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    Clinical Trial Results:
    An Open Label, Single Arm, Extension Study to Evaluate the Long Term Safety and Sustained Efficacy of Denosumab (AMG162) in the Treatment of Postmenopausal Osteoporosis

    Summary
    EudraCT number
    		 2007-001041-17
    Trial protocol
    		 DK   SE   EE   DE   LV   GB   LT   HU   AT   FI   BE   MT   CZ   FR   ES   GR   IT   BG   SK  
    Global end of trial date
    29 Jul 2015

    Results information
    Results version number
    		 v2(current)
    This version publication date
    01 Apr 2017
    First version publication date
    04 Aug 2016
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    add histomorphology endpoint data

    Trial information

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    Trial identification
    Sponsor protocol code
    20060289
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00523341
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Amgen, inc.
    Sponsor organisation address
    One Amgen Center Drive, Thousand oaks, CA, United States, 91320
    Public contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Scientific contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    29 Jul 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Jul 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to describe the safety and tolerability of up to 10 years or 7 years denosumab administration as measured by adverse event monitoring, immunogenicity and safety laboratory parameters in participants who previously received denosumab or placebo, respectively.
    Protection of trial subjects
    This study was conducted in accordance with the principles of the Food and Drug Administration (FDA) and International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines. 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
    07 Aug 2007
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 496
    Country: Number of subjects enrolled
    Denmark: 898
    Country: Number of subjects enrolled
    Czech Republic: 381
    Country: Number of subjects enrolled
    United Kingdom: 327
    Country: Number of subjects enrolled
    Estonia: 296
    Country: Number of subjects enrolled
    Brazil: 287
    Country: Number of subjects enrolled
    Argentina: 211
    Country: Number of subjects enrolled
    United States: 178
    Country: Number of subjects enrolled
    Spain: 165
    Country: Number of subjects enrolled
    Hungary: 132
    Country: Number of subjects enrolled
    Italy: 132
    Country: Number of subjects enrolled
    Germany: 116
    Country: Number of subjects enrolled
    Norway: 98
    Country: Number of subjects enrolled
    Austria: 86
    Country: Number of subjects enrolled
    Belgium: 84
    Country: Number of subjects enrolled
    France: 83
    Country: Number of subjects enrolled
    Sweden: 78
    Country: Number of subjects enrolled
    Latvia: 75
    Country: Number of subjects enrolled
    Mexico: 72
    Country: Number of subjects enrolled
    Canada: 66
    Country: Number of subjects enrolled
    Slovakia: 52
    Country: Number of subjects enrolled
    Lithuania: 45
    Country: Number of subjects enrolled
    Switzerland: 40
    Country: Number of subjects enrolled
    New Zealand: 33
    Country: Number of subjects enrolled
    Australia: 25
    Country: Number of subjects enrolled
    Bulgaria: 25
    Country: Number of subjects enrolled
    Finland: 19
    Country: Number of subjects enrolled
    Greece: 15
    Country: Number of subjects enrolled
    Malta: 15
    Country: Number of subjects enrolled
    Serbia: 15
    Country: Number of subjects enrolled
    Romania: 5
    Worldwide total number of subjects
    4550
    EEA total number of subjects
    3623
    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)
    107
    From 65 to 84 years
    4304
    85 years and over
    139

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was an extension study open to participants who had completed core study 20030216 (NCT00089791). The study was conducted at 178 centers in North America, South America, Europe, Australia, and New Zealand. Participants were enrolled from 7 August 2007 to 20 June 2008.

    Pre-assignment
    Screening details
    		 All participants received open-label denosumab during this study. Results are reported by the Study 20030216 randomized treatment groups (placebo versus denosumab).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo / Denosumab
    Arm description
    		 Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Denosumab
    Investigational medicinal product code
    AMG 162
    Other name
    Prolia
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered by subcutaneous injection once every 6 months.

    Arm title
    		 Denosumab / Denosumab
    Arm description
    		 Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Denosumab
    Investigational medicinal product code
    AMG 162
    Other name
    Prolia
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered by subcutaneous injection once every 6 months.

    Number of subjects in period 1
    		Placebo / Denosumab Denosumab / Denosumab
    Started
    2207
    2343
    Received Treatment
    2206
    2343
    Completed
    1283
    1343
    Not completed
    924
    1000
         Consent withdrawn by subject
    399
    427
         Physician decision
    14
    13
         Ineligibility Determined
    3
    4
         Adverse event, non-fatal
    122
    155
         Protocol Deviation
    6
    5
         Other
    181
    198
         Death
    101
    110
         Non-compliance
    20
    13
         Lost to follow-up
    73
    61
         Requirement for Alternative Therapy
    4
    14
         Disease Progression
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo / Denosumab
    Reporting group description
    		 Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.

    Reporting group title
    Denosumab / Denosumab
    Reporting group description
    		 Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).

    Reporting group values
    		 Placebo / Denosumab Denosumab / Denosumab Total
    Number of subjects
    		 2207 2343 4550
    Age, Customized
    Units: participants
        60 - 64 years
    		 58 49 107
        65 - 69 years
    		 326 320 646
        70 - 74 years
    		 672 716 1388
        ≥ 75 years
    		 1151 1258 2409
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 74.8 ( 5.1 ) 74.9 ( 5 ) -
    Gender, Male/Female
    Units: participants
        Female
    		 2207 2343 4550
        Male
    		 0 0 0
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 2063 2169 4232
        Black
    		 16 19 35
        Hispanic or Latino
    		 121 145 266
        Asian
    		 2 3 5
        Japanese
    		 3 5 8
        Native Hawaiian or Other Pacific Islander
    		 1 0 1
        Other
    		 1 2 3
    Bone Mineral Density T-score | Lumbar spine
    The T-score is the bone mineral density (BMD) at the site when compared to that of a healthy thirty-year-old. Normal is a T-score of −1.0 or higher; Osteopenia is defined as between −1.0 and −2.5; Osteoporosis is defined as −2.5 or lower, meaning a bone density that is two and a half standard deviations below the mean of a thirty-year-old man/woman.
    Units: T-score
        arithmetic mean (standard deviation)
    		 -2.81 ( 0.75 ) -2.14 ( 0.8 ) -
    Bone Mineral Density T-score | Total hip
    The T-score is the bone mineral density (BMD) at the site when compared to that of a healthy thirty-year-old. Normal is a T-score of −1.0 or higher; Osteopenia is defined as between −1.0 and −2.5; Osteoporosis is defined as −2.5 or lower, meaning a bone density that is two and a half standard deviations below the mean of a thirty-year-old man/woman.
    Units: T-score
        arithmetic mean (standard deviation)
    		 -1.93 ( 0.8 ) -1.5 ( 0.79 ) -
    Bone Mineral Density T-score | Femoral neck
    The T-score is the bone mineral density (BMD) at the site when compared to that of a healthy thirty-year-old. Normal is a T-score of −1.0 or higher; Osteopenia is defined as between −1.0 and −2.5; Osteoporosis is defined as −2.5 or lower, meaning a bone density that is two and a half standard deviations below the mean of a thirty-year-old man/woman.
    Units: T-score
        arithmetic mean (standard deviation)
    		 -2.17 ( 0.72 ) -1.83 ( 0.75 ) -
    Bone Mineral Density T-score at Study 20030216 Baseline | Lumbar spine
    Units: T-score
        arithmetic mean (standard deviation)
    		 -2.84 ( 0.68 ) -2.83 ( 0.67 ) -
    Bone Mineral Density T-score at Study 20030216 Baseline | Total hip
    Units: T-score
        arithmetic mean (standard deviation)
    		 -1.85 ( 0.79 ) -1.85 ( 0.79 ) -
    Bone Mineral Density T-score at Study 20030216 Baseline | Femoral neck
    Units: T-score
        arithmetic mean (standard deviation)
    		 -2.11 ( 0.71 ) -2.11 ( 0.71 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo / Denosumab
    Reporting group description
    		 Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.

    Reporting group title
    Denosumab / Denosumab
    Reporting group description
    		 Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).

    Primary: Number of participants with Adverse Events (AEs)

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    End point title
    		 Number of participants with Adverse Events (AEs) [1]
    End point description
    A serious adverse event (SAE) is defined as an AE that: • is fatal • is life threatening • requires in-patient hospitalization or prolongation of existing hospitalization • results in persistent or significant disability/incapacity • is a congenital anomaly/birth defect • is other significant medical hazard. Treatment-related adverse events includes only events for which the investigator indicated there was a reasonable possibility they may have been caused by study drug. The following were classified as adverse events of interest (events that are considered to be identified or potential risks of denosumab treatment): positively adjudicated osteonecrosis of the jaw, positively adjudicated atypical femoral fracture, hypocalcemia, adverse events potentially related to hypersensitivity, serious infection (including bacterial cellulitis), malignancy, cardiac disorders, vascular disorders, fracture healing complications, eczema, acute pancreatitis, and musculoskeletal pain.
    End point type
    Primary
    End point timeframe
    84 months
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical testing was performed.
    End point values
    		 Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    2206
    2343
    Units: participants
    number (not applicable)
        Any adverse event (AE)
    2070
    2173
        Serious adverse event
    945
    1014
        Fatal adverse event
    101
    108
        AE leading to study discontinuation
    145
    173
        AE leading to discontinuation of denosumab
    184
    216
        Treatment-related adverse events (TRAE)
    185
    188
        Serious treatment-related adverse events
    26
    28
        Fatal treatment-related adverse events
    1
    0
        TRAE leading to study discontinuation
    16
    9
        TRAE leading to discontinuation of denosumab
    30
    25
        Positively adjudicated osteonecrosis of the jaw
    6
    7
        Positively adjudicated atypical femoral fracture
    1
    1
        Hypocalcaemia
    10
    6
        AEs potentially related to hypersensitivity
    260
    280
        Serious infections
    161
    185
        Serious bacterial cellulitis
    7
    12
        Malignancy
    227
    237
        Cardiac disorders
    449
    492
        Vascular disorders
    693
    732
        Fracture healing complications
    0
    1
        Eczema
    99
    115
        Acute pancreatitis
    4
    8
        Musculoskeletal pain
    1125
    1206
    No statistical analyses for this end point

    Primary: Number of Participants with Laboratory Toxicities of Grade ≥ 3

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    End point title
    		 Number of Participants with Laboratory Toxicities of Grade ≥ 3 [2]
    End point description
    Laboratory toxicity grading was based on Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Grade 3 indicates severe toxicity and Grade 4 indicates life-threatening toxicity.
    End point type
    Primary
    End point timeframe
    84 months
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical testing was performed.
    End point values
    		 Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    2206
    2343
    Units: participants
    number (not applicable)
        Low sodium - Grade 3
    28
    25
        Low sodium - Grade 4
    1
    0
        High potassium - Grade 3
    9
    11
        High potassium - Grade 4
    0
    3
        Low potassium - Grade 3
    7
    7
        Low magnesium - Grade 3
    1
    1
        Low magnesium - Grade 4
    0
    1
        High calcium - Grade 3
    2
    3
        High calcium - Grade 4
    0
    2
        High corrected calcium - Grade 3
    2
    3
        High corrected calcium - Grade 4
    0
    2
        Low phosphorus - Grade 3
    3
    1
        High Creatinine - Grade 3
    0
    1
        High aspartate amino transferase (AST) - Grade 3
    5
    11
        High aspartate amino transferase (AST) - Grade 4
    1
    0
        High alanine amino transferase (ALT) - Grade 3
    8
    10
        High alanine amino transferase (ALT) - Grade 4
    1
    0
        High total bilirubin - Grade 3
    2
    3
        Low albumin - Grade 3
    0
    1
        High glucose - Grade 3
    35
    37
        High glucose - Grade 4
    0
    1
        Low glucose - Grade 3
    4
    1
        Low glucose - Grade 4
    1
    1
        Low hemoglobin - Grade 3
    6
    4
        Low platelets - Grade 3
    3
    7
        Low platelets - Grade 4
    2
    4
        Low white blood cells - Grade 3
    5
    7
        Low white blood cells - Grade 4
    0
    1
        Low lymphocytes - Grade 3
    17
    16
        Low lymphocytes - Grade 4
    2
    1
    No statistical analyses for this end point

