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    Clinical Trial Results:
    TECOS: A Randomized, Placebo Controlled Clinical Trial to Evaluate Cardiovascular Outcomes after Treatment with Sitagliptin in Patients with Type 2 Diabetes Mellitus and Inadequate Glycemic Control

    Summary
    EudraCT number
    2008-006719-20
    Trial protocol
    LT   NL   DE   ES   HU   LV   FR   CZ   GB   IE   SK   BG   IT   EE   FI   SE   BE  
    Global end of trial date
    30 Mar 2015

    Results information
    Results version number
    v2(current)
    This version publication date
    18 Aug 2016
    First version publication date
    09 Apr 2016
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    MK-0431-082
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00790205
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.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
    30 Mar 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Mar 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Mar 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This is a clinical trial designed to assess the cardiovascular (CV) outcome of long-term treatment with sitagliptin used as part of usual care compared to usual care without sitagliptin in participants with Type 2 Diabetes Mellitus having a history of cardiovascular disease and a hemoglobin A1c (HbA1c) of 6.5% to 8.0%. Primary hypothesis A is that sitagliptin, when used as part of usual care, is non-inferior to usual care without sitagliptin with regard to the risk of developing a confirmed event in the primary CV composite endpoint of Major Adverse Cardiovascular Event (MACE) plus. If hypothesis A is satisfied: hypothesis B is that sitagliptin, when used as part of usual care, is superior to usual care without sitagliptin with regard to the risk of developing a confirmed event in the primary CV composite endpoint.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice (GCP) standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research. The following additional measure defined for this individual study was in place for the protection of trial subjects: in the event that a participant experiences severe hypoglycemia, usual care physicians will be notified and may adjust antihyperglycemic agent (AHA) medications in order to prevent or minimize the occurrence of further hypoglycemia.
    Background therapy
    Background therapy included the following: stable doses of either monotherapy or dual combination therapy with metformin, pioglitazone, or a sulfonylurea, or, after a protocol amendment, stable doses of insulin (i.e., ±20% of the scheduled total daily insulin dose) either alone or in combination with metformin, for at least 3 months (i.e., no adjustments to oral antihyperglycemic therapy in the past 3 months).
    Evidence for comparator
    -
    Actual start date of recruitment
    10 Dec 2008
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Slovakia: 110
    Country: Number of subjects enrolled
    South Africa: 406
    Country: Number of subjects enrolled
    Spain: 202
    Country: Number of subjects enrolled
    Sweden: 81
    Country: Number of subjects enrolled
    Taiwan: 210
    Country: Number of subjects enrolled
    Turkey: 100
    Country: Number of subjects enrolled
    United Kingdom: 516
    Country: Number of subjects enrolled
    United States: 2045
    Country: Number of subjects enrolled
    Argentina: 542
    Country: Number of subjects enrolled
    Australia: 427
    Country: Number of subjects enrolled
    Belgium: 94
    Country: Number of subjects enrolled
    Brazil: 406
    Country: Number of subjects enrolled
    Bulgaria: 504
    Country: Number of subjects enrolled
    Canada: 549
    Country: Number of subjects enrolled
    Chile: 293
    Country: Number of subjects enrolled
    China: 31
    Country: Number of subjects enrolled
    Colombia: 230
    Country: Number of subjects enrolled
    Czech Republic: 462
    Country: Number of subjects enrolled
    Estonia: 88
    Country: Number of subjects enrolled
    Finland: 50
    Country: Number of subjects enrolled
    France: 86
    Country: Number of subjects enrolled
    Germany: 503
    Country: Number of subjects enrolled
    Hong Kong: 360
    Country: Number of subjects enrolled
    Hungary: 565
    Country: Number of subjects enrolled
    India: 1817
    Country: Number of subjects enrolled
    Israel: 362
    Country: Number of subjects enrolled
    Italy: 192
    Country: Number of subjects enrolled
    Korea, Republic of: 330
    Country: Number of subjects enrolled
    Latvia: 401
    Country: Number of subjects enrolled
    Lithuania: 320
    Country: Number of subjects enrolled
    Malaysia: 257
    Country: Number of subjects enrolled
    Netherlands: 309
    Country: Number of subjects enrolled
    New Zealand: 274
    Country: Number of subjects enrolled
    Norway: 43
    Country: Number of subjects enrolled
    Poland: 605
    Country: Number of subjects enrolled
    Romania: 345
    Country: Number of subjects enrolled
    Russian Federation: 465
    Country: Number of subjects enrolled
    Singapore: 91
    Worldwide total number of subjects
    14671
    EEA total number of subjects
    5476
    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)
    6764
    From 65 to 84 years
    7804
    85 years and over
    103

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 14,671 participants were randomized to treatment, provided consent and did not have any GCP deviations.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Sitagliptin
    Arm description
    Sitagliptin tablet taken orally once daily in the morning for up to approximately 5 years
    Arm type
    Experimental

    Investigational medicinal product name
    Sitagliptin phosphate
    Investigational medicinal product code
    MK-0431
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sitagliptin phosphate, one 50 mg or 100 mg tablet (dose dependant on renal function) orally, once daily

    Arm title
    Placebo
    Arm description
    Matching placebo tablet taken orally once daily in the morning for up to approximately 5 years
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo tablet matching the 50 mg or 100 mg sitagliptin phosphate tablet orally, once daily

    Number of subjects in period 1
    Sitagliptin Placebo
    Started
    7332
    7339
    Treated
    7266
    7274
    Completed
    6972
    6905
    Not completed
    360
    434
         Consent withdrawn by subject
    299
    363
         Lost to follow-up
    61
    71

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sitagliptin
    Reporting group description
    Sitagliptin tablet taken orally once daily in the morning for up to approximately 5 years

    Reporting group title
    Placebo
    Reporting group description
    Matching placebo tablet taken orally once daily in the morning for up to approximately 5 years

    Reporting group values
    Sitagliptin Placebo Total
    Number of subjects
    7332 7339 14671
    Age categorical
    Age was unavailable due to regulatory restrictions for 320 participants. The distribution of age in the other study participants was used to impute ages for those 320 participants in the “Age group breakdown for Trial” under the “Population of Trial Subjects” section of the record.
    Units: Subjects
        Adults (18-64 years)
    3315 3301 6616
        From 65-84 years
    3813 3821 7634
        85 years and over
    46 55 101
        Unknown age
    158 162 320
    Gender, Male/Female
    Units: Participants
        Female
    2134 2163 4297
        Male
    5198 5176 10374
    Estimated glomerular filtration rate (eGFR)
    Sitagliptin, n=7254; Placebo, n=7274
    Units: mL/min/1.73 m^2
        arithmetic mean (standard deviation)
    74.9 ± 21.3 74.9 ± 20.9 -
    Hemoglobin A1c (HbA1c)
    Sitagliptin, n=7330; Placebo, n=7336
    Units: Percentage of HbA1c
        arithmetic mean (standard deviation)
    7.2 ± 0.5 7.2 ± 0.5 -
    Urine albumin:creatinine ratio
    Sitagliptin, n=2606; Placebo, n=2542
    Units: g/mol Creatinine
        arithmetic mean (standard deviation)
    8.6 ± 37.4 8.4 ± 36 -

