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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
         Protocol Deviation
    5
    -
         Ineligibility Determined
    1
    6
         Disease Progression
    12
    10
         Death
    147
    137
         Noncompliance
    5
    3
         Other, Not Specified
    2
    3
         Administrative Decision
    10
    8
         Adverse event, non-fatal
    6
    13
         Completed Survival Follow-up
    21
    9
         Consent withdrawn by subject
    103
    112
         Lost to follow-up
    6
    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
         Protocol deviation
    -
    1
         Death
    49
    48
         Disease Progression
    17
    18
         Noncompliance
    5
    4
         Other, Not Specified
    9
    7
         Pregnancy
    1
    -
         Administrative Decision
    30
    15
         Adverse event, non-fatal
    30
    51
         Consent withdrawn by subject
    49
    47
         Lost to follow-up
    1
    2
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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