    Primary: Number of Participants with Antibodies to Denosumab

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    End point title
    		 Number of Participants with Antibodies to Denosumab [3]
    End point description
    End point type
    Primary
    End point timeframe
    Every 12 months through Month 84
    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: No formal statistical testing was performed.
    End point values
    		 Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    2206
    2343
    Units: participants
        number (not applicable)
    1
    0
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Lumbar Spine Bone Mineral Density by Visit

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    End point title
    		 Percent Change From Baseline in Lumbar Spine Bone Mineral Density by Visit
    End point description
    Lumbar spine bone mineral density (BMD) was measured by dual x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. Analysis includes participants with an Extension Study baseline and at least 1 post-baseline DXA BMD measurement. "n" indicates the number of participants with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline (of extension study) and months 12, 24, 36, 60 and 84
    End point values
    		 Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    2089
    2210
    Units: percent change
    least squares mean (confidence interval 95%)
        Month 12 (n = 2040, 2168)
    5.2 (5 to 5.3)
    2 (1.8 to 2.2)
        Month 24 (n = 1935, 2061)
    7.7 (7.5 to 7.9)
    3.5 (3.4 to 3.7)
        Month 36 (n = 1497, 1607)
    9.4 (9.1 to 9.6)
    4.9 (4.7 to 5.1)
        Month 60 (n = 1472, 1567)
    13 (12.7 to 13.3)
    7.9 (7.6 to 8.2)
        Month 84 (n = 1223, 1264)
    16.5 (16.1 to 16.9)
    10.8 (10.4 to 11.2)
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Total Hip Bone Mineral Density by Visit

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    End point title
    		 Percent Change From Baseline in Total Hip Bone Mineral Density by Visit
    End point description
    Total hip bone mineral density was measured by dual x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. Analysis includes participants with an Extension Study baseline and at least 1 post-baseline DXA BMD measurement. "n" indicates the number of participants with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline (of extension study) and months 12, 24, 36, 60 and 84
    End point values
    		 Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    2089
    2210
    Units: percent change
    least squares mean (confidence interval 95%)
        Month 12 (n = 2029, 2160)
    3 (2.8 to 3.1)
    0.8 (0.7 to 0.9)
        Month 24 (n = 1918, 2045)
    4.1 (4 to 4.2)
    1.4 (1.3 to 1.5)
        Month 36 (n = 1475, 1591)
    4.9 (4.7 to 5)
    1.8 (1.7 to 2)
        Month 60 (n = 1439, 1538)
    6.2 (6 to 6.4)
    2.6 (2.4 to 2.8)
        Month 84 (n = 1200, 1232)
    7.4 (7.1 to 7.6)
    3.4 (3.2 to 3.7)
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Femoral Neck Bone Mineral Density by Visit

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    End point title
    		 Percent Change From Baseline in Femoral Neck Bone Mineral Density by Visit
    End point description
    Femoral neck bone mineral density was measured by dual x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. Analysis includes participants with an Extension Study baseline and at least 1 post-baseline DXA BMD measurement. "n" indicates the number of participants with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline (of extension study) and months 12, 24, 36, 60 and 84
    End point values
    		 Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    2089
    2210
    Units: percent change
    least squares mean (confidence interval 95%)
        Month 12 (n = 2029, 2160)
    2.1 (1.9 to 2.3)
    0.8 (0.7 to 1)
        Month 24 (n = 1918, 2045)
    3.2 (3.1 to 3.4)
    1.2 (1 to 1.4)
        Month 36 (n = 1475, 1591)
    4 (3.8 to 4.3)
    1.7 (1.5 to 1.9)
        Month 60 (n = 1439, 1538)
    5.7 (5.4 to 5.9)
    2.8 (2.6 to 3.1)
        Month 84 (n = 1200, 1232)
    7.1 (6.8 to 7.4)
    3.8 (3.5 to 4.2)
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in 1/3 Radius Bone Mineral Density by Visit

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    End point title
    		 Percent Change From Baseline in 1/3 Radius Bone Mineral Density by Visit
    End point description
    1/3 radius bone mineral density was measured in a subset of participants by dual x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. Analysis includes participants in the DXA substudy with an Extension Study baseline and at least 1 post-baseline DXA BMD measurement. "n" indicates the number of participants with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline (of extension study) and months 12, 24, 36, 60 and 84
    End point values
    		 Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    449
    467
    Units: percent change
    least squares mean (confidence interval 95%)
        Month 12 (n = 114, 134)
    0.3 (-0.2 to 0.9)
    0.6 (0.1 to 1.2)
        Month 24 (n = 108, 127)
    0.2 (-0.4 to 0.9)
    0.2 (-0.4 to 0.8)
        Month 36 (n = 73, 93)
    1.3 (0.5 to 2)
    0.6 (-0.1 to 1.3)
        Month 60 (n = 59, 84)
    1.8 (0.9 to 2.7)
    1.4 (0.6 to 2.2)
        Month 84 (n = 39, 56)
    2.2 (0.9 to 3.6)
    1 (-0.1 to 2.2)
    No statistical analyses for this end point

    Secondary: Percent Change From Study 20030216 Baseline in Lumbar Spine Bone Mineral Density by Visit

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    End point title
    		 Percent Change From Study 20030216 Baseline in Lumbar Spine Bone Mineral Density by Visit
    End point description
    Lumbar spine bone mineral density was measured by dual x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. Analysis includes participants with an Extension Study baseline and at least 1 post-baseline DXA BMD measurement. "n" indicates the number of participants with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Study 20030216 baseline and extension study months 12, 24, 36, 60 and 84
    End point values
    		 Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    2089
    2210
    Units: percent change
    least squares mean (confidence interval 95%)
        Month 12 (n = 2030, 2148)
    5.9 (5.6 to 6.1)
    11.9 (11.7 to 12.2)
        Month 24 (n = 1924, 2041)
    8.4 (8.1 to 8.7)
    13.7 (13.4 to 13.9)
        Month 36 (n = 1487, 1589)
    10.1 (9.8 to 10.4)
    15.2 (14.9 to 15.5)
        Month 60 (n = 1464, 1551)
    13.8 (13.4 to 14.1)
    18.4 (18.1 to 18.8)
        Month 84 (n = 1216, 1251)
    17.3 (16.8 to 17.8)
    21.7 (21.2 to 22.2)
    No statistical analyses for this end point

    Secondary: Percent Change From Study 20030216 Baseline in Total Hip BMD by Visit

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    End point title
    		 Percent Change From Study 20030216 Baseline in Total Hip BMD by Visit
    End point description
    Total hip bone mineral density was measured by dual x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. M Analysis includes participants with an Extension Study baseline and at least 1 post-baseline DXA BMD measurement. "n" indicates the number of participants with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Study 20030216 baseline and extension study months 12, 24, 36, 60 and 84
    End point values
    		 Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    2089
    2210
    Units: percent change
    least squares mean (confidence interval 95%)
        Month 12 (n = 2006, 2132)
    1.7 (1.6 to 1.9)
    6.4 (6.3 to 6.6)
        Month 24 (n = 1895, 2017)
    2.9 (2.7 to 3)
    7.1 (6.9 to 7.2)
        Month 36 (n = 1457, 1567)
    3.6 (3.4 to 3.8)
    7.5 (7.3 to 7.7)
        Month 60 (n = 1424, 1518)
    4.9 (4.7 to 5.2)
    8.4 (8.1 to 8.6)
        Month 84 (n = 1189, 1215)
    6.1 (5.8 to 6.4)
    9.2 (8.9 to 9.5)
    No statistical analyses for this end point

    Secondary: Percent Change From Study 20030216 Baseline in Femoral Neck BMD by Visit

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    End point title
    		 Percent Change From Study 20030216 Baseline in Femoral Neck BMD by Visit
    End point description
    Femoral neck bone mineral density was measured by dual x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. Analysis includes participants with an Extension Study baseline and at least 1 post-baseline DXA BMD measurement. "n" indicates the number of participants with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Study 20030216 baseline and extension study months 12, 24, 36, 60 and 84
    End point values
    		 Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    2089
    2210
    Units: percent change
    least squares mean (confidence interval 95%)
        Month 12 (n = 2006, 2132)
    1.4 (1.2 to 1.7)
    5.8 (5.6 to 6)
        Month 24 (n = 1895, 2017)
    2.6 (2.3 to 2.8)
    6.2 (6 to 6.5)
        Month 36 (n = 1457, 1567)
    3.4 (3.1 to 3.6)
    6.7 (6.5 to 7)
        Month 60 (n = 1424, 1518)
    5 (4.7 to 5.3)
    7.9 (7.6 to 8.2)
        Month 84 (n = 1189, 1215)
    6.4 (6 to 6.8)
    9 (8.6 to 9.4)
    No statistical analyses for this end point

    Secondary: Percent Change From Study 20030216 Baseline in 1/3 Radius BMD by Visit

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    End point title
    		 Percent Change From Study 20030216 Baseline in 1/3 Radius BMD by Visit
    End point description
    1/3 radius BMD was measured by dual x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. Analysis includes participants in the DXA substudy with an Extension Study baseline and at least 1 post-baseline DXA BMD measurement. "n" indicates the number of participants with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Study 20030216 baseline and extension study months 12, 24, 36, 60, and 84
    End point values
    		 Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    449
    467
    Units: percent change
    least squares mean (confidence interval 95%)
        Month 12 (n = 113, 133)
    -1 (-1.7 to -0.3)
    2.6 (1.9 to 3.2)
        Month 24 (n = 107, 127)
    -1.2 (-1.9 to -0.4)
    2.1 (1.4 to 2.8)
        Month 36 (n = 73, 92)
    -0.2 (-1.1 to 0.7)
    2.4 (1.6 to 3.2)
        Month 60 (n = 59, 83)
    0.3 (-0.7 to 1.3)
    3.3 (2.4 to 4.2)
        Month 84 (n = 39, 56)
    0.6 (-0.8 to 2.1)
    2.8 (1.6 to 4.1)
    No statistical analyses for this end point

    Secondary: Number of Participants With New Vertebral Fractures

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    End point title
    		 Number of Participants With New Vertebral Fractures
    End point description
    A new vertebral fracture, assessed by lateral spine X-ray using Genant semiquantitative scoring method, was identified as an ≥ 1 grade increase from the previous grade of 0 in any vertebra from T4 to L4, excluding any fracture associated with high trauma severity or a pathologic fracture. Analysis includes all participants enrolled in the extension study who have vertebral X-ray assessment at the extension baseline and at least 1 post-extension baseline visit.
    End point type
    Secondary
    End point timeframe
    84 months
    End point values
    		 Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    1991
    2116
    Units: participants
        number (not applicable)
    145
    149
    No statistical analyses for this end point

    Secondary: Number of Participants With Non-Vertebral Fractures

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    End point title
    		 Number of Participants With Non-Vertebral Fractures
    End point description
    Non-vertebral fractures (osteoporotic) were defined as a fracture present on a copy of radiographs or other diagnostic images such as computerized tomography (CT) or magnetic resonance imaging (MRI) confirming the fracture, and/or documented in a copy of the radiology report, surgical report, or discharge summary, excluding skull, facial, mandible, cervical vertebrae, thoracic vertebrae, lumbar vertebrae, metacarpus, finger phalanges, and toe phalanges. In addition, fractures associated with high trauma severity or pathologic fractures were excluded. Analysis includes all enrolled participants.
    End point type
    Secondary
    End point timeframe
    84 months
    End point values
    		 Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    2207
    2343
    Units: participants
        number (not applicable)
    219
    172
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in C-Telopeptide 1 (CTX-1) by Visit

