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    Clinical Trial Results:
    A Randomized, Double-Blind, Multicenter Study of Denosumab Compared With Zoledronic Acid in the Treatment of Bone Disease in Subjects With Newly Diagnosed Multiple Myeloma

    Summary
    EudraCT number
    		 2010-020454-34
    Trial protocol
    		 GR   ES   DE   HU   CZ   GB   PT   IE   IT   AT   BG   SK   LT  
    Global end of trial date
    29 Mar 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Apr 2020
    First version publication date
    04 Apr 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    20090482
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01345019
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Amgen Inc.
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oaks, CA, United States,
    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
    29 Mar 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Mar 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to determine if denosumab is noninferior to zoledronic acid with respect to the first on-study occurrence of an SRE in subjects with multiple myeloma.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations and guidelines, and Food and Drug Administration (FDA) regulations, and guidelines set forth in 21 CFR Parts 11, 50, 54, 56, and 312. All subjects provided written informed consent before undergoing any study-related procedures, including screening procedures. The study protocol, amendments, and the informed consent form (ICF) were reviewed by the Institutional Review Boards (IRBs) and Independent Ethics Committees (IECs). No subjects were recruited into the study and no investigational product (IP) was shipped until the IRB/IEC gave written approval of the protocol and ICF and Amgen received copies of these approvals.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 May 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Slovakia: 7
    Country: Number of subjects enrolled
    Spain: 66
    Country: Number of subjects enrolled
    Switzerland: 15
    Country: Number of subjects enrolled
    Taiwan: 26
    Country: Number of subjects enrolled
    Turkey: 42
    Country: Number of subjects enrolled
    Ukraine: 60
    Country: Number of subjects enrolled
    United Kingdom: 33
    Country: Number of subjects enrolled
    United States: 324
    Country: Number of subjects enrolled
    Australia: 46
    Country: Number of subjects enrolled
    Austria: 26
    Country: Number of subjects enrolled
    Bulgaria: 81
    Country: Number of subjects enrolled
    Canada: 121
    Country: Number of subjects enrolled
    Czech Republic: 75
    Country: Number of subjects enrolled
    France: 125
    Country: Number of subjects enrolled
    Germany: 6
    Country: Number of subjects enrolled
    Greece: 94
    Country: Number of subjects enrolled
    Hong Kong: 9
    Country: Number of subjects enrolled
    Hungary: 47
    Country: Number of subjects enrolled
    Ireland: 14
    Country: Number of subjects enrolled
    Italy: 92
    Country: Number of subjects enrolled
    Japan: 42
    Country: Number of subjects enrolled
    Korea, Republic of: 84
    Country: Number of subjects enrolled
    Lithuania: 27
    Country: Number of subjects enrolled
    Malaysia: 14
    Country: Number of subjects enrolled
    New Zealand: 9
    Country: Number of subjects enrolled
    Poland: 77
    Country: Number of subjects enrolled
    Portugal: 25
    Country: Number of subjects enrolled
    Russian Federation: 110
    Country: Number of subjects enrolled
    Singapore: 21
    Worldwide total number of subjects
    1718
    EEA total number of subjects
    795
    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)
    936
    From 65 to 84 years
    752
    85 years and over
    30

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 259 centers across 29 countries in Europe, North America, Asia, Australia/New Zealand, and Japan. Participants were enrolled from 17 May 2012 to 29 March 2016.

    Pre-assignment
    Screening details
    		 Randomization was stratified according to: - intent to undergo autologous peripheral blood stem cell (PBSC) transplantation - the antimyeloma agent being utilized/planned to be utilized in first-line therapy - stage (International Staging System [ISS]) at diagnosis - previous SRE (yes or no) - region (Japan yes or no)

    Period 1
    Period 1 title
    Blinded Treatment Phase
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Zoledronic Acid
    Arm description
    		 Participants randomized to receive zoledronic acid 4 mg intravenously plus placebo to denosumab subcutaneously once every 4 weeks in the double-blind treatment phase.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    zoledronic acid (active comparator)
    Investigational medicinal product code
    Other name
    Zometa®
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered by intravenous infusion over 15 minutes once every 4 weeks

    Investigational medicinal product name
    placebo to denosumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered by subcutaneous injection once every 4 weeks

    Arm title
    		 Denosumab
    Arm description
    		 Participants randomized to receive denosumab 120 mg subcutaneously plus placebo to zoledronic acid intravenously once every 4 weeks in the double-blind treatment phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    denosumab (experimental)
    Investigational medicinal product code
    AMG 162
    Other name
    XGEVA®
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered by subcutaneous injection once every 4 weeks

    Investigational medicinal product name
    placebo to zoledronic acid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered by intravenous infusion over 15 minutes once every 4 weeks

    Number of subjects in period 1
    		Zoledronic Acid Denosumab
    Started
    859
    859
    Received Treatment
    852
    850
    Completed
    541
    555
    Not completed
    318
    304
         Consent withdrawn by subject
    103
    112
         Ineligibility Determined
    1
    6
         Adverse event, non-fatal
    6
    13
         Protocol Deviation
    5
    -
         Death
    147
    137
         Completed Survival Follow-up
    21
    9
         Administrative Decision
    10
    8
         Lost to follow-up
    6
    3
         Disease Progression
    12
    10
         Noncompliance
    5
    3
         Other, Not Specified
    2
    3
    Period 2
    Period 2 title
    Open Label Treatment Phase
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Zoledronic Acid / Denosumab
    Arm description
    		 Participants who randomized to receive zoledronic acid 4 mg intravenously plus placebo to denosumab subcutaneously (SC) once every 4 weeks (Q4W) in the double-blind treatment phase received denosumab 120 mg SC Q4W in the open-label treatment phase.
    Arm type
    		 Active comparator

    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 by subcutaneous injection once every 4 weeks

    Arm title
    		 Denosumab / Denosumab
    Arm description
    		 Participants who randomized to receive denosumab 120 mg subcutaneously (SC) plus placebo to zoledronic acid intravenouslyonce every 4 weeks (Q4W) in the double-blind treatment phase received denosumab 120 mg SC Q4W in the open-label treatment phase.
    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 by subcutaneous injection once every 4 weeks

    Number of subjects in period 2 [1]
    		Zoledronic Acid / Denosumab Denosumab / Denosumab
    Started
    418
    426
    Completed
    227
    233
    Not completed
    191
    193
         Consent withdrawn by subject
    49
    47
         Adverse event, non-fatal
    30
    51
         Death
    49
    48
         Administrative Decision
    30
    15
         Pregnancy
    1
    -
         Lost to follow-up
    1
    2
         Disease Progression
    17
    18
         Noncompliance
    5
    4
         Other, Not Specified
    9
    7
         Protocol deviation
    -
    1
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Note for Period 1: Number of participants listed as "completed" in Period 1 were those participants still on-study as of the blinded treatment analysis cutoff date of 05 January 2017. Note for Period 2: Participants who were still on study as of the blinded treatment analysis cutoff date but didn’t enter the open label treatment phase either entered a survival follow-up period or discontinued the study without the survival follow-up.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Zoledronic Acid
    Reporting group description
    		 Participants randomized to receive zoledronic acid 4 mg intravenously plus placebo to denosumab subcutaneously once every 4 weeks in the double-blind treatment phase.

    Reporting group title
    Denosumab
    Reporting group description
    		 Participants randomized to receive denosumab 120 mg subcutaneously plus placebo to zoledronic acid intravenously once every 4 weeks in the double-blind treatment phase.