    End points

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    End points reporting groups
    Reporting group title
    Sitagliptin
    Reporting group description
    Sitagliptin tablet taken orally once daily in the morning for up to approximately 5 years

    Reporting group title
    Placebo
    Reporting group description
    Matching placebo tablet taken orally once daily in the morning for up to approximately 5 years

    Primary: Percentage of participants with first confirmed cardiovascular (CV) event of Major Adverse Cardiovascular Event (MACE) plus (Per protocol population)

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    End point title
    Percentage of participants with first confirmed cardiovascular (CV) event of Major Adverse Cardiovascular Event (MACE) plus (Per protocol population)
    End point description
    Primary composite CV endpoint of MACE plus which includes CV-related death, nonfatal myocardial infarction (MI), nonfatal stroke, or unstable angina requiring hospitalization. Per protocol population included all randomized participants who received study medication except those participants who did not contribute at least 1 day of data to the study analysis due to a major protocol violation that excluded all of their data.
    End point type
    Primary
    End point timeframe
    Up to 5 years
    End point values
    Sitagliptin Placebo
    Number of subjects analysed
    7257
    7266
    Units: Percentage of participants
        number (not applicable)
    9.6
    9.6
    Statistical analysis title
    Between-treatment difference
    Statistical analysis description
    Hazard Ratio (HR) of Sitagliptin/Placebo: the between-treatment difference in time to the first primary composite CV endpoint was assessed by the HR between the sitagliptin and placebo groups. The confidence interval for the HR was computed and compared to 1.30, the non-inferiority margin.
    Comparison groups
    Placebo v Sitagliptin
    Number of subjects included in analysis
    14523
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.001 [1]
    Method
    Cox proportional hazards model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.98
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.88
         upper limit
    1.09
    Notes
    [1] - Model stratified by region with treatment group only as explanatory variable.

    Primary: Percentage of participants with first confirmed CV event of MACE plus (Intent to treat population)

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    End point title
    Percentage of participants with first confirmed CV event of MACE plus (Intent to treat population)
    End point description
    Primary composite CV endpoint of MACE plus which includes CV-related death, nonfatal MI, nonfatal stroke, or unstable angina requiring hospitalization. Intent to treat population included all randomized participants who received study medication, provided consent, and did not have a major GCP deviation.
    End point type
    Primary
    End point timeframe
    Up to 5 years
    End point values
    Sitagliptin Placebo
    Number of subjects analysed
    7332
    7339
    Units: Percentage of participants
        number (not applicable)
    11.4
    11.6
    Statistical analysis title
    Between-treatment difference
    Statistical analysis description
    HR of Sitagliptin/Placebo: the between-treatment difference in time to the first primary composite CV endpoint was assessed by the HR between the sitagliptin and placebo groups. The confidence interval for the HR was computed and compared to 1.30, the non-inferiority margin.
    Comparison groups
    Sitagliptin v Placebo
    Number of subjects included in analysis
    14671
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.001 [2]
    Method
    Cox proportional hazards model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.98
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.89
         upper limit
    1.08
    Notes
    [2] - Model stratified by region with treatment group as the only explanatory variable.

    Secondary: Percentage of participants with first confirmed CV event of MACE (Per protocol population)

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    End point title
    Percentage of participants with first confirmed CV event of MACE (Per protocol population)
    End point description
    CV composite endpoint of MACE which includes CV-related death, nonfatal MI, or nonfatal stroke. Per protocol population included all randomized participants who received study medication except those participants who did not contribute at least 1 day of data to the study analysis due to a major protocol violation that excluded all of their data.
    End point type
    Secondary
    End point timeframe
    Up to 5 years
    End point values
    Sitagliptin Placebo
    Number of subjects analysed
    7257
    7266
    Units: Percentage of participants
        number (not applicable)
    8.4
    8.3
    Statistical analysis title
    Between-treatment difference
    Statistical analysis description
    HR of Sitagliptin/Placebo: the between-treatment difference in time to the first primary composite CV endpoint was assessed by the HR between the sitagliptin and placebo groups. The confidence interval for the HR was computed and compared to 1.30, the non-inferiority margin.
    Comparison groups
    Sitagliptin v Placebo
    Number of subjects included in analysis
    14523
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.001 [3]
    Method
    Cox proportional hazards model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.99
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.89
         upper limit
    1.11
    Notes
    [3] - Model stratified by region with treatment group only as explanatory variable.

    Secondary: Percentage of participants with first confirmed CV event of MACE (Intent to treat population)

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    End point title
    Percentage of participants with first confirmed CV event of MACE (Intent to treat population)
    End point description
    CV composite endpoint of MACE which includes CV-related death, nonfatal MI, or nonfatal stroke. Intent to treat population included all randomized participants who received study medication, provided consent, and did not have a major GCP deviation.
    End point type
    Secondary
    End point timeframe
    Up to 5 years
    End point values
    Sitagliptin Placebo
    Number of subjects analysed
    7332
    7339
    Units: Percentage of participants
        number (not applicable)
    10.2
    10.2
    Statistical analysis title
    Between-treatment difference
    Statistical analysis description
    HR of Sitagliptin/Placebo: the between-treatment difference in time to the first primary composite CV endpoint was assessed by the HR between the sitagliptin and placebo groups. The confidence interval for the HR was computed and compared to 1.30, the non-inferiority margin.
    Comparison groups
    Sitagliptin v Placebo
    Number of subjects included in analysis
    14671
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.001 [4]
    Method
    Cox proportional hazards model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.99
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.89
         upper limit
    1.1
    Notes
    [4] - Model stratified by region with treatment group only as explanatory variable.

    Secondary: Percent incidence of all cause mortality (Per protocol population)

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    End point title
    Percent incidence of all cause mortality (Per protocol population)
    End point description
    Percent incidence of all cause mortality is reported as the percentage of participants who died due to any cause. Per protocol population included all randomized participants who received study medication except those participants who did not contribute at least 1 day of data to the study analysis due to a major protocol violation that excluded all of their data.
    End point type
    Secondary
    End point timeframe
    Up to 5 years
    End point values
    Sitagliptin Placebo
    Number of subjects analysed
    7257
    7266
    Units: Percentage of participants
        number (not applicable)
    4.7
    4.3
    Statistical analysis title
    Between-treatment difference
    Statistical analysis description
    HR of Sitagliptin/Placebo: the between-treatment difference in mortality due to all causes was assessed by the HR between the sitagliptin and placebo groups.
    Comparison groups
    Sitagliptin v Placebo
    Number of subjects included in analysis
    14523
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.435
    Method
    Cox proportional hazards model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.06
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.91
         upper limit
    1.24

    Secondary: Percent incidence of all cause mortality (Intent to treat population)