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    End point title
    		 Percent Change From Baseline in C-Telopeptide 1 (CTX-1) by Visit
    End point description
    Bone turnover markers were collected in a subset of participants who participated in the 20030216 Bone Marker sub-study and in new participants continuing beyond month 24 who were not previously in the Bone Turnover Markers sub-study.
    End point type
    Secondary
    End point timeframe
    Baseline (of extension study), day 10, and months 6, 12, 24, 36, 48, 60, 72, and 84
    End point values
    		 Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    318
    342
    Units: percent change
    median (inter-quartile range (Q1-Q3))
        Day 10 (n = 26, 47)
    -90 (-93 to -85)
    -72 (-86 to -47)
        Month 6 (n = 30, 56)
    -85 (-91 to -73)
    -26 (-63 to 1)
        Month 12 (n = 27, 56)
    -75 (-90 to -54)
    -13 (-37 to 24)
        Month 24 (n = 27, 47)
    -67 (-84 to -29)
    10 (-27 to 55)
        Month 36 (n = 68, 81)
    -59 (-84 to -28)
    2 (-32 to 68)
        Month 48 (n = 62, 75)
    -58 (-84 to -12)
    0 (-46 to 56)
        Month 60 (n = 59, 70)
    -65 (-90 to -19)
    0 (-47 to 83)
        Month 72 (n = 56, 62)
    -60 (-85 to -16)
    -1 (-47 to 76)
        Month 84 (n = 41, 41)
    -64 (-86 to -28)
    -6 (-26 to 68)
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Procollagen Type 1 N-telopeptide (P1NP) by Visit

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    End point title
    		 Percent Change From Baseline in Procollagen Type 1 N-telopeptide (P1NP) by Visit
    End point description
    Bone turnover markers were collected in a subset of participants who participated in the 20030216 Bone Marker sub-study and in new participants continuing beyond month 24 who were not previously in the Bone Turnover Markers sub-study.
    End point type
    Secondary
    End point timeframe
    Baseline (of extension study), day 10, and months 6, 12, 24, 36, 48, 60, 72, and 84
    End point values
    		 Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    318
    342
    Units: percent change
    median (inter-quartile range (Q1-Q3))
        Day 10 (n = 30, 51)
    6 (-5 to 30)
    14 (-1 to 25)
        Month 6 (n = 30, 53)
    -71 (-78 to -62)
    -23 (-50 to -2)
        Month 12 (n = 26, 56)
    -67 (-76 to -57)
    7 (-15 to 30)
        Month 24 (n = 27, 47)
    -63 (-77 to -41)
    11 (-17 to 42)
        Month 36 (n = 69, 83)
    -57 (-67 to -29)
    29 (-6 to 91)
        Month 48 (n = 61, 73)
    -60 (-70 to -41)
    8 (-21 to 49)
        Month 60 (n = 61, 71)
    -54 (-72 to -35)
    30 (-6 to 67)
        Month 72 (n = 55, 64)
    -50 (-60 to -36)
    44 (3 to 103)
        Month 84 (n = 48, 50)
    -59 (-73 to -40)
    32 (-4 to 75)
    No statistical analyses for this end point

    Secondary: Percent Change From Study 20030216 Baseline in CTX-1 by Visit

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    End point title
    		 Percent Change From Study 20030216 Baseline in CTX-1 by Visit
    End point description
    Bone turnover markers were collected in a subset of participants who participated in the 20030216 Bone Marker sub-study and in new participants continuing beyond month 24 who were not previously in the Bone Turnover Markers sub-study.
    End point type
    Secondary
    End point timeframe
    Study 20030216 Baseline and extension study day 10, and months 6, 12, 24, 36, 48, 60, 72, and 84
    End point values
    		 Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    318
    342
    Units: percent change
    median (inter-quartile range (Q1-Q3))
        Day 10 (n = 26, 56)
    -90 (-91 to -78)
    -91 (-93 to -86)
        Month 6 (n = 32, 72)
    -83 (-90 to -72)
    -77 (-87 to -49)
        Month 12 (n = 27, 65)
    -77 (-91 to -45)
    -63 (-87 to -11)
        Month 24 (n = 28, 60)
    -65 (-80 to -24)
    -53 (-82 to 0)
        Month 36 (n = 289, 313)
    -71 (-88 to -40)
    -52 (-86 to -4)
        Month 48 (n = 274, 290)
    -70 (-88 to -36)
    -61 (-85 to -24)
        Month 60 (n = 268, 276)
    -67 (-88 to -25)
    -53 (-86 to -18)
        Month 72 (n = 243, 248)
    -69 (-88 to -32)
    -59 (-86 to -21)
        Month 84 (n = 217, 216)
    -63 (-88 to -19)
    -53 (-84 to -12)
    No statistical analyses for this end point

    Secondary: Percent Change From Study 20030216 Baseline in P1NP by Visit

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    End point title
    		 Percent Change From Study 20030216 Baseline in P1NP by Visit
    End point description
    Bone turnover markers were collected in a subset of participants who participated in the 20030216 Bone Marker sub-study and in new participants continuing beyond month 24 who were not previously in the Bone Turnover Markers sub-study.
    End point type
    Secondary
    End point timeframe
    Study 20030216 Baseline and extension study day 10, and months 6, 12, 24, 36, 48, 60, 72, and 84
    End point values
    		 Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    318
    342
    Units: percent change
    median (inter-quartile range (Q1-Q3))
        Day 10 (n = 30, 51)
    9 (-14 to 34)
    -59 (-74 to -22)
        Month 6 (n = 32, 57)
    -74 (-80 to -67)
    -75 (-80 to -55)
        Month 12 (n = 26, 56)
    -74 (-79 to -51)
    -63 (-76 to -36)
        Month 24 (n = 28, 51)
    -67 (-75 to -51)
    -56 (-72 to -30)
        Month 36 (n = 70, 83)
    -59 (-75 to -37)
    -60 (-71 to -40)
        Month 48 (n = 61, 73)
    -67 (-75 to -46)
    -63 (-77 to -42)
        Month 60 (n = 61, 71)
    -62 (-75 to -42)
    -55 (-74 to -30)
        Month 72 (n = 56, 67)
    -62 (-71 to -35)
    -55 (-70 to -27)
        Month 84 (n =49, 53)
    -68 (-78 to -56)
    -57 (-74 to -38)
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Albumin-adjusted Serum Calcium at Day 10

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    End point title
    		 Percent Change From Baseline in Albumin-adjusted Serum Calcium at Day 10
    End point description
    Analysis includes participants who had a calcium corrected by albumin measurement within the Day 10 visit window up to May 31, 2008.
    End point type
    Secondary
    End point timeframe
    Baseline (of extension study) and day 10
    End point values
    		 Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    2027
    2154
    Units: percent change
        median (inter-quartile range (Q1-Q3))
    -3.1 (-6.1 to 0)
    -2 (-5.1 to 1.1)
    No statistical analyses for this end point

    Secondary: Serum Denosumab Concentration

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    End point title
    		 Serum Denosumab Concentration
    End point description
    Serum concentrations of denosumab were measured by a validated conventional sandwich enzyme-linked immunosorbent assay (ELISA). The lower limit of quantification (LLOQ) was 0.8 ng/mL. Values of 0 in the table below indicate data below the lower limit of quantification. Analysis includes participants who participated in the Study 20030216 PK substudy, for whom dosing information was not missing and for whom sampling was within 14 days of specified sampling times.
    End point type
    Secondary
    End point timeframe
    Baseline (pre-dose in extension study), day 10, and Months 3, 4 and 6 (pre-dose)
    End point values
    		 Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    97
    113
    Units: ng/mL
    arithmetic mean (standard deviation)
        Baseline (n = 97, 113)
    0 ( 0 )
    113 ( 107 )
        Day 10 (n = 92, 106)
    5890 ( 2010 )
    6010 ( 2530 )
        Month 3 (n = 81, 92)
    1000 ( 560 )
    1190 ( 690 )
        Month 4 (n = 87, 104)
    429 ( 378 )
    554 ( 480 )
        Month 6 (n = 87, 103)
    20.8 ( 61.7 )
    66 ( 147.2 )
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Cancellous Bone Volume

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    End point title
    		 Bone Histomorphometry: Cancellous Bone Volume
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Cancellous (trabecular) bone volume is the percent of the total marrow cavity that is occupied by cancellous bone (both mineralized and non-mineralized) measured by quantitative histomorphometry. The analysis incudes participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available cancellous bone volume data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    		 Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    13
    41
    Units: percentage of total bone tissue volume
    arithmetic mean (standard deviation)
        Month 24 (n=13, 25)
    15.253 ( 6.065 )
    14.64 ( 6.979 )
        Month 84 (n=0, 19)
    99999 ( 99999 )
    16.358 ( 4.438 )
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Trabecular Number

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    End point title
    		 Bone Histomorphometry: Trabecular Number
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Trabecular number is the number of trabeculae present per lineal mm and is calculated as trabecular bone volume/trabecular thickness. Trabecular number is a measure of trabecular connectivity and decreases with bone loss. The analysis includes participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available trabecular number data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    		 Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    13
    41
    Units: 1/mm
    arithmetic mean (standard deviation)
        Month 24 (n = 13, 25)
    1.005 ( 0.242 )
    0.904 ( 0.243 )
        Month 84 (n = 0, 19)
    99999 ( 99999 )
    1.235 ( 0.254 )
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Trabecular Separation

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    End point title
    		 Bone Histomorphometry: Trabecular Separation
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Trabecular separation is the mean distance between trabeculae (measured by integrated computer graphics). Trabecular separation increases with trabecular bone loss. The analysis includes participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available trabecular separation data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    		 Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    13
    41
    Units: μm
    arithmetic mean (standard deviation)
        Month 24 (n = 13, 25)
    919.693 ( 358.238 )
    1033.416 ( 352.259 )
        Month 84 (n = 0, 19)
    99999 ( 99999 )
    708.669 ( 171.782 )
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Trabecular Thickness

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    End point title
    		 Bone Histomorphometry: Trabecular Thickness
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Mean trabecular thickness is a measure of trabecular structure and is calculated as the reciprocal of total bone (trabecular) surfaces. Trabecular thickness is reduced by aging and osteoporosis. The analysis includes participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available trabecular thickness data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    		 Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    13
    41
    Units: μm
    arithmetic mean (standard deviation)
        Month 24 (n = 13, 25)
    153.878 ( 51.859 )
    156.335 ( 48.567 )
        Month 84 (n = 0, 19)
    99999 ( 99999 )
    132.965 ( 28.064 )
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Cortical Width

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    End point title
    		 Bone Histomorphometry: Cortical Width
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Cortical width is the average width of both inner and outer cortices. Analysis includes participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available cortical width data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    		 Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    13
    45
    Units: μm
    arithmetic mean (standard deviation)
        Month 24 (n = 13, 28)
    622.22 ( 246.7 )
    707.69 ( 237.97 )
        Month 84 (n = 0, 21)
    99999 ( 99999 )
    786.19 ( 279.81 )
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Cancellous Bone Volume by TRAP Histomorphometry