    Reporting group values
    		 Zoledronic Acid Denosumab Total
    Number of subjects
    		 859 859 1718
    Age Categorical
    Units: participants
        < 65 years
    		 464 472 936
        ≥ 65 years
    		 395 387 782
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 63.3 ( 10.5 ) 63.5 ( 10.6 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 386 397 783
        Male
    		 473 462 935
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 699 711 1410
        Asian
    		 101 107 208
        Black or African American
    		 36 29 65
        Other
    		 19 10 29
        American Indian or Alaska Native
    		 3 0 3
        Native Hawaiian or Other Pacific Islander
    		 0 1 1
        Multiracial
    		 0 1 1
        Missing
    		 1 0 1
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 35 35 70
        Not Hispanic or Latino
    		 819 823 1642
        Unknown or Not Reported
    		 5 1 6
    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)
    		 259 263 522
        1 (Restricted but ambulatory)
    		 413 400 813
        2 (Ambulatory but unable to work)
    		 187 196 383
    Randomization Stratifications: Autologous Peripheral Blood Stem Cell (PBSC) Transplantation
    Randomization was stratified by - Intent to undergo autologous peripheral blood stem cell (PBSC) transplantation: yes or no.
    Units: Subjects
        Intent to undergo PBSC transplantation=Yes
    		 465 465 930
        Intent to undergo PBSC transplantation=No
    		 394 394 788
    Randomization Stratifications: Anti-Myeloma Agent Utilized/Planned in First-Line Therapy
    Randomization was stratified by: - The anti-myeloma agent being utilized/planned to be utilized in first-line therapy: novel therapy (included bortezomib, lenalidomide, or thalidomide) based or non-novel therapy-based.
    Units: Subjects
        Novel therapy
    		 821 819 1640
        Non-novel therapy
    		 38 40 78
    Randomization Stratifications: International Staging System (ISS) Stage at Diagnosis
    Randomization was stratified by - International Staging System (ISS) stage at diagnosis: I (serum β2 microglobulin < 3.5 mg/L; serum albumin ≥ 3.5 g/dL) or II (neither stage I or III) or III (serum β2 microglobulin ≥ 5.5 mg/L).
    Units: Subjects
        Stage I
    		 268 263 531
        Stage II
    		 313 319 632
        Stage III
    		 278 277 555
    Randomization Stratifications: Previous skeletal-related event (SRE)
    Randomization was stratified by - Previous skeletal-related event (SRE): yes or no.
    Units: Subjects
        Previous SRE=Yes
    		 484 481 965
        Previous SRE=No
    		 375 378 753
    Randomization Stratifications: Region (Japan, non-Japan)
    Randomization was stratified by - Region (Japan, non-Japan).
    Units: Subjects
        Japan
    		 18 24 42
        Non-Japan
    		 841 835 1676

    End points

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    End points reporting groups
    Reporting group title
    Zoledronic Acid
    Reporting group description
    		 Participants randomized to receive zoledronic acid 4 mg intravenously plus placebo to denosumab subcutaneously once every 4 weeks in the double-blind treatment phase.

    Reporting group title
    Denosumab
    Reporting group description
    		 Participants randomized to receive denosumab 120 mg subcutaneously plus placebo to zoledronic acid intravenously once every 4 weeks in the double-blind treatment phase.
    Reporting group title
    Zoledronic Acid / Denosumab
    Reporting group description
    		 Participants who randomized to receive zoledronic acid 4 mg intravenously plus placebo to denosumab subcutaneously (SC) once every 4 weeks (Q4W) in the double-blind treatment phase received denosumab 120 mg SC Q4W in the open-label treatment phase.

    Reporting group title
    Denosumab / Denosumab
    Reporting group description
    		 Participants who randomized to receive denosumab 120 mg subcutaneously (SC) plus placebo to zoledronic acid intravenouslyonce every 4 weeks (Q4W) in the double-blind treatment phase received denosumab 120 mg SC Q4W in the open-label treatment phase.

    Primary: Time to First On-study Skeletal Related Event

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    End point title
    		 Time to First On-study Skeletal Related Event
    End point description
    A skeletal-related event (SRE) is defined as one of the following: pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression. Time to first on-study SRE is defined as the time interval (in days) from the randomization date to the date of first occurrence of on-study SRE. If there was no known event, and the participant was monitored for any one of the four SRE components, time to first on-study SRE was censored at the end of the treatment phase date or the primary analysis data cut-off date, whichever came first. 99999=Could not be estimated due to the low number of events.
    End point type
    Primary
    End point timeframe
    From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively.
    End point values
    		 Zoledronic Acid Denosumab
    Number of subjects analysed
    859
    859
    Units: days
        median (confidence interval 95%)
    730.0 (504.0 to 1014.0)
    695.0 (448.0 to 99999)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Zoledronic Acid v Denosumab
    Number of subjects included in analysis
    1718
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 = 0.01 [2]
    Method
    		 Cox proportional hazards model
    Parameter type
    		 Hazard Ratio (< 1 favors denosumab)
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.85
         upper limit
    		 1.14
    Notes
    [1] - A two-stage approach was used for the non-inferiority test. First, the fixed margin approach was used to ensure denosumab has an effect greater than placebo (ie, the non-inferiority margin M1, ie, the lower bound of the two-sided 95% confidence interval 1.28, is ruled out). Next, a synthesis method was used for the non-inferiority test of the hypothesis that denosumab preserved at least 50% of the effect of zoledronic acid (HR [95% CI] of 1.48 [1.28, 1.71] for placebo vs zoledronic acid.
    [2] - Based on a Cox proportional hazards model stratified by the randomization stratification factors.

    Primary: Percentage of Participants with an On-study Skeletal Related Event

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    End point title
    		 Percentage of Participants with an On-study Skeletal Related Event [3]
    End point description
    A skeletal-related event (SRE) is defined as one of the following: pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression.
    End point type
    Primary
    End point timeframe
    From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively.
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics are presented per protocol.
    End point values
    		 Zoledronic Acid Denosumab
    Number of subjects analysed
    859
    859
    Units: percentage of participants
        number (confidence interval 95%)
    44.6 (41.3 to 47.9)
    43.8 (40.5 to 47.1)
    No statistical analyses for this end point

    Primary: Kaplan-Meier Estimate of Percentage of Participants with an On-study Skeletal Related Event

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    End point title
    		 Kaplan-Meier Estimate of Percentage of Participants with an On-study Skeletal Related Event [4]
    End point description
    A skeletal-related event (SRE) is defined as one of the following: pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression.
    End point type
    Primary
    End point timeframe
    From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively. The Kaplan-Meier estimate at weeks 25, 49 and 109 is reported.
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistics for the Kaplan-Meier Estimate of Percentage of Participants With an On-study Skeletal Related Event are presented in the data table.
    End point values
    		 Zoledronic Acid Denosumab
    Number of subjects analysed
    859
    859
    Units: percentage of participants
    number (confidence interval 95%)
        At Week 25
    36.5 (33.3 to 39.9)
    35.9 (32.7 to 39.3)
        At Week 49
    43.2 (39.7 to 46.8)
    43.7 (40.2 to 47.3)
        At Week 109
    50.6 (46.6 to 54.6)
    50.5 (46.6 to 54.5)
    No statistical analyses for this end point

    Secondary: Time to First On-study Skeletal Related Event - Superiority Analysis

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    End point title
    		 Time to First On-study Skeletal Related Event - Superiority Analysis
    End point description
    A skeletal-related event (SRE) is defined as one of the following: pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression. Time to first on-study SRE is defined as the time interval (in days) from the randomization date to the date of first occurrence of on-study SRE. If there was no known event, and the participant was monitored for any one of the four SRE components, time to first on-study SRE was censored at the end of the treatment phase date or the primary analysis data cut-off date, whichever came first. 99999=Could not be estimated due to the low number of events.
    End point type
    Secondary
    End point timeframe
    From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively.
    End point values
    		 Zoledronic Acid Denosumab
    Number of subjects analysed
    859
    859
    Units: days
        median (confidence interval 95%)
    730.0 (504.0 to 1014.0)
    695.0 (448.0 to 99999)
    Statistical analysis title
    		 Statisitcal Analysis 1
    Comparison groups
    Zoledronic Acid v Denosumab
    Number of subjects included in analysis
    1718
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.82 [6]
    Method
    		 Logrank
    Confidence interval
    Notes
    [5] - The statistical inferences of the treatment effect on secondary efficacy endpoints (time to the first on study SRE [superiority] and time to first and subsequent on study SRE [superiority, multiple event analysis]) were to be conducted if denosumab was determined to be non-inferior to zoledronic acid. To control the overall type I error for multiple comparisons at a significant level of 0.05, these secondary efficacy endpoints were tested simultaneously using the Hochberg procedure.
    [6] - Based on a log rank test stratified by randomization stratification factors.

    Secondary: Time to First and Subsequent On-Study Skeletal Related Event - Number of Events per Patient

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    End point title
    		 Time to First and Subsequent On-Study Skeletal Related Event - Number of Events per Patient
    End point description
    A skeletal-related event (SRE) is defined as one of the following: pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression. Time to first on-study SRE is defined as the time interval (in days) from the randomization date to the date of first occurrence of on-study SRE. Time to a subsequent SRE is defined, similarly to the time to first on-study SRE, as the time interval from the randomization date to the date of a subsequent occurrence of on-study SRE, which had to be at least 21 days after the previous SRE. A multiple event analysis was used, which accounts for both the absolute number of SREs and for the time between two consecutive events, and therefore, provides a more sensitive assessment of the risk of experiencing an SRE. The average number of events per patient is reported.
    End point type
    Secondary
    End point timeframe
    From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively.
    End point values
    		 Zoledronic Acid Denosumab
    Number of subjects analysed
    859
    859
    Units: events/patient
        number (not applicable)
    0.66
    0.66
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Zoledronic Acid v Denosumab
    Number of subjects included in analysis
    1718
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.84 [8]
    Method
    		 Andersen-Gill model
    Parameter type
    		 Rate ratio (< 1 favors denosumab)
    Point estimate
    1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.89
         upper limit
    		 1.15
    Notes
    [7] - The statistical inferences of the treatment effect on secondary efficacy endpoints (time to the first on study SRE [superiority] and time to first and subsequent on study SRE [superiority, multiple event analysis]) were to be conducted if denosumab was determined to be non-inferior to zoledronic acid. To control the overall type I error for multiple comparisons at a significant level of 0.05, these secondary efficacy endpoints were tested simultaneously using the Hochberg procedure.
    [8] - Based on an Andersen-Gill model stratified by the randomization stratification factors.