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    End point title
    Percent incidence of all cause mortality (Intent to treat population)
    End point description
    Percent incidence of all cause mortality is reported as the percentage of participants who died due to any cause. Intent to treat population included all randomized participants who received study medication, provided consent, and did not have a major GCP deviation.
    End point type
    Secondary
    End point timeframe
    Up to 5 years
    End point values
    Sitagliptin Placebo
    Number of subjects analysed
    7332
    7339
    Units: Percentage of participants
        number (not applicable)
    7.5
    7.3
    Statistical analysis title
    Between-treatment difference
    Statistical analysis description
    HR of Sitagliptin/Placebo: the between-treatment difference in mortality due to all causes was assessed by the HR between the sitagliptin and placebo groups.
    Comparison groups
    Sitagliptin v Placebo
    Number of subjects included in analysis
    14671
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.875
    Method
    Cox proportional hazards model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.9
         upper limit
    1.14

    Secondary: Percent incidence of congestive heart failure requiring hospitalization (Per protocol population)

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    End point title
    Percent incidence of congestive heart failure requiring hospitalization (Per protocol population)
    End point description
    Percent incidence of congestive heart failure requiring hospitalization is reported as the percentage of participants who were admitted to the hospital for congestive heart failure. Per protocol population included all randomized participants who received study medication except those participants who did not contribute at least 1 day of data to the study analysis due to a major protocol violation that excluded all of their data.
    End point type
    Secondary
    End point timeframe
    Up to 5 years
    End point values
    Sitagliptin Placebo
    Number of subjects analysed
    7257
    7266
    Units: Percentage of participants
        number (not applicable)
    2.8
    2.8
    Statistical analysis title
    Between-treatment difference
    Statistical analysis description
    Hazard Ratio of Sitagliptin/Placebo: The between-treatment difference in congestive heart failure cases requiring hospitalization was assessed by the hazard ratio between the Sitagliptin and Placebo groups.
    Comparison groups
    Sitagliptin v Placebo
    Number of subjects included in analysis
    14523
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.858 [5]
    Method
    Cox proportional hazards model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.98
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.81
         upper limit
    1.19
    Notes
    [5] - Model stratified by region with treatment group and history of congestive heart failure at baseline as explanatory variables.

    Secondary: Percent incidence of congestive heart failure requiring hospitalization (Intent to treat population)

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    End point title
    Percent incidence of congestive heart failure requiring hospitalization (Intent to treat population)
    End point description
    Percent incidence of congestive heart failure requiring hospitalization is reported as the percentage of participants who were admitted to the hospital for congestive heart failure. Intent to treat population included all randomized participants who received study medication, provided consent, and did not have a major GCP deviation.
    End point type
    Secondary
    End point timeframe
    Up to 5 years
    End point values
    Sitagliptin Placebo
    Number of subjects analysed
    7332
    7339
    Units: Percentage of participants
        number (not applicable)
    3.1
    3.1
    Statistical analysis title
    Between-treatment difference
    Statistical analysis description
    Hazard Ratio of Sitagliptin/Placebo: The between-treatment difference in congestive heart failure cases requiring hospitalization was assessed by the hazard ratio between the Sitagliptin and Placebo groups.
    Comparison groups
    Sitagliptin v Placebo
    Number of subjects included in analysis
    14671
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.983 [6]
    Method
    Cox poportional hazards model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.83
         upper limit
    1.2
    Notes
    [6] - Model stratified by region with treatment group and history of congestive heart failure at baseline as explanatory variable.

    Secondary: Change from baseline in renal function over time (Per protocol population)

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    End point title
    Change from baseline in renal function over time (Per protocol population)
    End point description
    Change in renal function based on estimated glomerular filtration rate [eGFR] using the Modification of Diet in Renal Disease [MDRD] method. Per protocol population included all randomized participants who received study medication except those participants who did not contribute at least 1 day of data to the study analysis due to a major protocol violation that excluded all of their data. Number of subjects analyzed consists of those participants with a baseline value.
    End point type
    Secondary
    End point timeframe
    Baseline and up to 5 years
    End point values
    Sitagliptin Placebo
    Number of subjects analysed
    7182
    7203
    Units: mL/min/1.73 m^2
    arithmetic mean (standard deviation)
        Month 4; Sitagliptin, n=3859, Placebo, n=3864
    -1.9 ± 14.2
    -0.8 ± 14.3
        Month 8; Sitagliptin, n=3562, Placebo, n=3501
    -2.5 ± 14.9
    -0.9 ± 15.1
        Month 12; Sitagliptin, n=4912, Placebo, n=4778
    -1.8 ± 15.8
    -0.5 ± 16.2
        Month 24; Sitagliptin, n=4782, Placebo, n=4637
    -3.1 ± 17.9
    -1.7 ± 17.5
        Month 36; Sitagliptin, n=2776, Placebo, n=2614
    -3.7 ± 18
    -1.6 ± 18.8
        Month 48; Sitagliptin, n=1096, Placebo, n=1056
    -3.7 ± 18.3
    -2.8 ± 18.4
        Month 60; Sitagliptin, n=79, Placebo, n=88
    -3.5 ± 18.2
    -6.4 ± 17.3
    No statistical analyses for this end point

    Secondary: Change from baseline in renal function over time (Intent to treat population)

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    End point title
    Change from baseline in renal function over time (Intent to treat population)
    End point description
    Change in renal function based on estimated glomerular filtration rate [eGFR] using the Modification of Diet in Renal Disease [MDRD] method. Intent to treat population included all randomized participants who received study medication, provided consent, and did not have a major GCP deviation. Number of subjects analyzed consists of those participants with a baseline value.
    End point type
    Secondary
    End point timeframe
    Baseline and up to 5 years
    End point values
    Sitagliptin Placebo
    Number of subjects analysed
    7254
    7274
    Units: mL/min/ 1.73 m^2
    arithmetic mean (standard deviation)
        Month 4; Sitagliptin, n=3949, Placebo, n=3977
    -1.8 ± 14.3
    -0.8 ± 14.3
        Month 8; Sitagliptin, n=3687; Placebo, n=3648
    -2.4 ± 14.8
    -0.9 ± 15.2
        Month 12; Sitagliptin, n=5082, Placebo, n=5015
    -1.8 ± 15.8
    -0.5 ± 16.3
        Month 24; Sitagliptin, n=5157, Placebo, n=5071
    -3.2 ± 17.9
    -1.7 ± 17.7
        Month 36; Sitagliptin, n=3037, Placebo, n=2942
    -3.8 ± 18.1
    -1.6 ± 18.7
        Month 48; Sitagliptin, n=1237, Placebo, n=1210
    -4 ± 18.4
    -2.8 ± 18.3
        Month 60; Sitagliptin, n=93, Placebo, n=106
    -4.2 ± 17.4
    -5.7 ± 17.2
    No statistical analyses for this end point

    Secondary: Change from baseline in HbA1c over time (Per protocol population)