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    End point title
    		 Bone Histomorphometry: Cancellous Bone Volume by TRAP Histomorphometry
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Cancellous (trabecular) bone volume is the percent of the total marrow cavity that is occupied by cancellous bone (both mineralized and non-mineralized) measured by tartrate-resistant acid phosphatase (TRAP) staining histomorphometry. The analysis includes participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available cancellous bone volume data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    		 Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    13
    41
    Units: percentage of total bone tissue volume
    arithmetic mean (standard deviation)
        Month 24 (n = 13, 25)
    16.678 ( 7.27 )
    15.606 ( 6.986 )
        Month 84 (n = 0, 19)
    99999 ( 99999 )
    17.631 ( 4.387 )
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Surface Density

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    End point title
    		 Bone Histomorphometry: Surface Density
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Surface density is calculated by total bone (trabecular) surfaces / total tissue volume. The analysis includes participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available surface density data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    		 Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    13
    41
    Units: mm² /mm³
    arithmetic mean (standard deviation)
        Month 24 (n = 13, 25)
    2.009 ( 0.486 )
    1.807 ( 0.486 )
        Month 84 (n = 0, 19)
    99999 ( 99999 )
    2.472 ( 0.506 )
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Osteoblast - Osteoid Interface

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    End point title
    		 Bone Histomorphometry: Osteoblast - Osteoid Interface
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Osteoblast - osteoid interface is calculated as osteoblast surface / osteoid surface * 100. Analysis includes participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available osteoblast - osteoid interface data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    		 Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    13
    41
    Units: percentage of osteoid surface
    arithmetic mean (standard deviation)
        Month 24 (n = 13, 25)
    22.124 ( 34.879 )
    17.813 ( 28.381 )
        Month 84 (n = 0, 19)
    99999 ( 99999 )
    5.951 ( 15.223 )
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Osteoid Surface

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    End point title
    		 Bone Histomorphometry: Osteoid Surface
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Osteoid surface is the percent of bone surface covered in osteoid. The analysis includes participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available osteoid surface data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    		 Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    13
    41
    Units: percentage of total bone surface
    arithmetic mean (standard deviation)
        Month 24 (n = 13, 25)
    0.915 ( 1.382 )
    0.982 ( 2.489 )
        Month 84 (n = 0, 19)
    99999 ( 99999 )
    0.421 ( 1.068 )
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Osteoid Thickness

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    End point title
    		 Bone Histomorphometry: Osteoid Thickness
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Osteoid thickness (width) is the mean thickness of osteoid seams on cancellous surfaces. Osteoid thickness is normally <12.5 µm. Increased osteoid thickness suggests abnormal mineralization (osteomalacia). The analysis included participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available osteoid thickness data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    		 Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    13
    41
    Units: μm
    arithmetic mean (standard deviation)
        Month 24 (n = 13, 25)
    5.139 ( 3.261 )
    4.548 ( 4.973 )
        Month 84 (n = 0, 19)
    99999 ( 99999 )
    4.108 ( 3.476 )
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Wall Thickness

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    End point title
    		 Bone Histomorphometry: Wall Thickness
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Wall thickness is the average thickness of trabecular bone structural units (BSU) and is used to assess the overall balance between resorption and formation. The analysis includes participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available wall thickness data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    		 Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    13
    41
    Units: μm
    arithmetic mean (standard deviation)
        Month 24 (n = 13, 25)
    43.11 ( 6.08 )
    49.74 ( 10.51 )
        Month 84 (n = 0, 19)
    99999 ( 99999 )
    39.59 ( 7.49 )
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Eroded Surface/Bone Surface

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    End point title
    		 Bone Histomorphometry: Eroded Surface/Bone Surface
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Eroded surface/bone surface is the percentage of bone surface occupied by eroded (resorption) cavities (Howships lacunae), with or without osteoclasts. The analysis includes participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available eroded surface/bone surface data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    		 Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    13
    41
    Units: percentage of bone surface
    arithmetic mean (standard deviation)
        Month 24 (n = 13, 25)
    0.414 ( 0.701 )
    0.328 ( 0.613 )
        Month 84 (n = 0, 19)
    99999 ( 99999 )
    0.511 ( 0.579 )
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Osteoclast Number - Length Based

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    End point title
    		 Bone Histomorphometry: Osteoclast Number - Length Based
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Osteoclast number was measured by quantitative histomorphometry and is expressed per mm of bone. The analysis includes participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available osteoclast number data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    		 Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    13
    41
    Units: 1/mm
    arithmetic mean (standard deviation)
        Month 24 (n = 13, 25)
    0.086 ( 0.119 )
    0.107 ( 0.198 )
        Month 84 (n = 0, 19)
    99999 ( 99999 )
    0.074 ( 0.101 )
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Osteoclast Number - Surface Based

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    End point title
    		 Bone Histomorphometry: Osteoclast Number - Surface Based
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Osteoclast number was measured by quantitative histomorphometry and is expressed per 100 mm of bone surface. The analysis includes participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available osteoclast number data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    		 Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    13
    41
    Units: 1/100 mm
    arithmetic mean (standard deviation)
        Month 24 (n = 13, 25)
    8.6 ( 11.9 )
    10.7 ( 19.8 )
        Month 84 (n = 0, 19)
    99999 ( 99999 )
    7.4 ( 10.1 )
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Osteoclast Number by TRAP - Length Based

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    End point title
    		 Bone Histomorphometry: Osteoclast Number by TRAP - Length Based
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Osteoclast number was measured using TRAP staining and is expressed per mm of bone. The analysis includes participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available osteoclast number data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    		 Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    13
    41
    Units: 1/mm
    arithmetic mean (standard deviation)
        Month 24 (n = 13, 25)
    0.096 ( 0.134 )
    0.11 ( 0.185 )
        Month 84 (n = 0, 19)
    99999 ( 99999 )
    0.077 ( 0.107 )
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Osteoclast Number by TRAP - Surface Based

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    End point title
    		 Bone Histomorphometry: Osteoclast Number by TRAP - Surface Based
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Osteoclast number was measured using TRAP staining and is expressed per 100 mm of bone surface. The analysis included participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available osteoclast number data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    		 Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    13
    41
    Units: 1/100 mm
    arithmetic mean (standard deviation)
        Month 24 (n = 13, 25)
    9.6 ( 13.4 )
    11 ( 18.5 )
        Month 84 (n = 0, 19)
    99999 ( 99999 )
    7.7 ( 10.7 )
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Single-label Surface

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    End point title
    		 Bone Histomorphometry: Single-label Surface
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. A single label is deposited if formation either started or ended during the interval between the uses of the two courses of tetracycline administration. Single-label surface is expressed as a percentage of total bone surface. The analysis includes participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available single-label surface data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    		 Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    5
    20
    Units: percentage of bone surface
    arithmetic mean (standard deviation)
        Month 24 (n = 5, 10)
    0.304 ( 0.302 )
    0.643 ( 0.661 )
        Month 84 (n = 0, 10)
    99999 ( 99999 )
    0.611 ( 0.726 )
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Double-label Surface

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    End point title
    		 Bone Histomorphometry: Double-label Surface
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. The presence of double labels indicates that normal bone mineralization was actively occurring over the entire labeling interval. Double-label surface is expressed as a percentage of total bone surface. The analysis includes Participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available double-label surface data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    		 Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    5
    20
    Units: percentage of bone surface
    arithmetic mean (standard deviation)
        Month 24 (n = 5, 10)
    0.258 ( 0.207 )
    0.356 ( 0.295 )
        Month 84 (n = 0, 10)
    99999 ( 99999 )
    0.106 ( 0.237 )
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Mineralizing Surface

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    End point title
    		 Bone Histomorphometry: Mineralizing Surface
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. Total mineralizing surfaces (MS) include all double and half of single-labeled surfaces. MS is expressed as a percentage of total bone surface. The analysis includes participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available mineralizing surface data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    		 Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    5
    20
    Units: percentage of bone surface
    arithmetic mean (standard deviation)
        Month 24 (n = 5, 10)
    0.406 ( 0.323 )
    0.681 ( 0.453 )
        Month 84 (n = 0, 10)
    99999 ( 99999 )
    0.412 ( 0.458 )
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Mineral Apposition Rate

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    End point title
    		 Bone Histomorphometry: Mineral Apposition Rate
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. The mineral apposition rate (MAR) is the avarage rate at which new bone mineral is being added on any actively forming surface. MAR is calculated as the average distance between visible labels, divided by the labeling interval. The analysis includes participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available mineral apposition rate data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    		 Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    5
    20
    Units: μm/day
    arithmetic mean (standard deviation)
        Month 24 (n = 5, 10)
    0.616 ( 0.219 )
    0.722 ( 0.573 )
        Month 84 (n = 0, 10)
    99999 ( 99999 )
    0.394 ( 0.233 )
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Adjusted Apposition Rate

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    End point title
    		 Bone Histomorphometry: Adjusted Apposition Rate
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. MAR is the average rate at which new bone mineral is being added on any actively forming surface. Adjusted MAR is calculated as: (average distance between visible labels / labeling interval) * (total mineralizing surface/total bone surface). Analysis includes participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or 84 and with available adjusted apposition rate data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    		 Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    5
    19
    Units: μm/day
    arithmetic mean (standard deviation)
        Month 24 (n = 5, 9)
    0.394 ( 0.471 )
    0.517 ( 0.537 )
        Month 84 (n = 0, 10)
    99999 ( 99999 )
    0.818 ( 1.207 )
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Bone Formation Rate - Surface Based

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    End point title
    		 Bone Histomorphometry: Bone Formation Rate - Surface Based
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. Bone formation rate - surface based is the calculated rate at which cancellous bone surface is being replaced annually, derived from the Mineral Appositional Rate * 365 * (relative mineralizing surface / total bone surface). The analysis included participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available bone formation rate data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    		 Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    5
    20
    Units: μm³/μm²/year
    arithmetic mean (standard deviation)
        Month 24 (n = 5, 10)
    0.898 ( 0.706 )
    2.153 ( 2.468 )
        Month 84 (n = 0, 10)
    99999 ( 99999 )
    0.691 ( 0.868 )
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Bone Formation Rate - Volume Based

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    End point title
    		 Bone Histomorphometry: Bone Formation Rate - Volume Based
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. Bone formation rate - volume based is the calculated rate at which cancellous bone volume is being replaced annually, derived from the Mineral Appositional Rate * 365 * (relative mineralizing surface / total bone volume). The analyses includes participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available bone formation rate data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    		 Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    5
    20
    Units: percent of bone volume per year
    arithmetic mean (standard deviation)
        Month 24 (n = 5, 10)
    1.454 ( 1.265 )
    3.162 ( 3.773 )
        Month 84 (n = 0, 10)
    99999 ( 99999 )
    1.071 ( 1.308 )
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Activation Frequency

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    End point title
    		 Bone Histomorphometry: Activation Frequency
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. The average time that it takes for a new remodeling cycle to begin on any point on a cancellous surface is called the activation frequency. Activation frequency is calculated as the bone formation rate / wall width. The analysis includes participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available activation frequency data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    		 Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    5
    20
    Units: /year
    arithmetic mean (standard deviation)
        Month 24 (n = 5, 10)
    0.022 ( 0.019 )
    0.045 ( 0.049 )
        Month 84 (n = 0, 10)
    99999 ( 99999 )
    0.014 ( 0.024 )
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Formation Period

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    End point title
    		 Bone Histomorphometry: Formation Period
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. Formation period (FP) is the mean time required to rebuild a new bone structural unit or osteon from the cement line back to the bone surface at a single location, and is given by wall width / adjusted apposition rate. The analysis includes participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available formation period data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    		 Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    5
    20
    Units: days
    arithmetic mean (standard deviation)
        Month 24 (n = 5, 10)
    593.5 ( 996.8 )
    287.3 ( 391.5 )
        Month 84 (n = 0, 10)
    99999 ( 99999 )
    229.7 ( 512 )
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Osteoid Volume