    Secondary: Time to First and Subsequent On-Study Skeletal Related Event - Number of Events

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    End point title
    		 Time to First and Subsequent On-Study Skeletal Related Event - Number of Events
    End point description
    A skeletal-related event (SRE) is defined as one of the following: pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression. Time to first on-study SRE is defined as the time interval (in days) from the randomization date to the date of first occurrence of on-study SRE. Time to a subsequent SRE is defined, similarly to the time to first on-study SRE, as the time interval from the randomization date to the date of a subsequent occurrence of on-study SRE, which had to be at least 21 days after the previous SRE. A multiple event analysis was used, which accounts for both the absolute number of SREs and for the time between two consecutive events, and therefore, provides a more sensitive assessment of the risk of experiencing an SRE. The total number of events is reported.
    End point type
    Secondary
    End point timeframe
    From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively.
    End point values
    		 Zoledronic Acid Denosumab
    Number of subjects analysed
    859
    859
    Units: skeletal-related events
    565
    565
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Overall survival was defined as the time interval (in days) from the randomization date to the date of death. If a participant was still alive at the primary analysis data cut-off date or was lost to follow-up by the primary analysis data cut-off date, survival time was censored at their last contact date or the primary analysis data cut-off date, whichever was first. 999999=Not estimable
    End point type
    Secondary
    End point timeframe
    From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively.
    End point values
    		 Zoledronic Acid Denosumab
    Number of subjects analysed
    859
    859
    Units: days
        median (confidence interval 95%)
    999999 (-999999 to 999999)
    1507.0 (-999999 to 999999)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The survival function of time to death for each treatment group was estimated using Kaplan-Meier method and the hazard ratio of denosumab compared with zoledronic acid and its 2-sided 95% CI were estimated using a Cox proportional hazards model stratified by the randomization stratification factors and including treatment groups, age, race group, geographic region, baseline creatinine clearance, baseline risk per cytogenetic based prognosis, and baseline ECOG as independent variables.
    Comparison groups
    Zoledronic Acid v Denosumab
    Number of subjects included in analysis
    1718
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 = 0.41
    Method
    		 Cox proportional hazards model
    Parameter type
    		 Hazard Ratio (< 1 favors denosumab)
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 1.16
    Notes
    [9] - If superiority of denosumab over zoledronic acid was established for both time to first SRE and time to first and subsequent SRE, the additional secondary endpoint (overall survival) was to be tested at a significance level of 0.05.

    Secondary: Percentage of Participants who Died

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    End point title
    		 Percentage of Participants who Died
    End point description
    End point type
    Secondary
    End point timeframe
    From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively.
    End point values
    		 Zoledronic Acid Denosumab
    Number of subjects analysed
    859
    859
    Units: percentage of participants
        number (confidence interval 95%)
    15.0 (12.6 to 17.4)
    14.1 (11.8 to 16.4)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    DB: from 1st dose of study drug to the later of 30 days after last dose or end of treatment phase. OL: from 1st dose of OL study drug to end of study. Median months on study drug: 18.4 (ZA), 19.4 (Dmab) in DB; 23.2 (ZA/Dmab), 23.0 (Dmab/Dmab) in OL.
    Adverse event reporting additional description
    The timeframe for deaths (all causes) is from the 1st dose of study drug to end of study. Participants who did not receive OL study drug but died in the survival follow-up phase are included in the DB columns. One participant who died before the 1st dose of study drug is excluded.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    DB: Zoledronic Acid
    Reporting group description
    		 Participants received zoledronic acid 4 mg intravenously plus placebo to denosumab subcutaneously once every 4 weeks (Q4W) in the double-blind (DB) treatment phase.

    Reporting group title
    DB: Denosumab
    Reporting group description
    		 Participants received denosumab 120 mg subcutaneously plus placebo to zoledronic acid intravenously once every 4 weeks (Q4W) in the double-blind (DB) treatment phase.

    Reporting group title
    OL: Zoledronic Acid / Denosumab
    Reporting group description
    		 Participants who received zoledronic acid 4 mg intravenously plus placebo to denosumab subcutaneously (SC) once every 4 weeks (Q4W) in the double-blind treatment phase received denosumab 120 mg SC Q4W in the open-label (OL) treatment phase.

    Reporting group title
    OL: Denosumab / Denosumab
    Reporting group description
    		 Participants who received denosumab 120 mg subcutaneously (SC) plus placebo to zoledronic acid intravenously once every 4 weeks (Q4W) in the double-blind treatment phase received denosumab 120 mg SC Q4W in the open-label (OL) treatment phase.