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    End point title
    Change from baseline in HbA1c over time (Per protocol population)
    End point description
    HbA1c is a measure of the percentage of glycated hemoglobin in the blood. Estimated mean difference between sitagliptin and placebo controlling for baseline HbA1c and region. Per protocol population included all randomized participants who received study medication except those participants who did not contribute at least 1 day of data to the study analysis due to a major protocol violation that excluded all of their data. Number of subjects analyzed consists of those participants with a baseline value.
    End point type
    Secondary
    End point timeframe
    Baseline and up to 4 years
    End point values
    Sitagliptin Placebo
    Number of subjects analysed
    7250
    7258
    Units: Percentage of HbA1c
    arithmetic mean (standard deviation)
        Month 4; Sitagliptin, n=6632, Placebo, n=6588
    -0.3 ± 0.8
    0.1 ± 0.9
        Month 8; Sitagliptin, n=6294, Placebo, n=6197
    -0.3 ± 0.9
    0.1 ± 1
        Month 12; Sitagliptin, n=6217, Placebo, n=6092
    -0.2 ± 1
    0.1 ± 1
        Month 24; Sitagliptin, n=5668, Placebo, n=5475
    -0.1 ± 1
    0.2 ± 1.1
        Month 36; Sitagliptin, n=3227, Placebo, n=3083
    -0.1 ± 1.1
    0.1 ± 1.1
        Month 48; Sitagliptin, n=1271, Placebo, n=1224
    0 ± 1.1
    0.1 ± 1.2
        Month 60; Sitagliptin, n=106, Placebo, n=108
    -0.1 ± 1
    0 ± 0.9
    No statistical analyses for this end point

    Secondary: Change from baseline in HbA1c over time (Intent to treat population)

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    End point title
    Change from baseline in HbA1c over time (Intent to treat population)
    End point description
    HbA1c is a measure of the percentage of glycated hemoglobin in the blood. Estimated mean difference between sitagliptin and placebo controlling for baseline HbA1c and region. Intent to treat population included all randomized participants who received study medication, provided consent, and did not have a major GCP deviation. Number of subjects analyzed consists of those participants with a baseline value.
    End point type
    Secondary
    End point timeframe
    Baseline and up to 4 years
    End point values
    Sitagliptin Placebo
    Number of subjects analysed
    7325
    7331
    Units: Percentage of HbA1c
    arithmetic mean (standard deviation)
        Month 4; Sitagliptin, n=6772, Placebo, n=6738
    -0.3 ± 0.8
    0.1 ± 0.9
        Month 8; Sitagliptin, n=6478; Placebo, n=6414
    -0.2 ± 0.9
    0.1 ± 1
        Month 12; Sitagliptin, n=6448; Placebo, n=6384
    -0.2 ± 1
    0.1 ± 1
        Month 24; Sitagliptin, n=6105; Placebo, n=5975
    -0.1 ± 1
    0.1 ± 1.1
        Month 36; Sitagliptin, n=3521; Placebo, n=3439
    -0.1 ± 1.1
    0.1 ± 1.1
        Month 48; Sitagliptin, n=1432; Placebo, n=1383
    0 ± 1.1
    0.1 ± 1.2
        Month 60; Sitagliptin, n=123; Placebo, n=128
    0 ± 1
    0 ± 1
    No statistical analyses for this end point

    Secondary: Change from baseline in urine albumin:creatinine ratio over time (Per protocol population)

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    End point title
    Change from baseline in urine albumin:creatinine ratio over time (Per protocol population)
    End point description
    Change from baseline reflects the difference between the urine albumin:creatinine ratio reported time point and baseline value. Per protocol population included all randomized participants who received study medication except those participants who did not contribute at least 1 day of data to the study analysis due to a major protocol violation that excluded all of their data. Number of subjects analyzed consists of those participants with a baseline value.
    End point type
    Secondary
    End point timeframe
    Baseline and up to 5 years
    End point values
    Sitagliptin Placebo
    Number of subjects analysed
    2590
    2522
    Units: g/mol Creatinine
    arithmetic mean (standard deviation)
        Month 4; Sitagliptin, n=664, Placebo, n=688
    -2.2 ± 27.7
    -1.4 ± 24.6
        Month 8; Sitagliptin, n=635, Placebo, n=597
    1.7 ± 38.5
    0.2 ± 45.3
        Month 12; Sitagliptin, n=1126, Placebo, n=1059
    0.8 ± 27.7
    1.2 ± 33.1
        Month 24; Sitagliptin, n=930, Placebo, n=892
    0.7 ± 34
    3.2 ± 31.6
        Month 36; Sitagliptin, n=488, Placebo, n=513
    2.5 ± 24
    4 ± 31
        Month 48; Sitagliptin, n=238, Placebo, n=233
    1.3 ± 15.2
    1.5 ± 25.5
        Month 60; Sitagliptin, n=13, Placebo, n=17
    -2.7 ± 10.1
    4.8 ± 15.4
    No statistical analyses for this end point

    Secondary: Change from baseline in urine albumin:creatinine ratio over time (Intent to treat population)

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    End point title
    Change from baseline in urine albumin:creatinine ratio over time (Intent to treat population)
    End point description
    Change from baseline reflects the difference between the urine albumin:creatinine ratio reported time point and baseline value. Intent to treat population included all randomized participants who received study medication, provided consent, and did not have a major GCP deviation. Number of subjects analyzed consists of those participants with a baseline value.
    End point type
    Secondary
    End point timeframe
    Baseline and up to 5 years
    End point values
    Sitagliptin Placebo
    Number of subjects analysed
    2606
    2542
    Units: g/mol Creatinine
    arithmetic mean (standard deviation)
        Month 4; Sitagliptin, n=677, Placebo, n=713
    -2.1 ± 27.5
    -1.4 ± 24.1
        Month 8; Sitagliptin, n=658, Placebo, n=624
    2.1 ± 39.4
    0.5 ± 44.5
        Month 12; Sitagliptin, n=1167, Placebo, n=1115
    1.3 ± 30.2
    1.2 ± 32.3
        Month 24; Sitagliptin, n=1011, Placebo, n=964
    0.5 ± 33.1
    3.1 ± 30.7
        Month 36; Sitagliptin, n=537, Placebo, n=553
    2.6 ± 25.8
    3.9 ± 30.3
        Month 48; Sitagliptin,n=265, Placebo, n=256
    1.9 ± 16.3
    1.6 ± 24.5
        Month 60; Sitagliptin, n=14, Placebo, n=18
    -2.5 ± 9.7
    6.4 ± 16.4
    No statistical analyses for this end point

    Secondary: Percentage of participants who initiated chronic insulin therapy (Per protocol population)

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    End point title
    Percentage of participants who initiated chronic insulin therapy (Per protocol population)
    End point description
    Chronic insulin therapy is defined as a continuous period of insulin use of more than 3 months. Per protocol population included all randomized participants who received study medication except those participants who did not contribute at least 1 day of data to the study analysis due to a major protocol violation that excluded all of their data.
    End point type
    Secondary
    End point timeframe
    Up to 5 years
    End point values
    Sitagliptin Placebo
    Number of subjects analysed
    5554
    5601
    Units: Percentage of participants
        number (not applicable)
    8.6
    11.9
    Statistical analysis title
    Between-treatment difference
    Comparison groups
    Sitagliptin v Placebo
    Number of subjects included in analysis
    11155
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001 [7]
    Method
    Cox propotional hazards model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.69
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.61
         upper limit
    0.77
    Notes
    [7] - Model stratified by region with treatment group only as explanatory variable.