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    End point title
    		 Bone Histomorphometry: Osteoid Volume
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. Osteoid volume is the percentage of a given volume of bone tissue that consists of unmineralized bone (osteoid). The analysis includes participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available osteoid volume data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    		 Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    13
    41
    Units: percentage of total bone tissue
    arithmetic mean (standard deviation)
        Month 24 (n = 13, 25)
    0.108 ( 0.193 )
    0.146 ( 0.382 )
        Month 84 (n = 0, 19)
    99999 ( 99999 )
    0.048 ( 0.133 )
    No statistical analyses for this end point

    Secondary: Bone Histomorphometry: Mineralization Lag Time

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    End point title
    		 Bone Histomorphometry: Mineralization Lag Time
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histomorphometry. A double tetracycline labeling procedure was used to allow visualization and quantification of sites of new bone formation. Tetracycline was given for two periods of 3 days separated by 14 days where no tetracycline was taken. Mineralization lag time is the average time interval between osteoid formation and its subsequent mineralization and is calculated by dividing the osteoid width by the apposition rate. The analysis includes participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, had at least 1 bone biopsy evaluable for histomorphometry at extension month 24 or extension month 84 and with available mineralization lag time data. Biopsies were only collected from participants in the Denosumab/Denosumab group at month 84; "99999" indicates data not available.
    End point type
    Secondary
    End point timeframe
    Month 24 and month 84
    End point values
    		 Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    5
    20
    Units: days
    arithmetic mean (standard deviation)
        Month 24 (n = 5, 10)
    84.9 ( 136.8 )
    54.3 ( 76.1 )
        Month 84 (n = 0, 10)
    99999 ( 99999 )
    52.3 ( 114.5 )
    No statistical analyses for this end point

    Secondary: Bone Histology at Month 24

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    End point title
    		 Bone Histology at Month 24
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histology to determine if there were any histological abnormalities in the bone. Results are reported for the number of biopsies with normal bone micro-architecture: normal lamellar bone, normal mineralization, and osteoid, and biopsies with abnormal bone histology: osteomalacia, marrow fibrosis, or woven bone. Analysis includes participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, and had at least 1 evaluable bone biopsy at extension month 24.
    End point type
    Secondary
    End point timeframe
    Month 24
    End point values
    		 Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    13
    28
    Units: biopsies
        Normal lamellar bone
    13
    28
        Normal mineralization
    13
    28
        Osteoid
    13
    23
        Osteomalacia
    0
    0
        Marrow fibrosis
    0
    0
        Woven bone
    0
    0
    No statistical analyses for this end point

    Secondary: Bone Histology at Month 84

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    End point title
    		 Bone Histology at Month 84
    End point description
    Bone biopsy samples were prepared according to standard procedures for bone histology to determine if there were any histological abnormalities in the bone. Results are reported for the number of biopsies with normal bone micro-architecture: normal lamellar bone, normal mineralization, and osteoid, and biopsies with abnormal bone histology: osteomalacia, marrow fibrosis, or woven bone. Analysis includes participants who enrolled in the bone biopsy substudy, received at least 1 dose of denosumab during the extension study, and had at least 1 evaluable bone biopsy at extension month 84.
    End point type
    Secondary
    End point timeframe
    Month 84
    End point values
    		 Placebo / Denosumab Denosumab / Denosumab
    Number of subjects analysed
    0 [4]
    22
    Units: biopsies
        Normal lamellar bone
    22
        Normal mineralization
    22
        Osteoid
    18
        Osteomalacia
    0
        Marrow fibrosis
    0
        Woven bone
    0
    Notes
    [4] - No participants had biopsies collected at month 84
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    84 Months
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Placebo/Denosumab 60 mg Q6M
    Reporting group description
    		 Participants who were randomized to placebo in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study.

    Reporting group title
    Denosumab/Denosumab 60 mg Q6M
    Reporting group description
    		 Participants who were randomized to denosumab in the core study received a 60 mg subcutaneous injection of denosumab every 6 months for up to seven years in the extension study (total of 10 years treatment).