    Serious adverse events
    		 DB: Zoledronic Acid DB: Denosumab OL: Zoledronic Acid / Denosumab OL: Denosumab / Denosumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    447 / 852 (52.46%)
    434 / 850 (51.06%)
    159 / 418 (38.04%)
    156 / 426 (36.62%)
         number of deaths (all causes)
    169
    154
    49
    48
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 852 (0.00%)
    2 / 850 (0.24%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma pancreas
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    2 / 852 (0.23%)
    1 / 850 (0.12%)
    3 / 418 (0.72%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Basosquamous carcinoma of skin
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    2 / 852 (0.23%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder cancer recurrent
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervix carcinoma
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic myelomonocytic leukaemia
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 852 (0.12%)
    3 / 850 (0.35%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colorectal cancer metastatic
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Diffuse large B-cell lymphoma
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endometrial adenocarcinoma
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatocellular carcinoma
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant neoplasm of pleura
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant neoplasm of renal pelvis
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant pleural effusion
         subjects affected / exposed
    1 / 852 (0.12%)
    1 / 850 (0.12%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningioma
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to spine
         subjects affected / exposed
    1 / 852 (0.12%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Neoplasm of orbit
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuroendocrine tumour
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-Hodgkin's lymphoma
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-small cell lung cancer stage I
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paraproteinaemia
         subjects affected / exposed
    1 / 852 (0.12%)
    3 / 850 (0.35%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    Plasma cell leukaemia
         subjects affected / exposed
    4 / 852 (0.47%)
    1 / 850 (0.12%)
    1 / 418 (0.24%)
    2 / 426 (0.47%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Plasma cell myeloma
         subjects affected / exposed
    16 / 852 (1.88%)
    18 / 850 (2.12%)
    3 / 418 (0.72%)
    10 / 426 (2.35%)
         occurrences causally related to treatment / all
    0 / 19
    0 / 21
    0 / 3
    0 / 12
         deaths causally related to treatment / all
    0 / 8
    0 / 10
    0 / 3
    0 / 9
    Plasma cell myeloma recurrent
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Plasmacytoma
         subjects affected / exposed
    4 / 852 (0.47%)
    7 / 850 (0.82%)
    1 / 418 (0.24%)
    5 / 426 (1.17%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 8
    0 / 1
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 2
    Prostate cancer
         subjects affected / exposed
    2 / 852 (0.23%)
    3 / 850 (0.35%)
    1 / 418 (0.24%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal adenocarcinoma
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sarcoma
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    3 / 852 (0.35%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute leukaemia
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    2 / 426 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    Acute lymphocytic leukaemia
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute lymphocytic leukaemia recurrent
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Adenocarcinoma gastric
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaplastic large-cell lymphoma
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone marrow tumour cell infiltration
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clear cell renal cell carcinoma
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Glioblastoma multiforme
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intraductal proliferative breast lesion
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    0 / 852 (0.00%)
    2 / 850 (0.24%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oropharyngeal cancer
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer metastatic
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Spinal cord neoplasm
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 852 (0.12%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic aneurysm rupture
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Aortic dissection
         subjects affected / exposed
    1 / 852 (0.12%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic dissection rupture
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Aortic thrombosis
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    4 / 852 (0.47%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 4
    0 / 1
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    8 / 852 (0.94%)
    11 / 850 (1.29%)
    2 / 418 (0.48%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    1 / 9
    0 / 11
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Essential hypertension
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 852 (0.00%)
    4 / 850 (0.47%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 852 (0.12%)
    2 / 850 (0.24%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    3 / 852 (0.35%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery aneurysm
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    2 / 418 (0.48%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Superior vena cava syndrome
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombophlebitis superficial
         subjects affected / exposed
    1 / 852 (0.12%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vasospasm
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic stenosis
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arterial disorder
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive urgency
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Cataract operation
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fistula repair
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematopoietic stem cell mobilisation
         subjects affected / exposed
    0 / 852 (0.00%)
    2 / 850 (0.24%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Internal fixation of fracture
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intra-uterine contraceptive device removal
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Knee arthroplasty
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rehabilitation therapy
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Autologous haematopoietic stem cell transplant
         subjects affected / exposed
    0 / 852 (0.00%)
    2 / 850 (0.24%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    7 / 852 (0.82%)
    3 / 850 (0.35%)
    1 / 418 (0.24%)
    5 / 426 (1.17%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 3
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    1 / 852 (0.12%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    3 / 852 (0.35%)
    3 / 850 (0.35%)
    1 / 418 (0.24%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 3
    0 / 3
    0 / 1
    0 / 1
    Disease progression
         subjects affected / exposed
    1 / 852 (0.12%)
    2 / 850 (0.24%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 852 (0.12%)
    1 / 850 (0.12%)
    2 / 418 (0.48%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    1 / 852 (0.12%)
    2 / 850 (0.24%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    10 / 852 (1.17%)
    10 / 850 (1.18%)
    2 / 418 (0.48%)
    6 / 426 (1.41%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 15
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 2
    0 / 6
    0 / 1
    0 / 1
    Generalised oedema
         subjects affected / exposed
    0 / 852 (0.00%)
    3 / 850 (0.35%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperpyrexia
         subjects affected / exposed
    1 / 852 (0.12%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Hyperthermia
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Localised oedema
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 852 (0.00%)
    2 / 850 (0.24%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mucosal ulceration
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    6 / 852 (0.70%)
    5 / 850 (0.59%)
    3 / 418 (0.72%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 6
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 6
    0 / 5
    0 / 3
    0 / 1
    Non-cardiac chest pain
         subjects affected / exposed
    5 / 852 (0.59%)
    4 / 850 (0.47%)
    0 / 418 (0.00%)
    2 / 426 (0.47%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    3 / 852 (0.35%)
    5 / 850 (0.59%)
    2 / 418 (0.48%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 5
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Performance status decreased
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    28 / 852 (3.29%)
    24 / 850 (2.82%)
    2 / 418 (0.48%)
    4 / 426 (0.94%)
         occurrences causally related to treatment / all
    5 / 32
    0 / 37
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    1 / 852 (0.12%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    5 / 852 (0.59%)
    3 / 850 (0.35%)
    1 / 418 (0.24%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 5
    0 / 3
    0 / 1
    0 / 1
    Oedema
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    2 / 426 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Acute graft versus host disease
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute graft versus host disease in intestine
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaphylactic reaction
         subjects affected / exposed
    1 / 852 (0.12%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Serum sickness
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Adenomyosis
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Scrotal oedema
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Testicular mass
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    2 / 852 (0.23%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    2 / 852 (0.23%)
    2 / 850 (0.24%)
    2 / 418 (0.48%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchial obstruction
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumopathy
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    4 / 852 (0.47%)
    4 / 850 (0.47%)
    3 / 418 (0.72%)
    3 / 426 (0.70%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 5
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 852 (0.00%)
    3 / 850 (0.35%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    10 / 852 (1.17%)
    5 / 850 (0.59%)
    2 / 418 (0.48%)
    2 / 426 (0.47%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 5
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 852 (0.12%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    3 / 852 (0.35%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    3 / 852 (0.35%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    2 / 852 (0.23%)
    3 / 850 (0.35%)
    1 / 418 (0.24%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasal discomfort
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiogenic pulmonary oedema
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    4 / 852 (0.47%)
    6 / 850 (0.71%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 9
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 852 (0.00%)
    6 / 850 (0.71%)
    2 / 418 (0.48%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    2 / 852 (0.23%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Productive cough
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary artery thrombosis
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    13 / 852 (1.53%)
    16 / 850 (1.88%)
    5 / 418 (1.20%)
    3 / 426 (0.70%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 16
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    0 / 1
    0 / 1
    Pulmonary fibrosis
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    2 / 852 (0.23%)
    2 / 850 (0.24%)
    2 / 418 (0.48%)
    3 / 426 (0.70%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 3
    Respiratory acidosis
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 852 (0.12%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    11 / 852 (1.29%)
    4 / 850 (0.47%)
    4 / 418 (0.96%)
    2 / 426 (0.47%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 4
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 4
    0 / 1
    0 / 2
    0 / 2
    Stridor
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asphyxia
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchiectasis
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural disorder
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural thickening
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Pulmonary hypertension
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 852 (0.12%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    2 / 852 (0.23%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 0
    Confusional state
         subjects affected / exposed
    3 / 852 (0.35%)
    5 / 850 (0.59%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    2 / 852 (0.23%)
    4 / 850 (0.47%)
    0 / 418 (0.00%)
    2 / 426 (0.47%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 852 (0.00%)
    3 / 850 (0.35%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disorientation
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mutism
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adjustment disorder
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug dependence
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Organic brain syndrome
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric decompensation
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device breakage
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device failure
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device occlusion
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device dislocation
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Acute hepatic failure
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Bile duct stenosis
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholangitis acute
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 852 (0.00%)
    2 / 850 (0.24%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    2 / 852 (0.23%)
    0 / 850 (0.00%)
    2 / 418 (0.48%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    1 / 852 (0.12%)
    2 / 850 (0.24%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    0 / 852 (0.00%)
    2 / 850 (0.24%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis toxic
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bile duct obstruction
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gallbladder rupture
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 852 (0.00%)
    3 / 850 (0.35%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 852 (0.00%)
    3 / 850 (0.35%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bilirubin conjugated increased
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood creatine increased
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    3 / 852 (0.35%)
    2 / 850 (0.24%)
    1 / 418 (0.24%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    1 / 3
    2 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood electrolytes abnormal
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood immunoglobulin G increased
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Blood immunoglobulin M increased
         subjects affected / exposed
    2 / 852 (0.23%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Body temperature increased
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone marrow plasmacyte count increased
         subjects affected / exposed
    2 / 852 (0.23%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest X-ray abnormal