    Secondary: Percentage of participants who initiated chronic insulin therapy (Intent to treat population)

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    End point title
    Percentage of participants who initiated chronic insulin therapy (Intent to treat population)
    End point description
    Chronic insulin therapy is defined as a continuous period of insulin use of more than 3 months. Intent to treat population included all randomized participants who received study medication, provided consent, and did not have a major GCP deviation.
    End point type
    Secondary
    End point timeframe
    Up to 5 years
    End point values
    Sitagliptin Placebo
    Number of subjects analysed
    5608
    5655
    Units: Percentage of participants
        number (not applicable)
    9.7
    13.2
    Statistical analysis title
    Between-treatment difference
    Comparison groups
    Sitagliptin v Placebo
    Number of subjects included in analysis
    11263
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001 [8]
    Method
    Cox proportional hazards model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.63
         upper limit
    0.79
    Notes
    [8] - Model stratified by region with treatment group only as explanatory variable.

    Secondary: Percentage of participants who initiated a co-interventional agent (Per protocol population)

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    End point title
    Percentage of participants who initiated a co-interventional agent (Per protocol population)
    End point description
    In participants not receiving insulin at baseline, addition of first co-interventional agent (i.e., next oral antihyperglycemic agent [AHA] or chronic insulin, where chronic insulin therapy is defined as a continuous period of insulin use of more than 3 months). Per protocol population included all randomized participants who received study medication except those participants who did not contribute at least 1 day of data to the study analysis due to a major protocol violation that excluded all of their data.
    End point type
    Secondary
    End point timeframe
    Up to 5 years
    End point values
    Sitagliptin Placebo
    Number of subjects analysed
    7257
    7266
    Units: Percentage of participants
        number (not applicable)
    18.9
    24.5
    Statistical analysis title
    Between-treatment difference
    Comparison groups
    Sitagliptin v Placebo
    Number of subjects included in analysis
    14523
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001 [9]
    Method
    Cox proportional hazards model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.65
         upper limit
    0.75
    Notes
    [9] - Model stratified by region with treatment group only as explanatory variable.

    Secondary: Percentage of participants who initiated a co-interventional agent (Intent to treat population)

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    End point title
    Percentage of participants who initiated a co-interventional agent (Intent to treat population)
    End point description
    In participants not receiving insulin at baseline, addition of first co-interventional agent (i.e., next oral antihyperglycemic agent [AHA] or chronic insulin, where chronic insulin therapy is defined as a continuous period of insulin use of more than 3 months). Intent to treat population included all randomized participants who received study medication, provided consent, and did not have a major GCP deviation.
    End point type
    Secondary
    End point timeframe
    Up to 5 years
    End point values
    Sitagliptin Placebo
    Number of subjects analysed
    7332
    7339
    Units: Percentage of participants
        number (not applicable)
    21.7
    27.9
    Statistical analysis title
    Between-treatment difference
    Comparison groups
    Sitagliptin v Placebo
    Number of subjects included in analysis
    14671
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001 [10]
    Method
    Cox proportional hazards model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.72
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.68
         upper limit
    0.77
    Notes
    [10] - Model stratified by region with treatment group only as explanatory variable.

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Up to 68 months (including up to 28 days after last dose of study drug)
    Adverse event reporting additional description
    All participants as treated (APaT) population includes participants who received at least one dose of study drug.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Matching placebo tablet taken orally once daily in the morning

    Reporting group title
    Sitagliptin
    Reporting group description
    Sitagliptin tablet taken orally once daily in the morning

