy endpoints were updated; primary tumor size and lymph node status were added to the list of covariates - expected event rates at 3 years for bone metastasis-free survival and disease-free survival were updated
    17 Oct 2016
    - primary analysis was changed from an event-driven analysis to a landmark (time-based) analysis, triggered when all subjects had the opportunity to complete 5 years treatment with investigational product - second interim analysis from the study was removed - open-label phase from the study was removed - long-term follow-up visit frequency and assessments before and after the primary analysis cutoff date was redefined

    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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