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eastern Cooperative Oncology Group performance status worsened
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    1 / 852 (0.12%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Heart rate irregular
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Light chain analysis increased
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    1 / 852 (0.12%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Monoclonal immunoglobulin present
         subjects affected / exposed
    1 / 852 (0.12%)
    2 / 850 (0.24%)
    1 / 418 (0.24%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    6 / 852 (0.70%)
    2 / 850 (0.24%)
    1 / 418 (0.24%)
    2 / 426 (0.47%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 2
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 852 (0.12%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood immunoglobulin A increased
         subjects affected / exposed
    1 / 852 (0.12%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Influenza A virus test positive
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Light chain analysis abnormal
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Plasma cells increased
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Plasma cells present
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Protein urine present
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    White blood cell count increased
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Abdominal injury
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Anastomotic leak
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone contusion
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain contusion
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Cervical vertebral fracture
         subjects affected / exposed
    0 / 852 (0.00%)
    2 / 850 (0.24%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    0 / 852 (0.00%)
    2 / 850 (0.24%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    6 / 852 (0.70%)
    3 / 850 (0.35%)
    0 / 418 (0.00%)
    3 / 426 (0.70%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    7 / 852 (0.82%)
    2 / 850 (0.24%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    2 / 852 (0.23%)
    3 / 850 (0.35%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    2 / 852 (0.23%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    8 / 852 (0.94%)
    4 / 850 (0.47%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 4
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Patella fracture
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    2 / 852 (0.23%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    2 / 852 (0.23%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    2 / 426 (0.47%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    3 / 426 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sternal fracture
         subjects affected / exposed
    0 / 852 (0.00%)
    2 / 850 (0.24%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 852 (0.12%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    5 / 852 (0.59%)
    6 / 850 (0.71%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 7
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transfusion related complication
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Compression fracture
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Incarcerated incisional hernia
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Limb fracture
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Poisoning
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    Post procedural fever
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Procedural nausea
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary contusion
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin laceration
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Aplasia
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Odontogenic cyst
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 852 (0.12%)
    2 / 850 (0.24%)
    3 / 418 (0.72%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    6 / 852 (0.70%)
    2 / 850 (0.24%)
    1 / 418 (0.24%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 5
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    2 / 852 (0.23%)
    2 / 850 (0.24%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    2 / 418 (0.48%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    10 / 852 (1.17%)
    4 / 850 (0.47%)
    2 / 418 (0.48%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 5
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial tachycardia
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    4 / 852 (0.47%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac amyloidosis
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    11 / 852 (1.29%)
    6 / 850 (0.71%)
    1 / 418 (0.24%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 6
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 11
    0 / 5
    0 / 1
    0 / 1
    Cardiac disorder
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    7 / 852 (0.82%)
    11 / 850 (1.29%)
    3 / 418 (0.72%)
    4 / 426 (0.94%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 13
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 6
    0 / 2
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    2 / 852 (0.23%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    0 / 852 (0.00%)
    3 / 850 (0.35%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    5 / 852 (0.59%)
    5 / 850 (0.59%)
    1 / 418 (0.24%)
    3 / 426 (0.70%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 6
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    2 / 852 (0.23%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    2 / 852 (0.23%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Cardiovascular insufficiency
         subjects affected / exposed
    1 / 852 (0.12%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 852 (0.12%)
    2 / 850 (0.24%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Mitral valve stenosis
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    2 / 852 (0.23%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    2 / 426 (0.47%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    Myocardial ischaemia
         subjects affected / exposed
    1 / 852 (0.12%)
    2 / 850 (0.24%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    1 / 852 (0.12%)
    2 / 850 (0.24%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    2 / 852 (0.23%)
    3 / 850 (0.35%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachyarrhythmia
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tricuspid valve incompetence
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute left ventricular failure
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac valve disease
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular arrhythmia
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Basilar migraine
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain injury
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cauda equina syndrome
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    4 / 852 (0.47%)
    0 / 850 (0.00%)
    2 / 418 (0.48%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 1
    Cerebral ischaemia
         subjects affected / exposed
    3 / 852 (0.35%)
    2 / 850 (0.24%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral vasoconstriction
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    5 / 852 (0.59%)
    5 / 850 (0.59%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 6
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coma
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    4 / 852 (0.47%)
    2 / 850 (0.24%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    3 / 852 (0.35%)
    2 / 850 (0.24%)
    2 / 418 (0.48%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    3 / 852 (0.35%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 852 (0.12%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemiplegia
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic cerebral infarction
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 852 (0.12%)
    3 / 850 (0.35%)
    1 / 418 (0.24%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Lacunar infarction
         subjects affected / exposed
    0 / 852 (0.00%)
    2 / 850 (0.24%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    2 / 852 (0.23%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbosacral radiculopathy
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nerve degeneration
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 852 (0.12%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paralysis
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paraparesis
         subjects affected / exposed
    2 / 852 (0.23%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Paraplegia
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paresis
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Polyneuropathy
         subjects affected / exposed
    1 / 852 (0.12%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radiculopathy
         subjects affected / exposed
    2 / 852 (0.23%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    2 / 852 (0.23%)
    2 / 850 (0.24%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 852 (0.12%)
    3 / 850 (0.35%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure like phenomena
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    8 / 852 (0.94%)
    4 / 850 (0.47%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 4
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 852 (0.12%)
    1 / 850 (0.12%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    9 / 852 (1.06%)
    7 / 850 (0.82%)
    0 / 418 (0.00%)
    2 / 426 (0.47%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 7
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 852 (0.12%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral atrophy
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral haematoma
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular disorder
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervical cord compression
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dementia
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalitis post varicella
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intracranial mass
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Myelopathy
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Parkinson's disease
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Agranulocytosis
         subjects affected / exposed
    1 / 852 (0.12%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    26 / 852 (3.05%)
    12 / 850 (1.41%)
    5 / 418 (1.20%)
    8 / 426 (1.88%)
         occurrences causally related to treatment / all
    1 / 33
    0 / 17
    0 / 6
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Autoimmune haemolytic anaemia
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bicytopenia
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone marrow failure
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    25 / 852 (2.93%)
    23 / 850 (2.71%)
    7 / 418 (1.67%)
    6 / 426 (1.41%)
         occurrences causally related to treatment / all
    0 / 29
    0 / 25
    0 / 9
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Haemolytic anaemia
         subjects affected / exposed
    1 / 852 (0.12%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperviscosity syndrome
         subjects affected / exposed
    0 / 852 (0.00%)
    3 / 850 (0.35%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    2 / 852 (0.23%)
    2 / 850 (0.24%)
    2 / 418 (0.48%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    13 / 852 (1.53%)
    4 / 850 (0.47%)
    4 / 418 (0.96%)
    3 / 426 (0.70%)
         occurrences causally related to treatment / all
    0 / 16
    0 / 4
    0 / 7
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    4 / 852 (0.47%)
    2 / 850 (0.24%)
    3 / 418 (0.72%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    12 / 852 (1.41%)
    9 / 850 (1.06%)
    2 / 418 (0.48%)
    7 / 426 (1.64%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 9
    0 / 3
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acquired haemophilia with anti FVIII, XI, or XIII
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaemia of malignant disease
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cytopenia
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Platelet disorder
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytosis
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 852 (0.12%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vertigo positional
         subjects affected / exposed
    1 / 852 (0.12%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    2 / 852 (0.23%)
    0 / 850 (0.00%)
    2 / 418 (0.48%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diplopia
         subjects affected / exposed
    1 / 852 (0.12%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Exophthalmos
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Extraocular muscle paresis
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ulcerative keratitis
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vision blurred
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal distension
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal hernia
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal incarcerated hernia
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    5 / 852 (0.59%)
    1 / 850 (0.12%)
    4 / 418 (0.96%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    2 / 852 (0.23%)
    2 / 850 (0.24%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal wall haematoma
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic gastritis
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 852 (0.12%)
    2 / 850 (0.24%)
    1 / 418 (0.24%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    4 / 852 (0.47%)
    3 / 850 (0.35%)
    2 / 418 (0.48%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    10 / 852 (1.17%)
    9 / 850 (1.06%)
    1 / 418 (0.24%)
    4 / 426 (0.94%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 10
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea haemorrhagic
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulum intestinal
         subjects affected / exposed
    0 / 852 (0.00%)
    2 / 850 (0.24%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    1 / 852 (0.12%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 852 (0.12%)
    3 / 850 (0.35%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 852 (0.12%)
    2 / 850 (0.24%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal amyloidosis
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    5 / 852 (0.59%)
    3 / 850 (0.35%)
    1 / 418 (0.24%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 3
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal perforation
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    Gingivitis ulcerative
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hiatus hernia
         subjects affected / exposed
    0 / 852 (0.00%)
    2 / 850 (0.24%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    2 / 418 (0.48%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    2 / 852 (0.23%)
    2 / 850 (0.24%)
    1 / 418 (0.24%)
    3 / 426 (0.70%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal haemorrhage
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    3 / 852 (0.35%)
    1 / 850 (0.12%)
    2 / 418 (0.48%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    1 / 852 (0.12%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 852 (0.23%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    2 / 426 (0.47%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mechanical ileus
         subjects affected / exposed
    0 / 852 (0.00%)
    2 / 850 (0.24%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mouth haemorrhage
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    4 / 852 (0.47%)
    4 / 850 (0.47%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    2 / 852 (0.23%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Proctitis
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    2 / 852 (0.23%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 852 (0.00%)