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: No non-serious adverse events exceeded the 5% threshold for any treatment group.
    Serious adverse events
    Placebo Sitagliptin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    909 / 7274 (12.50%)
    928 / 7266 (12.77%)
         number of deaths (all causes)
    57
    54
         number of deaths resulting from adverse events
    3
    0
    Vascular disorders
    Angiodysplasia
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic dissection
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic stenosis
         subjects affected / exposed
    1 / 7274 (0.01%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arterial haemorrhage
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriovenous fistula
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bleeding varicose vein
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral artery aneurysm
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (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 / 7274 (0.03%)
    6 / 7266 (0.08%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intra-abdominal haematoma
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphocele
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphoedema
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphorrhoea
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         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
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varicose vein
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Abdominal neoplasm
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myeloid leukaemia
         subjects affected / exposed
    1 / 7274 (0.01%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma
         subjects affected / exposed
    1 / 7274 (0.01%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma gastric
         subjects affected / exposed
    2 / 7274 (0.03%)
    2 / 7266 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Adenocarcinoma of appendix
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    12 / 7274 (0.16%)
    11 / 7266 (0.15%)
         occurrences causally related to treatment / all
    1 / 12
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Adenocarcinoma of salivary gland
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma of the cervix
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma pancreas
         subjects affected / exposed
    2 / 7274 (0.03%)
    2 / 7266 (0.03%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 2
    Adenoid cystic carcinoma
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenolymphoma
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         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 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal squamous cell carcinoma
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaplastic large-cell lymphoma
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angioimmunoblastic T-cell lymphoma
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (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
    4 / 7274 (0.05%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    55 / 7274 (0.76%)
    44 / 7266 (0.61%)
         occurrences causally related to treatment / all
    0 / 86
    0 / 50
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basosquamous carcinoma
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign gastric neoplasm
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         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 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct cancer
         subjects affected / exposed
    0 / 7274 (0.00%)
    3 / 7266 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Bladder cancer
         subjects affected / exposed
    10 / 7274 (0.14%)
    15 / 7266 (0.21%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 15
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Bladder cancer recurrent
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder neoplasm
         subjects affected / exposed
    2 / 7274 (0.03%)
    2 / 7266 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder papilloma
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder transitional cell carcinoma
         subjects affected / exposed
    6 / 7274 (0.08%)
    6 / 7266 (0.08%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bone cancer
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone neoplasm
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone sarcoma
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bowen's disease
         subjects affected / exposed
    2 / 7274 (0.03%)
    4 / 7266 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    5 / 7274 (0.07%)
    5 / 7266 (0.07%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer in situ
         subjects affected / exposed
    1 / 7274 (0.01%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer metastatic
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer recurrent
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial carcinoma
         subjects affected / exposed
    1 / 7274 (0.01%)
    3 / 7266 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Carcinoid tumour of the small bowel
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carcinoid tumour pulmonary
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central nervous system lymphoma
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cervix carcinoma
         subjects affected / exposed
    0 / 7274 (0.00%)
    2 / 7266 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangiocarcinoma
         subjects affected / exposed
    4 / 7274 (0.05%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Cholesteatoma
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic lymphocytic leukaemia
         subjects affected / exposed
    3 / 7274 (0.04%)
    4 / 7266 (0.06%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Chronic lymphocytic leukaemia recurrent
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic myeloid leukaemia
         subjects affected / exposed
    3 / 7274 (0.04%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Clear cell renal cell carcinoma
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Colon adenoma
         subjects affected / exposed
    1 / 7274 (0.01%)
    4 / 7266 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    14 / 7274 (0.19%)
    11 / 7266 (0.15%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 11
         deaths causally related to treatment / all
    0 / 4
    0 / 0
    Colon cancer metastatic
         subjects affected / exposed
    2 / 7274 (0.03%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer stage I
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer stage IV
         subjects affected / exposed
    2 / 7274 (0.03%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon neoplasm
         subjects affected / exposed
    1 / 7274 (0.01%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colorectal adenocarcinoma
         subjects affected / exposed
    2 / 7274 (0.03%)
    1 / 7266 (0.01%)
         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
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diffuse large B-cell lymphoma
         subjects affected / exposed
    0 / 7274 (0.00%)
    2 / 7266 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Endometrial adenocarcinoma
         subjects affected / exposed
    5 / 7274 (0.07%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial cancer
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gallbladder cancer
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric adenoma
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         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
    2 / 7274 (0.03%)
    5 / 7266 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastric cancer recurrent
         subjects affected / exposed
    1 / 7274 (0.01%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastric cancer stage IV
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal cancer metastatic
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal carcinoma
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (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
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glioblastoma multiforme
         subjects affected / exposed
    1 / 7274 (0.01%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Glioma
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic cancer
         subjects affected / exposed
    2 / 7274 (0.03%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Hepatic cancer metastatic
         subjects affected / exposed
    0 / 7274 (0.00%)
    2 / 7266 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hepatic neoplasm
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (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
    3 / 7274 (0.04%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Intraductal papilloma of breast
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intraductal proliferative breast lesion
         subjects affected / exposed
    2 / 7274 (0.03%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intraocular melanoma
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    4 / 7274 (0.05%)
    2 / 7266 (0.03%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Laryngeal cancer
         subjects affected / exposed
    4 / 7274 (0.05%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal squamous cell carcinoma
         subjects affected / exposed
    0 / 7274 (0.00%)
    2 / 7266 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leiomyosarcoma
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leiomyosarcoma metastatic
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lentigo maligna
         subjects affected / exposed
    1 / 7274 (0.01%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukaemia
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lip and/or oral cavity cancer
         subjects affected / exposed
    0 / 7274 (0.00%)
    2 / 7266 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lip squamous cell carcinoma
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lipoma
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         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
    4 / 7274 (0.05%)
    6 / 7266 (0.08%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Lung adenocarcinoma metastatic
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lung adenocarcinoma stage I
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma stage IV
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lung cancer metastatic
         subjects affected / exposed
    4 / 7274 (0.05%)
    2 / 7266 (0.03%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Lung carcinoma cell type unspecified stage IV
         subjects affected / exposed
    0 / 7274 (0.00%)
    3 / 7266 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Lung neoplasm
         subjects affected / exposed
    1 / 7274 (0.01%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    12 / 7274 (0.16%)
    12 / 7266 (0.17%)
         occurrences causally related to treatment / all
    1 / 12
    0 / 12
         deaths causally related to treatment / all
    0 / 4
    0 / 3
    Lung squamous cell carcinoma stage III
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lymphocytic leukaemia
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Malignant melanoma
         subjects affected / exposed
    6 / 7274 (0.08%)
    10 / 7266 (0.14%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 10
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Malignant melanoma in situ
         subjects affected / exposed
    4 / 7274 (0.05%)
    2 / 7266 (0.03%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant neoplasm of ampulla of Vater
         subjects affected / exposed
    0 / 7274 (0.00%)
    2 / 7266 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant neoplasm of renal pelvis
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melanocytic naevus
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningeal neoplasm
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningioma
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningioma malignant
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    0 / 7274 (0.00%)
    2 / 7266 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastases to central nervous system
         subjects affected / exposed
    1 / 7274 (0.01%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Metastases to liver
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to spine
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastatic bronchial carcinoma
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastatic malignant melanoma
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metastatic renal cell carcinoma
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic squamous cell carcinoma
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic uterine cancer
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucinous adenocarcinoma of appendix
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    1 / 7274 (0.01%)
    3 / 7266 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nasal cavity cancer
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasopharyngeal cancer
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasm recurrence
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuroendocrine carcinoma metastatic
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuroendocrine tumour
         subjects affected / exposed
    1 / 7274 (0.01%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurofibroma
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (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
         subjects affected / exposed
    1 / 7274 (0.01%)
    6 / 7266 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Non-small cell lung cancer
         subjects affected / exposed
    2 / 7274 (0.03%)
    2 / 7266 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-small cell lung cancer metastatic
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Oesophageal adenocarcinoma
         subjects affected / exposed
    1 / 7274 (0.01%)
    2 / 7266 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Oesophageal carcinoma
         subjects affected / exposed
    3 / 7274 (0.04%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Oesophageal squamous cell carcinoma
         subjects affected / exposed
    2 / 7274 (0.03%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oropharyngeal squamous cell carcinoma
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ovarian adenoma
         subjects affected / exposed
    1 / 7274 (0.01%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cancer
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cancer metastatic
         subjects affected / exposed