    Serious adverse events
    		 Placebo/Denosumab 60 mg Q6M Denosumab/Denosumab 60 mg Q6M
    Total subjects affected by serious adverse events
         subjects affected / exposed
    945 / 2206 (42.84%)
    1014 / 2343 (43.28%)
         number of deaths (all causes)
    101
    108
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Adenocarcinoma
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    4 / 2206 (0.18%)
    5 / 2343 (0.21%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma pancreas
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenoma benign
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adrenal adenoma
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenosquamous cell lung cancer
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adrenal neoplasm
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal cancer
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    B-cell lymphoma
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign breast neoplasm
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    16 / 2206 (0.73%)
    14 / 2343 (0.60%)
         occurrences causally related to treatment / all
    0 / 17
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign hepatic neoplasm
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign lung neoplasm
         subjects affected / exposed
    2 / 2206 (0.09%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign gastrointestinal neoplasm
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign neoplasm of bladder
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign neoplasm
         subjects affected / exposed
    1 / 2206 (0.05%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign neoplasm of thyroid gland
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign pancreatic neoplasm
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign neoplasm of skin
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign salivary gland neoplasm
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign vulval neoplasm
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    2 / 2206 (0.09%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain cancer metastatic
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain neoplasm malignant
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer metastatic
         subjects affected / exposed
    2 / 2206 (0.09%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    21 / 2206 (0.95%)
    24 / 2343 (1.02%)
         occurrences causally related to treatment / all
    0 / 21
    1 / 26
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bronchial carcinoma
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast neoplasm
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Breast cancer recurrent
         subjects affected / exposed
    3 / 2206 (0.14%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carcinoma in situ of skin
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervix carcinoma
         subjects affected / exposed
    1 / 2206 (0.05%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central nervous system lymphoma
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangiocarcinoma
         subjects affected / exposed
    2 / 2206 (0.09%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholesteatoma
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic lymphocytic leukaemia
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon adenoma
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    7 / 2206 (0.32%)
    12 / 2343 (0.51%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Colon cancer metastatic
         subjects affected / exposed
    1 / 2206 (0.05%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Colon neoplasm
         subjects affected / exposed
    2 / 2206 (0.09%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Colorectal cancer
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatofibrosarcoma protuberans
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colorectal adenocarcinoma
         subjects affected / exposed
    2 / 2206 (0.09%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diffuse large B-cell lymphoma
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diffuse large B-cell lymphoma stage IV
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial adenocarcinoma
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Follicular thyroid cancer
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial cancer
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal stromal tumour
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    1 / 2206 (0.05%)
    5 / 2343 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Gallbladder cancer
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal tract adenoma
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gingival cancer
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hairy cell leukaemia
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic cancer
         subjects affected / exposed
    1 / 2206 (0.05%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Hepatic neoplasm
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intraductal proliferative breast lesion
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatocellular carcinoma
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    10 / 2206 (0.45%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    1 / 11
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive papillary breast carcinoma
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive breast carcinoma
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leiomyosarcoma
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Laryngeal papilloma
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukaemia
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lip neoplasm malignant stage unspecified
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lentigo maligna
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lipoma
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    2 / 2206 (0.09%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung cancer metastatic
         subjects affected / exposed
    4 / 2206 (0.18%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Lung carcinoma cell type unspecified recurrent
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphocytic leukaemia
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    11 / 2206 (0.50%)
    13 / 2343 (0.55%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 13
         deaths causally related to treatment / all
    0 / 3
    0 / 2
    Lung squamous cell carcinoma stage 0
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    3 / 2206 (0.14%)
    5 / 2343 (0.21%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphoma
         subjects affected / exposed
    2 / 2206 (0.09%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant neoplasm of spinal cord
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant peritoneal neoplasm
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Mantle cell lymphoma
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningioma
         subjects affected / exposed
    1 / 2206 (0.05%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant urinary tract neoplasm
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mesothelioma
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to liver
         subjects affected / exposed
    3 / 2206 (0.14%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastases to lung
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to peritoneum
         subjects affected / exposed
    1 / 2206 (0.05%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastases to lymph nodes
         subjects affected / exposed
    2 / 2206 (0.09%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic carcinoma of the bladder
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastatic gastric cancer
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastasis
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic neoplasm
         subjects affected / exposed
    3 / 2206 (0.14%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metastatic renal cell carcinoma
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic squamous cell carcinoma
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Monoclonal gammopathy
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle neoplasm
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myeloproliferative disorder
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasm malignant
         subjects affected / exposed
    1 / 2206 (0.05%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Neoplasm progression
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuroendocrine carcinoma
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuroma
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nodular fasciitis
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-Hodgkin's lymphoma
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Non-small cell lung cancer
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-Hodgkin's lymphoma stage IV
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal adenocarcinoma
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal squamous cell carcinoma
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral neoplasm
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal carcinoma
         subjects affected / exposed
    0 / 2206 (0.00%)
    4 / 2343 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian adenoma
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cancer
         subjects affected / exposed
    1 / 2206 (0.05%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ovarian cancer metastatic
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cancer stage III
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian fibroma
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian epithelial cancer
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    6 / 2206 (0.27%)
    5 / 2343 (0.21%)
         occurrences causally related to treatment / all
    0 / 6
    1 / 5
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Pancreatic neoplasm
         subjects affected / exposed
    1 / 2206 (0.05%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pelvic neoplasm
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parathyroid tumour benign
         subjects affected / exposed
    2 / 2206 (0.09%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Papillary thyroid cancer
         subjects affected / exposed
    2 / 2206 (0.09%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Plasma cell myeloma
         subjects affected / exposed
    3 / 2206 (0.14%)
    4 / 2343 (0.17%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Phyllodes tumour
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Plasmacytoma
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polycythaemia vera
         subjects affected / exposed
    2 / 2206 (0.09%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal adenocarcinoma
         subjects affected / exposed
    5 / 2206 (0.23%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal adenoma
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal cancer
         subjects affected / exposed
    1 / 2206 (0.05%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cancer
         subjects affected / exposed
    2 / 2206 (0.09%)
    4 / 2343 (0.17%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Rectosigmoid cancer
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal neoplasm
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin cancer
         subjects affected / exposed
    1 / 2206 (0.05%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    3 / 2206 (0.14%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of the oral cavity
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroid adenoma
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    1 / 2206 (0.05%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tongue neoplasm malignant stage unspecified
         subjects affected / exposed
    2 / 2206 (0.09%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroid cancer
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteric cancer
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine cancer
         subjects affected / exposed
    6 / 2206 (0.27%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vulval cancer
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Accelerated hypertension
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic aneurysm
         subjects affected / exposed
    1 / 2206 (0.05%)
    5 / 2343 (0.21%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Aortic dissection
         subjects affected / exposed
    2 / 2206 (0.09%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Arterial disorder
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic stenosis
         subjects affected / exposed
    5 / 2206 (0.23%)
    8 / 2343 (0.34%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arterial haemorrhage
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arterial occlusive disease
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriosclerosis
         subjects affected / exposed
    5 / 2206 (0.23%)
    5 / 2343 (0.21%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Circulatory collapse
         subjects affected / exposed
    3 / 2206 (0.14%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    8 / 2206 (0.36%)
    8 / 2343 (0.34%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism venous
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Essential hypertension
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral artery occlusion
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral artery aneurysm
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    2 / 2206 (0.09%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    18 / 2206 (0.82%)
    21 / 2343 (0.90%)
         occurrences causally related to treatment / all
    0 / 23
    0 / 23
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 2206 (0.00%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    7 / 2206 (0.32%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Intermittent claudication
         subjects affected / exposed
    0 / 2206 (0.00%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemia
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    1 / 2206 (0.05%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    4 / 2206 (0.18%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery stenosis
         subjects affected / exposed
    2 / 2206 (0.09%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral embolism
         subjects affected / exposed
    2 / 2206 (0.09%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral vascular disorder
         subjects affected / exposed
    2 / 2206 (0.09%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral venous disease
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 2206 (0.00%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Phlebolith
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    1 / 2206 (0.05%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subclavian artery occlusion
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Temporal arteritis
         subjects affected / exposed
    2 / 2206 (0.09%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    4 / 2206 (0.18%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis superficial
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varicose vein
         subjects affected / exposed
    5 / 2206 (0.23%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vasculitis
         subjects affected / exposed
    2 / 2206 (0.09%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vasculitis necrotising
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Arthrodesis
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anticoagulant therapy
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign tumour excision
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac pacemaker replacement
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chemotherapy
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip arthroplasty
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hospitalisation
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hysterectomy
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint arthroplasty
         subjects affected / exposed
    1 / 2206 (0.05%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Knee arthroplasty
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal decompression
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rehabilitation therapy
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urethral operation
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth extraction
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Adverse drug reaction
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    3 / 2206 (0.14%)
    4 / 2343 (0.17%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    9 / 2206 (0.41%)
    8 / 2343 (0.34%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    16 / 2206 (0.73%)
    13 / 2343 (0.55%)
         occurrences causally related to treatment / all
    0 / 16
    0 / 13
         deaths causally related to treatment / all
    0 / 16
    0 / 13
    Device dislocation
         subjects affected / exposed
    3 / 2206 (0.14%)
    5 / 2343 (0.21%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic fatigue syndrome
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device failure
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device malfunction
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foreign body reaction
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Face oedema
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    4 / 2206 (0.18%)
    4 / 2343 (0.17%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Gait disturbance
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inflammation
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incarcerated hernia
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hernia
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    2 / 2206 (0.09%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic ulcer
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Medical device complication
         subjects affected / exposed
    2 / 2206 (0.09%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    2 / 2206 (0.09%)
    4 / 2343 (0.17%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 3
    Nodule
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    7 / 2206 (0.32%)
    5 / 2343 (0.21%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    4 / 2206 (0.18%)
    5 / 2343 (0.21%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyp
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral swelling
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    4 / 2206 (0.18%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 4
    0 / 1
    Sudden cardiac death
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ulcer haemorrhage
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune disorder
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaphylactic reaction
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sarcoidosis
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Social circumstances
    Physical assault
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Activities of daily living impaired
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Cystocele
         subjects affected / exposed
    11 / 2206 (0.50%)
    5 / 2343 (0.21%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast mass
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colpocele
         subjects affected / exposed
    2 / 2206 (0.09%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial atrophy
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial metaplasia
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibrocystic breast disease
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Genital prolapse
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Female genital tract fistula
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mammary duct ectasia
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metrorrhagia
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    4 / 2206 (0.18%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectocele
         subjects affected / exposed
    4 / 2206 (0.18%)
    5 / 2343 (0.21%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine cyst
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine polyp
         subjects affected / exposed
    4 / 2206 (0.18%)
    4 / 2343 (0.17%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine haemorrhage
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine prolapse
         subjects affected / exposed
    9 / 2206 (0.41%)
    9 / 2343 (0.38%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal cyst
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal prolapse
         subjects affected / exposed
    5 / 2206 (0.23%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vulval leukoplakia
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    4 / 2206 (0.18%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Aspiration
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bronchial hyperreactivity
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    4 / 2206 (0.18%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    1 / 2206 (0.05%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis chronic
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiectasis
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphonia
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchomalacia
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    14 / 2206 (0.63%)
    6 / 2343 (0.26%)
         occurrences causally related to treatment / all
    0 / 20
    0 / 8
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dyspnoea
         subjects affected / exposed
    6 / 2206 (0.27%)
    7 / 2343 (0.30%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dyspnoea exertional
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    2 / 2206 (0.09%)
    4 / 2343 (0.17%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    2 / 2206 (0.09%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Emphysema
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrothorax
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infiltration
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal cyst
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasal ulcer
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mediastinal cyst
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Painful respiration
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 2206 (0.05%)
    5 / 2343 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary congestion
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    19 / 2206 (0.86%)
    13 / 2343 (0.55%)
         occurrences causally related to treatment / all
    0 / 19
    1 / 16
         deaths causally related to treatment / all
    0 / 4
    0 / 1
    Pneumothorax
         subjects affected / exposed
    2 / 2206 (0.09%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary mass
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    6 / 2206 (0.27%)
    5 / 2343 (0.21%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 6
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    Pulmonary fibrosis
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    3 / 2206 (0.14%)
    4 / 2343 (0.17%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Tonsillar cyst
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheomalacia
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aggression
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anxiety disorder
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Emotional distress
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    6 / 2206 (0.27%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    11 / 2206 (0.50%)
    9 / 2343 (0.38%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hallucination
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental disorder
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Schizophrenia, paranoid type
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct obstruction
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct stone
         subjects affected / exposed
    0 / 2206 (0.00%)
    4 / 2343 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct stenosis
         subjects affected / exposed
    1 / 2206 (0.05%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary colic
         subjects affected / exposed
    2 / 2206 (0.09%)
    5 / 2343 (0.21%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cholangitis
         subjects affected / exposed
    4 / 2206 (0.18%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary cirrhosis primary
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    22 / 2206 (1.00%)
    30 / 2343 (1.28%)
         occurrences causally related to treatment / all
    0 / 25
    0 / 31
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    4 / 2206 (0.18%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    6 / 2206 (0.27%)
    4 / 2343 (0.17%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gallbladder oedema
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gallbladder necrosis
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gallbladder polyp
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic cirrhosis
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic cyst
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver disorder
         subjects affected / exposed
    1 / 2206 (0.05%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Jaundice cholestatic
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood pressure increased
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Antinuclear antibody positive
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carcinoembryonic antigen increased
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood pressure orthostatic