    4 / 850 (0.47%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    11 / 852 (1.29%)
    7 / 850 (0.82%)
    3 / 418 (0.72%)
    3 / 426 (0.70%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 7
    1 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal fissure
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendiceal mucocoele
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Crohn's disease
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal pain
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gingival bleeding
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Jejunal perforation
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestinal haemorrhage
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Obstructive pancreatitis
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retroperitoneal mass
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Small intestinal perforation
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toothache
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Drug eruption
         subjects affected / exposed
    2 / 852 (0.23%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erythema multiforme
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperhidrosis
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Keloid scar
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Purpura
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 852 (0.00%)
    2 / 850 (0.24%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash macular
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin disorder
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angioedema
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Decubitus ulcer
         subjects affected / exposed
    2 / 852 (0.23%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash generalised
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    24 / 852 (2.82%)
    17 / 850 (2.00%)
    8 / 418 (1.91%)
    2 / 426 (0.47%)
         occurrences causally related to treatment / all
    5 / 27
    2 / 18
    0 / 9
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
    Bladder perforation
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    1 / 852 (0.12%)
    2 / 850 (0.24%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystitis haemorrhagic
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysuria
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 852 (0.00%)
    2 / 850 (0.24%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal disorder
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    7 / 852 (0.82%)
    4 / 850 (0.47%)
    1 / 418 (0.24%)
    6 / 426 (1.41%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 4
    0 / 1
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Renal impairment
         subjects affected / exposed
    1 / 852 (0.12%)
    2 / 850 (0.24%)
    1 / 418 (0.24%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ureteric obstruction
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    2 / 852 (0.23%)
    2 / 850 (0.24%)
    2 / 418 (0.48%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder obstruction
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephropathy toxic
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oliguria
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia of malignancy
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperparathyroidism primary
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Steroid withdrawal syndrome
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adrenocortical insufficiency acute
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperthyroidism
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 852 (0.59%)
    3 / 850 (0.35%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    16 / 852 (1.88%)
    9 / 850 (1.06%)
    1 / 418 (0.24%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 19
    0 / 13
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    7 / 852 (0.82%)
    1 / 850 (0.12%)
    3 / 418 (0.72%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    1 / 7
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    2 / 852 (0.23%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint effusion
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    2 / 852 (0.23%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    3 / 852 (0.35%)
    3 / 850 (0.35%)
    1 / 418 (0.24%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 3
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    2 / 852 (0.23%)
    2 / 850 (0.24%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal discomfort
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    2 / 852 (0.23%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    1 / 852 (0.12%)
    2 / 850 (0.24%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    2 / 852 (0.23%)
    2 / 850 (0.24%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    13 / 852 (1.53%)
    18 / 850 (2.12%)
    11 / 418 (2.63%)
    12 / 426 (2.82%)
         occurrences causally related to treatment / all
    13 / 14
    18 / 18
    10 / 11
    12 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    5 / 852 (0.59%)
    3 / 850 (0.35%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    0 / 852 (0.00%)
    2 / 850 (0.24%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    2 / 852 (0.23%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    1 / 418 (0.24%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spondylolisthesis
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tendonitis
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vertebral lesion
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone lesion
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone swelling
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Costochondritis
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc disorder
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mobility decreased
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteolysis
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Periarthritis
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess bacterial
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adenoviral haemorrhagic cystitis
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    3 / 852 (0.35%)
    2 / 850 (0.24%)
    1 / 418 (0.24%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    1 / 852 (0.12%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis infective
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    2 / 852 (0.23%)
    1 / 850 (0.12%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    1 / 852 (0.12%)
    3 / 850 (0.35%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacterial pyelonephritis
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    2 / 852 (0.23%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    7 / 852 (0.82%)
    11 / 850 (1.29%)
    4 / 418 (0.96%)
    2 / 426 (0.47%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 11
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Bursitis infective
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    5 / 852 (0.59%)
    4 / 850 (0.47%)
    0 / 418 (0.00%)
    4 / 426 (0.94%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 4
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis orbital
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis infective
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic sinusitis
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium bacteraemia
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    4 / 852 (0.47%)
    6 / 850 (0.71%)
    1 / 418 (0.24%)
    2 / 426 (0.47%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 6
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 852 (0.00%)
    3 / 850 (0.35%)
    1 / 418 (0.24%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Creutzfeldt-Jakob disease
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus chorioretinitis
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    1 / 852 (0.12%)
    2 / 850 (0.24%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    2 / 852 (0.23%)
    3 / 850 (0.35%)
    1 / 418 (0.24%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 852 (0.12%)
    3 / 850 (0.35%)
    1 / 418 (0.24%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    2 / 852 (0.23%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 852 (0.12%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Extradural abscess
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    2 / 852 (0.23%)
    2 / 850 (0.24%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Folliculitis
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    3 / 852 (0.35%)
    1 / 850 (0.12%)
    1 / 418 (0.24%)
    2 / 426 (0.47%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 852 (0.00%)
    2 / 850 (0.24%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gingivitis
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    9 / 852 (1.06%)
    5 / 850 (0.59%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 6
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Human herpesvirus 6 infection
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 852 (0.00%)
    3 / 850 (0.35%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Infection in an immunocompromised host
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection reactivation
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    6 / 852 (0.70%)
    10 / 850 (1.18%)
    3 / 418 (0.72%)
    5 / 426 (1.17%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 10
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Intervertebral discitis
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    12 / 852 (1.41%)
    5 / 850 (0.59%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 16
    0 / 5
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection fungal
         subjects affected / exposed
    1 / 852 (0.12%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection viral
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 852 (0.00%)
    2 / 850 (0.24%)
    2 / 418 (0.48%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningitis meningococcal
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Meningitis pneumococcal
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Necrotising fasciitis
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenic infection
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    3 / 852 (0.35%)
    2 / 850 (0.24%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 852 (0.12%)
    3 / 850 (0.35%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 3
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    3 / 852 (0.35%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Perineal abscess
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Periodontitis
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 852 (0.00%)
    2 / 850 (0.24%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Peritonsillar abscess
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumococcal sepsis
         subjects affected / exposed
    1 / 852 (0.12%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumocystis jirovecii infection
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    82 / 852 (9.62%)
    79 / 850 (9.29%)
    34 / 418 (8.13%)
    31 / 426 (7.28%)
         occurrences causally related to treatment / all
    0 / 114
    2 / 95
    1 / 45
    0 / 46
         deaths causally related to treatment / all
    0 / 11
    0 / 6
    0 / 3
    0 / 8
    Pneumonia bacterial
         subjects affected / exposed
    0 / 852 (0.00%)
    2 / 850 (0.24%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia klebsiella
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia legionella
         subjects affected / exposed
    1 / 852 (0.12%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia respiratory syncytial viral
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia staphylococcal
         subjects affected / exposed
    1 / 852 (0.12%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    1 / 852 (0.12%)
    1 / 850 (0.12%)
    1 / 418 (0.24%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural sepsis
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pseudomonal sepsis
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary mycosis
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    8 / 852 (0.94%)
    7 / 850 (0.82%)
    8 / 418 (1.91%)
    5 / 426 (1.17%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 8
    0 / 8
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Respiratory tract infection fungal
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Salmonellosis
         subjects affected / exposed
    1 / 852 (0.12%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Scrotal abscess
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    24 / 852 (2.82%)
    19 / 850 (2.24%)
    8 / 418 (1.91%)
    11 / 426 (2.58%)
         occurrences causally related to treatment / all
    1 / 31
    0 / 21
    0 / 9
    0 / 17
         deaths causally related to treatment / all
    0 / 9
    0 / 2
    0 / 3
    0 / 3
    Sepsis syndrome
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Septic necrosis
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    7 / 852 (0.82%)
    6 / 850 (0.71%)
    7 / 418 (1.67%)
    2 / 426 (0.47%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 8
    0 / 9
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 4
    0 / 4
    0 / 0
    Sinusitis
         subjects affected / exposed
    2 / 852 (0.23%)
    2 / 850 (0.24%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal cord infection
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    2 / 852 (0.23%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    2 / 852 (0.23%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal skin infection
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    0 / 852 (0.00%)
    2 / 850 (0.24%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 852 (0.23%)
    7 / 850 (0.82%)
    2 / 418 (0.48%)
    2 / 426 (0.47%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 7
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    9 / 852 (1.06%)
    6 / 850 (0.71%)
    2 / 418 (0.48%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 10
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 852 (0.12%)
    3 / 850 (0.35%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Varicella
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    3 / 852 (0.35%)
    2 / 850 (0.24%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral myositis
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal abscess
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abscess jaw
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abscess neck
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abscess soft tissue
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    2 / 418 (0.48%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute sinusitis
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacterial parotitis
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    2 / 418 (0.48%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Campylobacter gastroenteritis
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Candida infection
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis bacterial
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epiglottitis
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis norovirus
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis salmonella
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis B
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes virus infection
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster cutaneous disseminated
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infected dermal cyst
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine infection
         subjects affected / exposed
    1 / 852 (0.12%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningitis cryptococcal
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metapneumovirus infection
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Opportunistic infection
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Otitis externa
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Parvovirus B19 infection
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural infection