    1 / 7274 (0.01%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ovarian germ cell teratoma benign
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian granulosa-theca cell tumour
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian neoplasm
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    7 / 7274 (0.10%)
    8 / 7266 (0.11%)
         occurrences causally related to treatment / all
    2 / 7
    0 / 8
         deaths causally related to treatment / all
    2 / 6
    0 / 4
    Pancreatic carcinoma metastatic
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Papillary thyroid cancer
         subjects affected / exposed
    1 / 7274 (0.01%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parathyroid tumour benign
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Penile cancer
         subjects affected / exposed
    2 / 7274 (0.03%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Penile squamous cell carcinoma
         subjects affected / exposed
    1 / 7274 (0.01%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Phaeochromocytoma
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pituitary tumour
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pituitary tumour benign
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Plasma cell myeloma
         subjects affected / exposed
    6 / 7274 (0.08%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Plasmablastic lymphoma
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Plasmacytoma
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleomorphic liposarcoma
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural mesothelioma
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Polycythaemia vera
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    45 / 7274 (0.62%)
    36 / 7266 (0.50%)
         occurrences causally related to treatment / all
    0 / 45
    0 / 36
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Prostate cancer metastatic
         subjects affected / exposed
    5 / 7274 (0.07%)
    5 / 7266 (0.07%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 3
    0 / 2
    Prostate cancer recurrent
         subjects affected / exposed
    2 / 7274 (0.03%)
    3 / 7266 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer stage I
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatic adenoma
         subjects affected / exposed
    2 / 7274 (0.03%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal adenocarcinoma
         subjects affected / exposed
    2 / 7274 (0.03%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Rectal cancer
         subjects affected / exposed
    4 / 7274 (0.05%)
    2 / 7266 (0.03%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal cancer metastatic
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectosigmoid cancer
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Renal cancer
         subjects affected / exposed
    3 / 7274 (0.04%)
    7 / 7266 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cancer metastatic
         subjects affected / exposed
    0 / 7274 (0.00%)
    2 / 7266 (0.03%)
         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
    2 / 7274 (0.03%)
    3 / 7266 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cell carcinoma recurrent
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cell carcinoma stage I
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cell carcinoma stage III
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         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
    1 / 7274 (0.01%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal oncocytoma
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retroperitoneal cancer
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sarcoma
         subjects affected / exposed
    1 / 7274 (0.01%)
    1 / 7266 (0.01%)
         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
    3 / 7274 (0.04%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Small cell lung cancer
         subjects affected / exposed
    1 / 7274 (0.01%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Squamous cell carcinoma
         subjects affected / exposed
    38 / 7274 (0.52%)
    26 / 7266 (0.36%)
         occurrences causally related to treatment / all
    0 / 44
    0 / 38
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Squamous cell carcinoma of head and neck
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    7 / 7274 (0.10%)
    2 / 7266 (0.03%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    20 / 7274 (0.27%)
    12 / 7266 (0.17%)
         occurrences causally related to treatment / all
    0 / 23
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of the oral cavity
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of the tongue
         subjects affected / exposed
    1 / 7274 (0.01%)
    2 / 7266 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    T-cell lymphoma
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    T-cell prolymphocytic leukaemia
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Testis cancer
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thymic cancer metastatic
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroid adenoma
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroid cancer
         subjects affected / exposed
    0 / 7274 (0.00%)
    2 / 7266 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tongue cancer recurrent
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tongue neoplasm malignant stage unspecified
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsil cancer
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsil cancer metastatic
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Tracheal cancer
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheal neoplasm
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         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
    7 / 7274 (0.10%)
    7 / 7266 (0.10%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 8
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Urethral neoplasm
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine cancer
         subjects affected / exposed
    4 / 7274 (0.05%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (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
    Corneal graft rejection
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Adverse drug reaction
         subjects affected / exposed
    1 / 7274 (0.01%)
    3 / 7266 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    3 / 7274 (0.04%)
    2 / 7266 (0.03%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    8 / 7274 (0.11%)
    6 / 7266 (0.08%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device dislocation
         subjects affected / exposed
    0 / 7274 (0.00%)
    2 / 7266 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device malfunction
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug intolerance
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fat necrosis
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Granuloma
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hernia
         subjects affected / exposed
    1 / 7274 (0.01%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal hyperaemia
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    0 / 7274 (0.00%)
    2 / 7266 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Non-cardiac chest pain
         subjects affected / exposed
    26 / 7274 (0.36%)
    17 / 7266 (0.23%)
         occurrences causally related to treatment / all
    0 / 31
    0 / 19
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Puncture site haemorrhage
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Submandibular mass
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Alcohol abuse
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    3 / 7274 (0.04%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    3 / 7274 (0.04%)
    4 / 7266 (0.06%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dissociative disorder
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug abuse
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug dependence
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    3 / 7274 (0.04%)
    2 / 7266 (0.03%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nicotine dependence
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paranoid personality disorder
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 7274 (0.00%)
    2 / 7266 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    2 / 7274 (0.03%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Atrophic vulvovaginitis
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign prostatic hyperplasia
         subjects affected / exposed
    11 / 7274 (0.15%)
    15 / 7266 (0.21%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus prostatic
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervical polyp
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epididymal cyst
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epididymitis
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Genital rash
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metrorrhagia
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orchitis noninfective
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (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
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic floor muscle weakness
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postmenopausal haemorrhage
         subjects affected / exposed
    2 / 7274 (0.03%)
    2 / 7266 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatic obstruction
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatism
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatitis
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatomegaly
         subjects affected / exposed
    3 / 7274 (0.04%)
    4 / 7266 (0.06%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine polyp
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterovaginal prolapse
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Abdominal wound dehiscence
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Accidental overdose
         subjects affected / exposed
    19 / 7274 (0.26%)
    17 / 7266 (0.23%)
         occurrences causally related to treatment / all
    15 / 19
    13 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acetabulum fracture
         subjects affected / exposed
    0 / 7274 (0.00%)
    2 / 7266 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alcohol poisoning
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    3 / 7274 (0.04%)
    6 / 7266 (0.08%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthropod bite
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthropod sting
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Avulsion fracture
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (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
    0 / 7274 (0.00%)
    3 / 7266 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Burns second degree
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Burns third degree
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervical vertebral fracture
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chemical burns of eye
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Comminuted fracture
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    4 / 7274 (0.05%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    2 / 7274 (0.03%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    3 / 7274 (0.04%)
    3 / 7266 (0.04%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Delayed recovery from anaesthesia
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dislocation of vertebra
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         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
    4 / 7274 (0.05%)
    3 / 7266 (0.04%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    9 / 7274 (0.12%)
    9 / 7266 (0.12%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    3 / 7274 (0.04%)
    5 / 7266 (0.07%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Femur fracture
         subjects affected / exposed
    11 / 7274 (0.15%)
    7 / 7266 (0.10%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    1 / 7274 (0.01%)
    3 / 7266 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    1 / 7274 (0.01%)
    4 / 7266 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Forearm fracture
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foreign body
         subjects affected / exposed
    2 / 7274 (0.03%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture displacement
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal stoma complication
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    2 / 7274 (0.03%)
    5 / 7266 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Heat stroke
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    6 / 7274 (0.08%)
    5 / 7266 (0.07%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Humerus fracture
         subjects affected / exposed
    9 / 7274 (0.12%)
    4 / 7266 (0.06%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    1 / 7274 (0.01%)
    2 / 7266 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intentional overdose
         subjects affected / exposed
    2 / 7274 (0.03%)
    2 / 7266 (0.03%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    2 / 7274 (0.03%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    2 / 7274 (0.03%)
    4 / 7266 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament injury
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         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
    0 / 7274 (0.00%)
    3 / 7266 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament sprain
         subjects affected / exposed
    2 / 7274 (0.03%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb traumatic amputation
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    2 / 7274 (0.03%)
    4 / 7266 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    2 / 7274 (0.03%)
    3 / 7266 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    2 / 7274 (0.03%)
    2 / 7266 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mouth injury
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle injury
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Near drowning
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    2 / 7274 (0.03%)
    2 / 7266 (0.03%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Patella fracture
         subjects affected / exposed
    1 / 7274 (0.01%)
    2 / 7266 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    0 / 7274 (0.00%)
    2 / 7266 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periorbital haematoma
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periprosthetic fracture
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periprosthetic osteolysis
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural fistula