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Occult blood positive
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigation
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Troponin increased
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Protein total decreased
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    3 / 2206 (0.14%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Acetabulum fracture
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone fissure
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain contusion
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Animal bite
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carbon monoxide poisoning
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cartilage injury
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervical vertebral fracture
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cataract traumatic
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    7 / 2206 (0.32%)
    8 / 2343 (0.34%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    4 / 2206 (0.18%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dislocation of vertebra
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    1 / 2206 (0.05%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Coronary artery restenosis
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    0 / 2206 (0.00%)
    9 / 2343 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye penetration
         subjects affected / exposed
    2 / 2206 (0.09%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    16 / 2206 (0.73%)
    15 / 2343 (0.64%)
         occurrences causally related to treatment / all
    1 / 16
    0 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    13 / 2206 (0.59%)
    16 / 2343 (0.68%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 18
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    14 / 2206 (0.63%)
    11 / 2343 (0.47%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    16 / 2206 (0.73%)
    12 / 2343 (0.51%)
         occurrences causally related to treatment / all
    0 / 16
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fractured sacrum
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal stoma complication
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Graft complication
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    4 / 2206 (0.18%)
    6 / 2343 (0.26%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    13 / 2206 (0.59%)
    5 / 2343 (0.21%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury corneal
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    2 / 2206 (0.09%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ilium fracture
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    7 / 2206 (0.32%)
    6 / 2343 (0.26%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint injury
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament rupture
         subjects affected / exposed
    2 / 2206 (0.09%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament injury
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    2 / 2206 (0.09%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb crushing injury
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament sprain
         subjects affected / exposed
    2 / 2206 (0.09%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    5 / 2206 (0.23%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    4 / 2206 (0.18%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle rupture
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    3 / 2206 (0.14%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple injuries
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Patella fracture
         subjects affected / exposed
    5 / 2206 (0.23%)
    5 / 2343 (0.21%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perineal injury
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax traumatic
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural complication
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haematoma
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    2 / 2206 (0.09%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative hernia
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative ileus
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Procedural hypotension
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Procedural pain
         subjects affected / exposed
    1 / 2206 (0.05%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pubis fracture
         subjects affected / exposed
    3 / 2206 (0.14%)
    5 / 2343 (0.21%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiation mucositis
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    7 / 2206 (0.32%)
    4 / 2343 (0.17%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 2206 (0.05%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Radius fracture
         subjects affected / exposed
    25 / 2206 (1.13%)
    22 / 2343 (0.94%)
         occurrences causally related to treatment / all
    0 / 26
    0 / 22
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Scar
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shunt malfunction
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skull fracture
         subjects affected / exposed
    5 / 2206 (0.23%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skeletal injury
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin abrasion
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue injury
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    8 / 2206 (0.36%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Subdural haemorrhage
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    1 / 2206 (0.05%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thermal burn
         subjects affected / exposed
    2 / 2206 (0.09%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 2206 (0.05%)
    9 / 2343 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    17 / 2206 (0.77%)
    12 / 2343 (0.51%)
         occurrences causally related to treatment / all
    0 / 17
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transplant dysfunction
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    4 / 2206 (0.18%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ulna fracture
         subjects affected / exposed
    9 / 2206 (0.41%)
    9 / 2343 (0.38%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulnar nerve injury
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic intracranial haemorrhage
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound
         subjects affected / exposed
    2 / 2206 (0.09%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Congenital ureteric anomaly
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cancer gene carrier
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Corneal dystrophy
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular dystrophy
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    8 / 2206 (0.36%)
    18 / 2343 (0.77%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 19
         deaths causally related to treatment / all
    0 / 2
    0 / 4
    Acute coronary syndrome
         subjects affected / exposed
    2 / 2206 (0.09%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    7 / 2206 (0.32%)
    12 / 2343 (0.51%)
         occurrences causally related to treatment / all
    0 / 7
    1 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    17 / 2206 (0.77%)
    19 / 2343 (0.81%)
         occurrences causally related to treatment / all
    0 / 17
    0 / 25
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adams-Stokes syndrome
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic valve incompetence
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic valve disease
         subjects affected / exposed
    0 / 2206 (0.00%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic valve stenosis
         subjects affected / exposed
    4 / 2206 (0.18%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia supraventricular
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    3 / 2206 (0.14%)
    4 / 2343 (0.17%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    3 / 2206 (0.14%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    50 / 2206 (2.27%)
    40 / 2343 (1.71%)
         occurrences causally related to treatment / all
    4 / 69
    0 / 47
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 2206 (0.00%)
    4 / 2343 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    2 / 2206 (0.09%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    5 / 2206 (0.23%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    5 / 2206 (0.23%)
    4 / 2343 (0.17%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    4 / 2206 (0.18%)
    4 / 2343 (0.17%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Bundle branch block left
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    15 / 2206 (0.68%)
    21 / 2343 (0.90%)
         occurrences causally related to treatment / all
    0 / 17
    0 / 24
         deaths causally related to treatment / all
    0 / 3
    0 / 5
    Cardiac failure acute
         subjects affected / exposed
    1 / 2206 (0.05%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cardiac disorder
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    1 / 2206 (0.05%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure congestive
         subjects affected / exposed
    10 / 2206 (0.45%)
    9 / 2343 (0.38%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 9
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    Cardiac fibrillation
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac valve disease
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac valve sclerosis
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 2206 (0.05%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Cardiomyopathy
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    4 / 2206 (0.18%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    Chronic right ventricular failure
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiovascular insufficiency
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    9 / 2206 (0.41%)
    17 / 2343 (0.73%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 19
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Coronary artery insufficiency
         subjects affected / exposed
    3 / 2206 (0.14%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extrasystoles
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    1 / 2206 (0.05%)
    6 / 2343 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive heart disease
         subjects affected / exposed
    2 / 2206 (0.09%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Heart valve calcification
         subjects affected / exposed
    2 / 2206 (0.09%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Heart valve incompetence
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left atrial dilatation
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic cardiomyopathy
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    2 / 2206 (0.09%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Mitral valve disease
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral valve disease mixed
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    1 / 2206 (0.05%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    21 / 2206 (0.95%)
    24 / 2343 (1.02%)
         occurrences causally related to treatment / all
    0 / 26
    1 / 27
         deaths causally related to treatment / all
    0 / 3
    0 / 2
    Myocardial ischaemia
         subjects affected / exposed
    4 / 2206 (0.18%)
    13 / 2343 (0.55%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pericardial effusion
         subjects affected / exposed
    1 / 2206 (0.05%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    2 / 2206 (0.09%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial haemorrhage
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    2 / 2206 (0.09%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus arrest
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinoatrial block
         subjects affected / exposed
    2 / 2206 (0.09%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    6 / 2206 (0.27%)
    10 / 2343 (0.43%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular extrasystoles
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    2 / 2206 (0.09%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachyarrhythmia
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachyarrhythmia
         subjects affected / exposed
    2 / 2206 (0.09%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia induced cardiomyopathy
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tricuspid valve disease
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular arrhythmia
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular extrasystoles
         subjects affected / exposed
    2 / 2206 (0.09%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Acoustic neuritis
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Akinesia
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Amnesia
         subjects affected / exposed
    0 / 2206 (0.00%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Amyotrophic lateral sclerosis
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aphasia
         subjects affected / exposed
    3 / 2206 (0.14%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ataxia
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid artery occlusion
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    1 / 2206 (0.05%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid artery thrombosis
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carpal tunnel syndrome
         subjects affected / exposed
    1 / 2206 (0.05%)
    5 / 2343 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cauda equina syndrome
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebellar haemorrhage
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebellar infarction
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral artery embolism
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral arteriosclerosis
         subjects affected / exposed
    1 / 2206 (0.05%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral atrophy
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    5 / 2206 (0.23%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Cerebral infarction
         subjects affected / exposed
    5 / 2206 (0.23%)
    17 / 2343 (0.73%)
         occurrences causally related to treatment / all
    0 / 5
    1 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebral thrombosis
         subjects affected / exposed
    8 / 2206 (0.36%)
    8 / 2343 (0.34%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    6 / 2206 (0.27%)
    6 / 2343 (0.26%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral microangiopathy
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    22 / 2206 (1.00%)
    29 / 2343 (1.24%)
         occurrences causally related to treatment / all
    0 / 23
    0 / 30
         deaths causally related to treatment / all
    0 / 6
    0 / 3
    Cerebrovascular disorder
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular insufficiency
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervicogenic headache
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    3 / 2206 (0.14%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coma
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cubital tunnel syndrome
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dementia
         subjects affected / exposed
    2 / 2206 (0.09%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic hyperosmolar coma
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dementia Alzheimer's type
         subjects affected / exposed
    2 / 2206 (0.09%)
    5 / 2343 (0.21%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dysaesthesia
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic neuropathy
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    5 / 2206 (0.23%)
    5 / 2343 (0.21%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolic stroke
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extrapyramidal disorder
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    2 / 2206 (0.09%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Facial paresis
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 2206 (0.05%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    3 / 2206 (0.14%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Headache
         subjects affected / exposed
    4 / 2206 (0.18%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotonia
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive encephalopathy
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxic-ischaemic encephalopathy
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intercostal neuralgia
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial aneurysm
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic cerebral infarction
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    2 / 2206 (0.09%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    11 / 2206 (0.50%)
    9 / 2343 (0.38%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 10
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Lacunar infarction
         subjects affected / exposed
    2 / 2206 (0.09%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar radiculopathy
         subjects affected / exposed
    2 / 2206 (0.09%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental impairment
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Motor neurone disease
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Motor dysfunction
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mononeuropathy multiplex
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myasthenia gravis
         subjects affected / exposed
    2 / 2206 (0.09%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Optic neuritis
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    2 / 2206 (0.09%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parkinson's disease
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parkinsonism
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Partial seizures
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudoradicular syndrome
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyneuropathy
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    2 / 2206 (0.09%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radicular syndrome
         subjects affected / exposed
    1 / 2206 (0.05%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiculitis
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyramidal tract syndrome
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiculopathy
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    6 / 2206 (0.27%)
    12 / 2343 (0.51%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    2 / 2206 (0.09%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Senile dementia
         subjects affected / exposed
    2 / 2206 (0.09%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    2 / 2206 (0.09%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sensory disturbance
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tarsal tunnel syndrome
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    18 / 2206 (0.82%)
    20 / 2343 (0.85%)
         occurrences causally related to treatment / all
    0 / 18
    0 / 21
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombotic cerebral infarction
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient global amnesia
         subjects affected / exposed
    2 / 2206 (0.09%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Trigeminal neuralgia
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VIIth nerve paralysis
         subjects affected / exposed
    3 / 2206 (0.14%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    21 / 2206 (0.95%)
    19 / 2343 (0.81%)
         occurrences causally related to treatment / all
    0 / 24
    0 / 21
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular dementia
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular headache
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertebrobasilar insufficiency
         subjects affected / exposed
    1 / 2206 (0.05%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    11 / 2206 (0.50%)
    11 / 2343 (0.47%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic disorder
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone marrow oedema
         subjects affected / exposed
    2 / 2206 (0.09%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenitis
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    3 / 2206 (0.14%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Microcytic anaemia
         subjects affected / exposed
    2 / 2206 (0.09%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polycythaemia
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Splenomegaly
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytosis
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    3 / 2206 (0.14%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness unilateral
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniere's disease
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoacusis
         subjects affected / exposed
    0 / 2206 (0.00%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertigo
         subjects affected / exposed
    14 / 2206 (0.63%)
    8 / 2343 (0.34%)
         occurrences causally related to treatment / all
    0 / 18
    1 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertigo positional
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otosclerosis
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vestibular disorder
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Blindness
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blepharochalasis
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blindness unilateral
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cataract
         subjects affected / exposed
    17 / 2206 (0.77%)
    15 / 2343 (0.64%)
         occurrences causally related to treatment / all
    0 / 26
    0 / 19
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cataract diabetic
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Detachment of macular retinal pigment epithelium
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diplopia
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye haemorrhage
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ectropion
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glaucoma
         subjects affected / exposed
    3 / 2206 (0.14%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Keratopathy
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iridocyclitis
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Macular fibrosis
         subjects affected / exposed
    0 / 2206 (0.00%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    0 / 2206 (0.00%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Maculopathy
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Open angle glaucoma
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal tear
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal haemorrhage
         subjects affected / exposed
    1 / 2206 (0.05%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal vascular thrombosis
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulcerative keratitis
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Visual impairment
         subjects affected / exposed
    2 / 2206 (0.09%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vitreous haemorrhage
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal adhesions
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal hernia
         subjects affected / exposed
    4 / 2206 (0.18%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal distension
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    2 / 2206 (0.09%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal hernia obstructive
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    10 / 2206 (0.45%)
    8 / 2343 (0.34%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal rigidity
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acquired oesophageal web
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal haemorrhage
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Anal prolapse
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal sphincter atony
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    3 / 2206 (0.14%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic gastritis
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coeliac disease
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis microscopic
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    2 / 2206 (0.09%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    3 / 2206 (0.14%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    8 / 2206 (0.36%)
    6 / 2343 (0.26%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Crohn's disease
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diaphragmatic hernia
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    9 / 2206 (0.41%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulum intestinal
         subjects affected / exposed
    1 / 2206 (0.05%)
    6 / 2343 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulum
         subjects affected / exposed
    3 / 2206 (0.14%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal stenosis
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulum oesophageal
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    5 / 2206 (0.23%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    3 / 2206 (0.14%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer perforation
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenitis
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Faecal incontinence
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epigastric discomfort