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia fungal
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Pneumonia haemophilus
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia pseudomonal
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia streptococcal
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pseudomembranous colitis
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection fungal
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular device infection
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    1 / 852 (0.12%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    2 / 852 (0.23%)
    2 / 850 (0.24%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    12 / 852 (1.41%)
    10 / 850 (1.18%)
    3 / 418 (0.72%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 12
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    1 / 852 (0.12%)
    2 / 850 (0.24%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    3 / 852 (0.35%)
    1 / 850 (0.12%)
    1 / 418 (0.24%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 1
    Fluid imbalance
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    2 / 852 (0.23%)
    2 / 850 (0.24%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemosiderosis
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    8 / 852 (0.94%)
    2 / 850 (0.24%)
    0 / 418 (0.00%)
    3 / 426 (0.70%)
         occurrences causally related to treatment / all
    1 / 9
    0 / 2
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 852 (0.00%)
    3 / 850 (0.35%)
    1 / 418 (0.24%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 852 (0.00%)
    2 / 850 (0.24%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypernatraemia
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperproteinaemia
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperuricaemia
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    2 / 852 (0.23%)
    8 / 850 (0.94%)
    2 / 418 (0.48%)
    2 / 426 (0.47%)
         occurrences causally related to treatment / all
    1 / 2
    7 / 8
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    2 / 852 (0.23%)
    3 / 850 (0.35%)
    1 / 418 (0.24%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    7 / 852 (0.82%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    2 / 426 (0.47%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    3 / 852 (0.35%)
    3 / 850 (0.35%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lactic acidosis
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    1 / 852 (0.12%)
    0 / 850 (0.00%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemic hyperosmolar nonketotic syndrome
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    0 / 852 (0.00%)
    0 / 850 (0.00%)
    1 / 418 (0.24%)
    1 / 426 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Obesity
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Steroid diabetes
         subjects affected / exposed
    0 / 852 (0.00%)
    1 / 850 (0.12%)
    0 / 418 (0.00%)
    0 / 426 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 DB: Zoledronic Acid DB: Denosumab OL: Zoledronic Acid / Denosumab OL: Denosumab / Denosumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    778 / 852 (91.31%)
    757 / 850 (89.06%)
    313 / 418 (74.88%)
    312 / 426 (73.24%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    70 / 852 (8.22%)
    63 / 850 (7.41%)
    13 / 418 (3.11%)
    16 / 426 (3.76%)
         occurrences all number
    101
    83
    18
    18
    Hypotension
         subjects affected / exposed
    39 / 852 (4.58%)
    50 / 850 (5.88%)
    6 / 418 (1.44%)
    7 / 426 (1.64%)
         occurrences all number
    43
    57
    6
    10
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    128 / 852 (15.02%)
    112 / 850 (13.18%)
    26 / 418 (6.22%)
    18 / 426 (4.23%)
         occurrences all number
    190
    182
    31
    20
    Fatigue
         subjects affected / exposed
    215 / 852 (25.23%)
    206 / 850 (24.24%)
    43 / 418 (10.29%)
    38 / 426 (8.92%)
         occurrences all number
    357
    312
    66
    52
    Mucosal inflammation
         subjects affected / exposed
    55 / 852 (6.46%)
    76 / 850 (8.94%)
    5 / 418 (1.20%)
    3 / 426 (0.70%)
         occurrences all number
    67
    100
    5
    3
    Oedema peripheral
         subjects affected / exposed
    147 / 852 (17.25%)
    152 / 850 (17.88%)
    29 / 418 (6.94%)
    14 / 426 (3.29%)
         occurrences all number
    208
    226
    31
    18
    Pyrexia
         subjects affected / exposed
    210 / 852 (24.65%)
    182 / 850 (21.41%)
    30 / 418 (7.18%)
    44 / 426 (10.33%)
         occurrences all number
    311
    268
    42
    67
    Pain
         subjects affected / exposed
    39 / 852 (4.58%)
    45 / 850 (5.29%)
    5 / 418 (1.20%)
    16 / 426 (3.76%)
         occurrences all number
    48
    57
    5
    19
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    170 / 852 (19.95%)
    159 / 850 (18.71%)
    51 / 418 (12.20%)
    47 / 426 (11.03%)
         occurrences all number
    261
    228
    63
    66
    Dyspnoea
         subjects affected / exposed
    96 / 852 (11.27%)
    83 / 850 (9.76%)
    22 / 418 (5.26%)
    25 / 426 (5.87%)
         occurrences all number
    130
    117
    27
    35
    Oropharyngeal pain
         subjects affected / exposed
    46 / 852 (5.40%)
    65 / 850 (7.65%)
    13 / 418 (3.11%)
    12 / 426 (2.82%)
         occurrences all number
    56
    77
    14
    16
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    72 / 852 (8.45%)
    61 / 850 (7.18%)
    4 / 418 (0.96%)
    7 / 426 (1.64%)
         occurrences all number
    83
    68
    4
    7
    Depression
         subjects affected / exposed
    66 / 852 (7.75%)
    47 / 850 (5.53%)
    4 / 418 (0.96%)
    8 / 426 (1.88%)
         occurrences all number
    73
    54
    4
    8
    Insomnia
         subjects affected / exposed
    135 / 852 (15.85%)
    132 / 850 (15.53%)
    20 / 418 (4.78%)
    15 / 426 (3.52%)
         occurrences all number
    174
    171
    22
    16
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    80 / 852 (9.39%)
    36 / 850 (4.24%)
    15 / 418 (3.59%)
    9 / 426 (2.11%)
         occurrences all number
    136
    54
    31
    12
    Platelet count decreased
         subjects affected / exposed
    55 / 852 (6.46%)
    55 / 850 (6.47%)
    10 / 418 (2.39%)
    14 / 426 (3.29%)
         occurrences all number
    163
    178
    23
    35
    Weight decreased
         subjects affected / exposed
    61 / 852 (7.16%)
    61 / 850 (7.18%)
    12 / 418 (2.87%)
    9 / 426 (2.11%)
         occurrences all number
    78
    80
    12
    10
    Injury, poisoning and procedural complications
    Lumbar vertebral fracture
         subjects affected / exposed
    72 / 852 (8.45%)
    70 / 850 (8.24%)
    1 / 418 (0.24%)
    1 / 426 (0.23%)
         occurrences all number
    82
    94
    1
    1
    Rib fracture
         subjects affected / exposed
    70 / 852 (8.22%)
    69 / 850 (8.12%)
    2 / 418 (0.48%)
    3 / 426 (0.70%)
         occurrences all number
    118
    119
    2
    3
    Thoracic vertebral fracture
         subjects affected / exposed
    75 / 852 (8.80%)
    95 / 850 (11.18%)
    0 / 418 (0.00%)
    1 / 426 (0.23%)
         occurrences all number
    108
    141
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    94 / 852 (11.03%)
    92 / 850 (10.82%)
    19 / 418 (4.55%)
    14 / 426 (3.29%)
         occurrences all number
    119
    121
    19
    16
    Headache
         subjects affected / exposed
    88 / 852 (10.33%)
    100 / 850 (11.76%)
    12 / 418 (2.87%)
    19 / 426 (4.46%)
         occurrences all number
    124
    145
    17
    25
    Hypoaesthesia
         subjects affected / exposed
    47 / 852 (5.52%)
    52 / 850 (6.12%)
    11 / 418 (2.63%)
    9 / 426 (2.11%)
         occurrences all number
    58
    72
    15
    9
    Neuropathy peripheral
         subjects affected / exposed
    147 / 852 (17.25%)
    134 / 850 (15.76%)
    17 / 418 (4.07%)
    14 / 426 (3.29%)
         occurrences all number
    215
    182
    18
    14
    Paraesthesia
         subjects affected / exposed
    73 / 852 (8.57%)
    70 / 850 (8.24%)
    12 / 418 (2.87%)
    11 / 426 (2.58%)
         occurrences all number
    93
    79
    12
    12
    Peripheral sensory neuropathy
         subjects affected / exposed
    73 / 852 (8.57%)
    80 / 850 (9.41%)
    12 / 418 (2.87%)
    5 / 426 (1.17%)
         occurrences all number
    127
    136
    17
    8
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    185 / 852 (21.71%)
    208 / 850 (24.47%)
    51 / 418 (12.20%)
    62 / 426 (14.55%)
         occurrences all number
    472
    678
    164
    205
    Febrile neutropenia
         subjects affected / exposed
    82 / 852 (9.62%)
    89 / 850 (10.47%)
    9 / 418 (2.15%)
    2 / 426 (0.47%)
         occurrences all number
    92
    97
    10
    2
    Neutropenia
         subjects affected / exposed
    166 / 852 (19.48%)
    173 / 850 (20.35%)
    40 / 418 (9.57%)
    51 / 426 (11.97%)
         occurrences all number
    455
    590
    66
    162
    Thrombocytopenia
         subjects affected / exposed
    151 / 852 (17.72%)
    174 / 850 (20.47%)
    27 / 418 (6.46%)
    27 / 426 (6.34%)
         occurrences all number
    439
    665
    107
    115
    Leukopenia
         subjects affected / exposed
    41 / 852 (4.81%)
    47 / 850 (5.53%)
    10 / 418 (2.39%)
    10 / 426 (2.35%)
         occurrences all number
    104
    163
    40
    57
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    49 / 852 (5.75%)
    78 / 850 (9.18%)
    16 / 418 (3.83%)
    13 / 426 (3.05%)
         occurrences all number
    68
    97
    22
    17
    Constipation
         subjects affected / exposed
    214 / 852 (25.12%)
    207 / 850 (24.35%)
    19 / 418 (4.55%)
    27 / 426 (6.34%)
         occurrences all number
    298
    296
    21
    35
    Diarrhoea
         subjects affected / exposed
    301 / 852 (35.33%)
    304 / 850 (35.76%)
    73 / 418 (17.46%)
    57 / 426 (13.38%)
         occurrences all number
    516
    507
    103
    102
    Dyspepsia
         subjects affected / exposed
    62 / 852 (7.28%)
    60 / 850 (7.06%)
    12 / 418 (2.87%)
    11 / 426 (2.58%)
         occurrences all number
    85
    83
    12
    14
    Nausea
         subjects affected / exposed
    274 / 852 (32.16%)
    284 / 850 (33.41%)
    32 / 418 (7.66%)
    35 / 426 (8.22%)
         occurrences all number
    466
    474
    43
    48
    Stomatitis
         subjects affected / exposed
    53 / 852 (6.22%)
    63 / 850 (7.41%)
    5 / 418 (1.20%)
    8 / 426 (1.88%)
         occurrences all number
    64
    77
    7
    11
    Vomiting
         subjects affected / exposed
    159 / 852 (18.66%)
    147 / 850 (17.29%)
    18 / 418 (4.31%)
    19 / 426 (4.46%)
         occurrences all number
    238
    211
    25
    23
    Abdominal pain upper
         subjects affected / exposed
    44 / 852 (5.16%)
    42 / 850 (4.94%)
    9 / 418 (2.15%)
    6 / 426 (1.41%)
         occurrences all number
    56
    47
    9
    7
    Toothache
         subjects affected / exposed
    45 / 852 (5.28%)
    50 / 850 (5.88%)
    27 / 418 (6.46%)
    16 / 426 (3.76%)
         occurrences all number
    51
    64
    31
    19
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    48 / 852 (5.63%)
    56 / 850 (6.59%)
    0 / 418 (0.00%)
    4 / 426 (0.94%)
         occurrences all number
    65
    74
    0
    5
    Pruritus
         subjects affected / exposed
    51 / 852 (5.99%)
    54 / 850 (6.35%)
    6 / 418 (1.44%)
    12 / 426 (2.82%)
         occurrences all number
    69
    64
    6
    13
    Rash
         subjects affected / exposed
    102 / 852 (11.97%)
    132 / 850 (15.53%)
    17 / 418 (4.07%)
    17 / 426 (3.99%)
         occurrences all number
    135
    174
    19
    23
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    118 / 852 (13.85%)
    131 / 850 (15.41%)
    44 / 418 (10.53%)
    36 / 426 (8.45%)
         occurrences all number
    195
    191
    65
    48
    Back pain
         subjects affected / exposed
    181 / 852 (21.24%)
    194 / 850 (22.82%)
    46 / 418 (11.00%)
    56 / 426 (13.15%)
         occurrences all number
    262
    268
    64
    64
    Bone pain
         subjects affected / exposed
    105 / 852 (12.32%)
    99 / 850 (11.65%)
    16 / 418 (3.83%)
    13 / 426 (3.05%)
         occurrences all number
    145
    128
    19
    13
    Muscle spasms
         subjects affected / exposed
    50 / 852 (5.87%)
    63 / 850 (7.41%)
    28 / 418 (6.70%)
    27 / 426 (6.34%)
         occurrences all number
    71
    89
    31
    28
    Musculoskeletal pain
         subjects affected / exposed
    82 / 852 (9.62%)
    72 / 850 (8.47%)
    20 / 418 (4.78%)
    23 / 426 (5.40%)
         occurrences all number
    108
    96
    29
    29
    Myalgia
         subjects affected / exposed
    55 / 852 (6.46%)
    50 / 850 (5.88%)
    15 / 418 (3.59%)
    6 / 426 (1.41%)
         occurrences all number
    72
    68
    17
    6
    Pain in extremity
         subjects affected / exposed
    138 / 852 (16.20%)
    127 / 850 (14.94%)
    29 / 418 (6.94%)
    28 / 426 (6.57%)
         occurrences all number
    198
    178
    42
    32
    Musculoskeletal chest pain
         subjects affected / exposed
    44 / 852 (5.16%)
    42 / 850 (4.94%)
    7 / 418 (1.67%)
    13 / 426 (3.05%)
         occurrences all number
    52
    46
    9
    16
    Osteonecrosis of jaw
         subjects affected / exposed
    24 / 852 (2.82%)
    38 / 850 (4.47%)
    22 / 418 (5.26%)
    36 / 426 (8.45%)
         occurrences all number
    28
    42
    26
    41
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    72 / 852 (8.45%)
    72 / 850 (8.47%)
    31 / 418 (7.42%)
    32 / 426 (7.51%)
         occurrences all number
    88
    87
    47
    41
    Herpes zoster
         subjects affected / exposed
    68 / 852 (7.98%)
    62 / 850 (7.29%)
    13 / 418 (3.11%)
    5 / 426 (1.17%)
         occurrences all number
    73
    68
    16
    5
    Nasopharyngitis
         subjects affected / exposed
    79 / 852 (9.27%)
    84 / 850 (9.88%)
    42 / 418 (10.05%)
    38 / 426 (8.92%)
         occurrences all number
    129
    129
    60
    54
    Respiratory tract infection
         subjects affected / exposed
    53 / 852 (6.22%)
    56 / 850 (6.59%)
    25 / 418 (5.98%)
    26 / 426 (6.10%)
         occurrences all number
    77
    81
    44
    36
    Upper respiratory tract infection
         subjects affected / exposed
    127 / 852 (14.91%)
    143 / 850 (16.82%)
    62 / 418 (14.83%)
    58 / 426 (13.62%)
         occurrences all number
    219
    231
    106
    104
    Urinary tract infection
         subjects affected / exposed
    51 / 852 (5.99%)
    63 / 850 (7.41%)
    17 / 418 (4.07%)
    19 / 426 (4.46%)
         occurrences all number
    68
    88
    17
    25
    Influenza
         subjects affected / exposed
    33 / 852 (3.87%)
    26 / 850 (3.06%)
    23 / 418 (5.50%)
    23 / 426 (5.40%)
         occurrences all number
    40
    33
    25
    30
    Pneumonia
         subjects affected / exposed
    50 / 852 (5.87%)
    41 / 850 (4.82%)
    20 / 418 (4.78%)
    13 / 426 (3.05%)
         occurrences all number
    63
    45
    22
    15
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    166 / 852 (19.48%)
    140 / 850 (16.47%)
    12 / 418 (2.87%)
    12 / 426 (2.82%)
         occurrences all number
    230
    191
    12
    13
    Hypocalcaemia
         subjects affected / exposed
    99 / 852 (11.62%)
    141 / 850 (16.59%)
    27 / 418 (6.46%)
    30 / 426 (7.04%)
         occurrences all number
    188
    330
    51
    62
    Hypokalaemia
         subjects affected / exposed
    140 / 852 (16.43%)
    129 / 850 (15.18%)
    26 / 418 (6.22%)
    26 / 426 (6.10%)
         occurrences all number
    292
    224
    51
    69
    Hypomagnesaemia
         subjects affected / exposed
    52 / 852 (6.10%)
    39 / 850 (4.59%)
    7 / 418 (1.67%)
    9 / 426 (2.11%)
         occurrences all number
    76
    50
    10
    21
    Hypophosphataemia
         subjects affected / exposed
    48 / 852 (5.63%)
    59 / 850 (6.94%)
    15 / 418 (3.59%)
    12 / 426 (2.82%)
         occurrences all number
    128
    145
    29
    27