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    3 / 7274 (0.04%)
    2 / 7266 (0.03%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative ileus
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound complication
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prescribed overdose
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural complication
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pubis fracture
         subjects affected / exposed
    2 / 7274 (0.03%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary contusion
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    3 / 7274 (0.04%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal haematoma
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         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
    5 / 7274 (0.07%)
    2 / 7266 (0.03%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 7274 (0.01%)
    5 / 7266 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skull fracture
         subjects affected / exposed
    3 / 7274 (0.04%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue injury
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal column injury
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    4 / 7274 (0.05%)
    5 / 7266 (0.07%)
         occurrences causally related to treatment / all
    0 / 5
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Splinter
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sternal fracture
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    4 / 7274 (0.05%)
    2 / 7266 (0.03%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Subdural haemorrhage
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Tendon rupture
         subjects affected / exposed
    5 / 7274 (0.07%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Testicular injury
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thermal burn
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 7274 (0.01%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tongue injury
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 7274 (0.00%)
    5 / 7266 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheal injury
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic intracranial haemorrhage
         subjects affected / exposed
    1 / 7274 (0.01%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulnar nerve injury
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    3 / 7274 (0.04%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary bladder rupture
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular pseudoaneurysm
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    0 / 7274 (0.00%)
    4 / 7266 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Anticoagulation drug level increased
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme abnormal
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    2 / 7274 (0.03%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    International normalised ratio increased
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatic specific antigen increased
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count increased
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cor pulmonale
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery thrombosis
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    1 / 7274 (0.01%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus arrhythmia
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Arteriovenous malformation
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hamartoma
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrocele
         subjects affected / exposed
    1 / 7274 (0.01%)
    2 / 7266 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Phimosis
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyloric stenosis
         subjects affected / exposed
    2 / 7274 (0.03%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syringomyelia
         subjects affected / exposed
    2 / 7274 (0.03%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vitello-intestinal duct remnant
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    3 / 7274 (0.04%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 7274 (0.01%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    5 / 7274 (0.07%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alveolitis
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alveolitis allergic
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (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 / 7274 (0.05%)
    8 / 7266 (0.11%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiectasis
         subjects affected / exposed
    1 / 7274 (0.01%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    30 / 7274 (0.41%)
    13 / 7266 (0.18%)
         occurrences causally related to treatment / all
    0 / 37
    0 / 18
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Chronic respiratory disease
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 7274 (0.01%)
    2 / 7266 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Emphysema
         subjects affected / exposed
    3 / 7274 (0.04%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    6 / 7274 (0.08%)
    9 / 7266 (0.12%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    2 / 7274 (0.03%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemothorax
         subjects affected / exposed
    1 / 7274 (0.01%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrothorax
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperventilation
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    2 / 7274 (0.03%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Idiopathic pulmonary fibrosis
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 7274 (0.01%)
    2 / 7266 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal cyst
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         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 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nasal obstruction
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasal polyps
         subjects affected / exposed
    2 / 7274 (0.03%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthopnoea
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 7274 (0.03%)
    4 / 7266 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    4 / 7274 (0.05%)
    3 / 7266 (0.04%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Productive cough
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary alveolar haemorrhage
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary arterial hypertension
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         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
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    2 / 7274 (0.03%)
    2 / 7266 (0.03%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    1 / 7274 (0.01%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    2 / 7274 (0.03%)
    3 / 7266 (0.04%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 7274 (0.00%)
    4 / 7266 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sinus polyp
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sleep apnoea syndrome
         subjects affected / exposed
    0 / 7274 (0.00%)
    2 / 7266 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stridor
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheal disorder
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    23 / 7274 (0.32%)
    23 / 7266 (0.32%)
         occurrences causally related to treatment / all
    0 / 23
    0 / 24
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia vitamin B12 deficiency
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune haemolytic anaemia
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemolytic anaemia
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic anaemia
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    6 / 7274 (0.08%)
    6 / 7266 (0.08%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenopathy mediastinal
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Microcytic anaemia
         subjects affected / exposed
    1 / 7274 (0.01%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Normochromic normocytic anaemia
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pernicious anaemia
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 7274 (0.01%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Acoustic neuritis
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arachnoid cyst
         subjects affected / exposed
    1 / 7274 (0.01%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ataxia
         subjects affected / exposed
    2 / 7274 (0.03%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal ganglia haemorrhage
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain injury
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         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
    2 / 7274 (0.03%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cauda equina syndrome
         subjects affected / exposed
    2 / 7274 (0.03%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central nervous system lesion
         subjects affected / exposed
    1 / 7274 (0.01%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervical cord compression
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervical myelopathy
         subjects affected / exposed
    3 / 7274 (0.04%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervical radiculopathy
         subjects affected / exposed
    1 / 7274 (0.01%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervicobrachial syndrome
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         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
    0 / 7274 (0.00%)
    2 / 7266 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Complex partial seizures
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    6 / 7274 (0.08%)
    5 / 7266 (0.07%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cubital tunnel syndrome
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dementia
         subjects affected / exposed
    2 / 7274 (0.03%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dementia Alzheimer's type
         subjects affected / exposed
    1 / 7274 (0.01%)
    2 / 7266 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 7274 (0.01%)
    7 / 7266 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness postural
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (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
    2 / 7274 (0.03%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    3 / 7274 (0.04%)
    2 / 7266 (0.03%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial paresis
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 7274 (0.01%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersomnia
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial aneurysm
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (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
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar radiculopathy
         subjects affected / exposed
    1 / 7274 (0.01%)
    3 / 7266 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    1 / 7274 (0.01%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Monoplegia
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myasthenia gravis
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myasthenia gravis crisis
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelopathy
         subjects affected / exposed
    2 / 7274 (0.03%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nerve compression
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nerve root compression
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurological symptom
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Normal pressure hydrocephalus
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parkinson's disease
         subjects affected / exposed
    3 / 7274 (0.04%)
    2 / 7266 (0.03%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Partial seizures
         subjects affected / exposed
    3 / 7274 (0.04%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral sensorimotor neuropathy
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Petit mal epilepsy
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Piriformis syndrome
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Posterior reversible encephalopathy syndrome
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postictal state
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiculitis lumbosacral
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retrograde amnesia
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    4 / 7274 (0.05%)
    2 / 7266 (0.03%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sensory disturbance
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord disorder
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 7274 (0.01%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural effusion
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 7274 (0.01%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic outlet syndrome
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulnar tunnel syndrome
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular dementia
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (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 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertigo CNS origin
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Amaurosis fugax
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angle closure glaucoma
         subjects affected / exposed
    0 / 7274 (0.00%)
    2 / 7266 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cataract
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Corneal degeneration
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dacryostenosis acquired
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Optic ischaemic neuropathy
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Visual acuity reduced
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vitreous haemorrhage
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness bilateral
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoacusis
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniere's disease
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden hearing loss
         subjects affected / exposed
    0 / 7274 (0.00%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tinnitus
         subjects affected / exposed
    1 / 7274 (0.01%)
    1 / 7266 (0.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertigo
         subjects affected / exposed
    2 / 7274 (0.03%)
    4 / 7266 (0.06%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertigo labyrinthine
         subjects affected / exposed
    1 / 7274 (0.01%)
    0 / 7266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0