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis haemorrhagic
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral hernia
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Faeces discoloured
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    6 / 2206 (0.27%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    4 / 2206 (0.18%)
    9 / 2343 (0.38%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroduodenal ulcer
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    1 / 2206 (0.05%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    6 / 2206 (0.27%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal motility disorder
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal inflammation
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal mucosal disorder
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal obstruction
         subjects affected / exposed
    2 / 2206 (0.09%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal stenosis
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    3 / 2206 (0.14%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    1 / 2206 (0.05%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 2206 (0.05%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hiatus hernia
         subjects affected / exposed
    2 / 2206 (0.09%)
    4 / 2343 (0.17%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    7 / 2206 (0.32%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hernial eventration
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    14 / 2206 (0.63%)
    7 / 2343 (0.30%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal angina
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal fistula
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal haemorrhage
         subjects affected / exposed
    4 / 2206 (0.18%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Intestinal obstruction
         subjects affected / exposed
    5 / 2206 (0.23%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 1
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal strangulation
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Irritable bowel syndrome
         subjects affected / exposed
    2 / 2206 (0.09%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal haemorrhage
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    4 / 2206 (0.18%)
    5 / 2343 (0.21%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal stenosis
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malabsorption
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mesenteric artery embolism
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Mechanical ileus
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    2 / 2206 (0.09%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal polyp
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 2206 (0.09%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic cyst
         subjects affected / exposed
    2 / 2206 (0.09%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic necrosis
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 2206 (0.00%)
    4 / 2343 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pancreatitis acute
         subjects affected / exposed
    1 / 2206 (0.05%)
    4 / 2343 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis chronic
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peptic ulcer
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis necrotising
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritoneal perforation
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngo-oesophageal diverticulum
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periodontal disease
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    2 / 2206 (0.09%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal polyp
         subjects affected / exposed
    2 / 2206 (0.09%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    2 / 2206 (0.09%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retroperitoneal haematoma
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal prolapse
         subjects affected / exposed
    1 / 2206 (0.05%)
    4 / 2343 (0.17%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    2 / 2206 (0.09%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toothache
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tongue oedema
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Volvulus
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 2206 (0.09%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Volvulus of small bowel
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    4 / 2206 (0.18%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decubitus ulcer
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic foot
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis allergic
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug eruption
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lichenoid keratosis
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lichen sclerosus
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pemphigoid
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pruritus
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psoriasis
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash pruritic
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    3 / 2206 (0.14%)
    5 / 2343 (0.21%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Bladder disorder
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder irritation
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    1 / 2206 (0.05%)
    6 / 2343 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder prolapse
         subjects affected / exposed
    0 / 2206 (0.00%)
    6 / 2343 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus bladder
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus ureteric
         subjects affected / exposed
    2 / 2206 (0.09%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus urethral
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    3 / 2206 (0.14%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Diabetic nephropathy
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis interstitial
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    2 / 2206 (0.09%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incontinence
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mixed incontinence
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 2206 (0.00%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    3 / 2206 (0.14%)
    5 / 2343 (0.21%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Nephropathy
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stress urinary incontinence
         subjects affected / exposed
    2 / 2206 (0.09%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tubulointerstitial nephritis
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteric stenosis
         subjects affected / exposed
    2 / 2206 (0.09%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urethral disorder
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urethral stenosis
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary bladder polyp
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urge incontinence
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary incontinence
         subjects affected / exposed
    4 / 2206 (0.18%)
    5 / 2343 (0.21%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 2206 (0.05%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal mass
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Goitre
         subjects affected / exposed
    6 / 2206 (0.27%)
    5 / 2343 (0.21%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basedow's disease
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperthyroidism
         subjects affected / exposed
    2 / 2206 (0.09%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroiditis
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxic nodular goitre
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    10 / 2206 (0.45%)
    15 / 2343 (0.64%)
         occurrences causally related to treatment / all
    1 / 10
    0 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acquired claw toe
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    6 / 2206 (0.27%)
    4 / 2343 (0.17%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    16 / 2206 (0.73%)
    10 / 2343 (0.43%)
         occurrences causally related to treatment / all
    0 / 17
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthropathy
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone loss
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone disorder
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chondrocalcinosis
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Compartment syndrome
         subjects affected / exposed
    2 / 2206 (0.09%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dupuytren's contracture
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chondropathy
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fistula
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibromyalgia
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture pain
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemarthrosis
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot deformity
         subjects affected / exposed
    4 / 2206 (0.18%)
    7 / 2343 (0.30%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc disorder
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc degeneration
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    12 / 2206 (0.54%)
    7 / 2343 (0.30%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint effusion
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint swelling
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    4 / 2206 (0.18%)
    5 / 2343 (0.21%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Kyphosis
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mobility decreased
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Monarthritis
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Morphoea
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle disorder
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    2 / 2206 (0.09%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 2206 (0.05%)
    4 / 2343 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    4 / 2206 (0.18%)
    4 / 2343 (0.17%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myopathy
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nodal osteoarthritis
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthropathy
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteochondrosis
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    79 / 2206 (3.58%)
    99 / 2343 (4.23%)
         occurrences causally related to treatment / all
    1 / 87
    0 / 118
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    3 / 2206 (0.14%)
    6 / 2343 (0.26%)
         occurrences causally related to treatment / all
    3 / 3
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    5 / 2206 (0.23%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    5 / 2206 (0.23%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoporosis
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in jaw
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periarthritis
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Plica syndrome
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polymyalgia rheumatica
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudarthrosis
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    4 / 2206 (0.18%)
    4 / 2343 (0.17%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    2 / 2206 (0.09%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sacroiliitis
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seronegative arthritis
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sjogren's syndrome
         subjects affected / exposed
    2 / 2206 (0.09%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal column stenosis
         subjects affected / exposed
    14 / 2206 (0.63%)
    22 / 2343 (0.94%)
         occurrences causally related to treatment / all
    0 / 15
    1 / 27
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    4 / 2206 (0.18%)
    4 / 2343 (0.17%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    1 / 2206 (0.05%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spondyloarthropathy
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Synovial cyst
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spondylolisthesis
         subjects affected / exposed
    1 / 2206 (0.05%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Synovial disorder
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic lupus erythematosus
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Synovitis
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendonitis
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal sepsis
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Abdominal abscess
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendiceal abscess
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess neck
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    4 / 2206 (0.18%)
    5 / 2343 (0.21%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    2 / 2206 (0.09%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    1 / 2206 (0.05%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis infective
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial pyelonephritis
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    6 / 2206 (0.27%)
    6 / 2343 (0.26%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bronchitis
         subjects affected / exposed
    8 / 2206 (0.36%)
    7 / 2343 (0.30%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis fungal
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    3 / 2206 (0.14%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis infective
         subjects affected / exposed
    0 / 2206 (0.00%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic tonsillitis
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic sinusitis
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dengue fever
         subjects affected / exposed
    2 / 2206 (0.09%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    6 / 2206 (0.27%)
    5 / 2343 (0.21%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    2 / 2206 (0.09%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear infection
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    11 / 2206 (0.50%)
    10 / 2343 (0.43%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis bacterial
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    4 / 2206 (0.18%)
    9 / 2343 (0.38%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    9 / 2206 (0.41%)
    9 / 2343 (0.38%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    2 / 2206 (0.09%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Helicobacter gastritis
         subjects affected / exposed
    2 / 2206 (0.09%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemophilus infection
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    H1N1 influenza
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis C
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic cyst infection
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    2 / 2206 (0.09%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Infection
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    2 / 2206 (0.09%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella infection
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella bacteraemia
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    0 / 2206 (0.00%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Listeriosis
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    2 / 2206 (0.09%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    2 / 2206 (0.09%)
    4 / 2343 (0.17%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 2206 (0.09%)
    6 / 2343 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lymph node tuberculosis
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    3 / 2206 (0.14%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis viral
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis aseptic
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mycobacterium avium complex infection
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Necrotising fasciitis
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Onychomycosis
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    2 / 2206 (0.09%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    2 / 3
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parotitis
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia
         subjects affected / exposed
    44 / 2206 (1.99%)
    48 / 2343 (2.05%)
         occurrences causally related to treatment / all
    0 / 52
    0 / 59
         deaths causally related to treatment / all
    0 / 5
    0 / 2
    Pneumonia bacterial
         subjects affected / exposed
    3 / 2206 (0.14%)
    4 / 2343 (0.17%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia influenzal
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    3 / 2206 (0.14%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia haemophilus
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia pseudomonal
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia staphylococcal
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia streptococcal
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomembranous colitis
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    5 / 2206 (0.23%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salmonellosis
         subjects affected / exposed
    1 / 2206 (0.05%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis chronic
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    2 / 2206 (0.09%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salpingo-oophoritis
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salpingitis
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    5 / 2206 (0.23%)
    5 / 2343 (0.21%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 3
    0 / 3
    Sepsis
         subjects affected / exposed
    6 / 2206 (0.27%)
    15 / 2343 (0.64%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 16
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Skin infection
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    3 / 2206 (0.14%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestine gangrene
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Stenotrophomonas infection
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tick-borne viral encephalitis
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural empyema
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth infection
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheitis
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tuberculosis of peripheral lymph nodes
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    13 / 2206 (0.59%)
    11 / 2343 (0.47%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    6 / 2206 (0.27%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal infection
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vestibular neuronitis
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    2 / 2206 (0.09%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    3 / 2206 (0.14%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    6 / 2206 (0.27%)
    7 / 2343 (0.30%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Diabetes mellitus
         subjects affected / exposed
    2 / 2206 (0.09%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 2206 (0.05%)
    3 / 2343 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    2 / 2206 (0.09%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 2206 (0.05%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercholesterolaemia
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 2206 (0.00%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 2206 (0.05%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    4 / 2206 (0.18%)
    2 / 2343 (0.09%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    2 / 2206 (0.09%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    2 / 2206 (0.09%)
    0 / 2343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    2 / 2206 (0.09%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vitamin B12 deficiency
         subjects affected / exposed
    0 / 2206 (0.00%)
    1 / 2343 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo/Denosumab 60 mg Q6M Denosumab/Denosumab 60 mg Q6M
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1809 / 2206 (82.00%)
    1920 / 2343 (81.95%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    240 / 2206 (10.88%)
    268 / 2343 (11.44%)
         occurrences all number
    338
    373
    Contusion
         subjects affected / exposed
    181 / 2206 (8.20%)
    176 / 2343 (7.51%)
         occurrences all number
    251
    245
    Vascular disorders
    Hypertension
         subjects affected / exposed
    460 / 2206 (20.85%)
    498 / 2343 (21.25%)
         occurrences all number
    581
    606
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    173 / 2206 (7.84%)
    163 / 2343 (6.96%)
         occurrences all number
    203
    193
    Headache
         subjects affected / exposed
    121 / 2206 (5.49%)
    103 / 2343 (4.40%)
         occurrences all number
    158
    120
    Sciatica
         subjects affected / exposed
    149 / 2206 (6.75%)
    165 / 2343 (7.04%)
         occurrences all number
    175
    198
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    141 / 2206 (6.39%)
    168 / 2343 (7.17%)
         occurrences all number
    169
    194
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    138 / 2206 (6.26%)
    140 / 2343 (5.98%)
         occurrences all number
    174
    177
    Eye disorders
    Cataract
         subjects affected / exposed
    319 / 2206 (14.46%)
    317 / 2343 (13.53%)
         occurrences all number
    492
    467
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    139 / 2206 (6.30%)
    152 / 2343 (6.49%)
         occurrences all number
    169
    175
    Constipation
         subjects affected / exposed
    141 / 2206 (6.39%)
    118 / 2343 (5.04%)
         occurrences all number
    147
    134
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    172 / 2206 (7.80%)
    168 / 2343 (7.17%)
         occurrences all number
    217
    204
    Psychiatric disorders
    Depression
         subjects affected / exposed
    135 / 2206 (6.12%)
    143 / 2343 (6.10%)
         occurrences all number
    161
    161
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    527 / 2206 (23.89%)
    541 / 2343 (23.09%)
         occurrences all number
    755
    763
    Osteoarthritis
         subjects affected / exposed
    332 / 2206 (15.05%)
    355 / 2343 (15.15%)
         occurrences all number
    449
    484
    Back pain
         subjects affected / exposed
    501 / 2206 (22.71%)
    493 / 2343 (21.04%)
         occurrences all number
    693
    665
    Musculoskeletal pain
         subjects affected / exposed
    197 / 2206 (8.93%)
    231 / 2343 (9.86%)
         occurrences all number
    243
    290
    Pain in extremity
         subjects affected / exposed
    264 / 2206 (11.97%)
    293 / 2343 (12.51%)
         occurrences all number
    333
    387
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    372 / 2206 (16.86%)
    385 / 2343 (16.43%)
         occurrences all number
    565
    576
    Influenza
         subjects affected / exposed
    179 / 2206 (8.11%)
    192 / 2343 (8.19%)
         occurrences all number
    225
    238
    Cystitis
         subjects affected / exposed
    194 / 2206 (8.79%)
    212 / 2343 (9.05%)
         occurrences all number
    372
    396
    Bronchitis
         subjects affected / exposed
    206 / 2206 (9.34%)
    226 / 2343 (9.65%)
         occurrences all number
    290
    350
    Urinary tract infection
         subjects affected / exposed
    242 / 2206 (10.97%)
    250 / 2343 (10.67%)
         occurrences all number
    385
    389
    Pneumonia
         subjects affected / exposed
    137 / 2206 (6.21%)
    167 / 2343 (7.13%)
         occurrences all number
    217
    246
    Upper respiratory tract infection
         subjects affected / exposed
    139 / 2206 (6.30%)
    128 / 2343 (5.46%)
         occurrences all number
    169
    159
    Metabolism and nutrition disorders
    Hypercholesterolaemia
         subjects affected / exposed
    215 / 2206 (9.75%)
    200 / 2343 (8.54%)
         occurrences all number
    223
    207

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Oct 2007
    - Added a PK/PD substudy to provide additional data to characterize the PK and PD profiles at additional time points during the subject¡¦s dosing interval. - Incorporated investigational product from a new manufacturing facility (BIP) to be administered by prefilled syringe. - Added an assessment of antidenosumab antibodies at extension month 6 in subjects who received investigational product from BIP to evaluate the immunogenicity for BIP drug substance in prefilled syringes.
    09 Mar 2009
    - Extended the study beyond extension month 24 for 5 additional years to allow reporting of descriptive analyses of safety and assessments of the cumulative effect of denosumab on BMD, BTMs, and vertebral and nonvertebral fractures following up to ten years of therapy.
    01 Sep 2010
    - Added procedures to assess incident vertebral fractures at 2-year intervals starting at year 3.
    13 Jan 2013
    - Updated the procedures for reporting adverse events and serious adverse events to IRB/IECs and regulatory authorities.
    15 May 2014
    - Added quantitative computer tomography assessments for a subset of approximately 30 subjects who had participated in a similar substudy in Study 20030216. - Added blood sample collection to analyze bone turnover markers CTX-1 and P1NP.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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