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Aug 2011
    - specified that antimyeloma therapy (excluding bisphosphonates) could start before randomization if the subject has signed informed consent and screening blood samples have been collected for central analysis. Also, the first dose of investigational product was not linked to the initiation of antimyeloma therapy, and it could be before or after antimyeloma therapy was started. This permitted the initiation of antimyeloma therapy without delays because of the protocol screening process. - eliminated the requirement that the SC injection of blinded investigational product must be before the IV infusion of blinded investigational product - added citations and made modifications to the response criteria - clarified that serious adverse events would be submitted to Amgen using an electronic method - removed the PRO assessment on day 8 - made minor changes to exploratory endpoints and covariates
    11 Feb 2013
    - changed the assessments of myeloma disease response and progression from central analysis to local analysis as per standard of care in the management of multiple myeloma - permitted a limited duration of prior antimyeloma therapy before enrollment - reduced the number and timing of laboratory tests - reassigned the endpoint of progression-free survival from additional secondary to exploratory, and deleted exploratory endpoints related to disease response - modified the prestudy bisphosphonate exposure to allow a limited duration - provided additional guidance regarding investigational product dosing and oral/dental procedures - reduced the skeletal surveys after 3 years from every 12 weeks to every 24 weeks
    12 Aug 2015
    - increased the study sample size by 180 subjects and decreased power to 85% - deleted the trade name "Zometa" to allow for the use of branded or generic zoledronic acid supplied for the study - updated pregnancy and contraception language and included updated pregnancy and lactation notification worksheets - defined potentially unblinding test values that would remain blinded
    18 Dec 2017
    - updated information about the DMC meetings; after the DMC review of the primary analysis in July 2016, no further DMC meetings were to be held for this study (aligned with the expectations set forth in the DMC charter) - updated the schedule of assessment to provide information aligned to support the primary objectives of the open-label treatment period of the study

    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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