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    Clinical Trial Results:
    An open-label, multicenter, expanded access study of INC424 for patients with primary myelofibrosis (PMF) of post polycythemia vera myelofibrosis (PPV MF) or post-essential thrombocythemia myelofibrosis (PET-MF)

    Summary
    EudraCT number
    		 2010-024473-39
    Trial protocol
    		 AT   CZ   BE   DE   ES   GR   HU   PT   SK   PL   IT   IE  
    Global end of trial date
    26 Jan 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Feb 2018
    First version publication date
    11 Feb 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CINC424A2401
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01493414
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, +41 613241111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, +41 613241111,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    26 Jan 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Jan 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To collect additional safety data of ruxolitinib in patients with PMF, PPV-MF, or PET-MF who have either received prior treatment with commercially available agents, investigational drug or who have never received treatment.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Aug 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Algeria: 19
    Country: Number of subjects enrolled
    Argentina: 42
    Country: Number of subjects enrolled
    Brazil: 104
    Country: Number of subjects enrolled
    Canada: 53
    Country: Number of subjects enrolled
    Colombia: 18
    Country: Number of subjects enrolled
    Mexico: 26
    Country: Number of subjects enrolled
    Poland: 39
    Country: Number of subjects enrolled
    Portugal: 27
    Country: Number of subjects enrolled
    Slovakia: 17
    Country: Number of subjects enrolled
    Spain: 363
    Country: Number of subjects enrolled
    Austria: 31
    Country: Number of subjects enrolled
    Belgium: 55
    Country: Number of subjects enrolled
    Czech Republic: 12
    Country: Number of subjects enrolled
    Germany: 376
    Country: Number of subjects enrolled
    Greece: 17
    Country: Number of subjects enrolled
    Hungary: 26
    Country: Number of subjects enrolled
    Ireland: 1
    Country: Number of subjects enrolled
    Italy: 861
    Country: Number of subjects enrolled
    Luxembourg: 6
    Country: Number of subjects enrolled
    Morocco: 3
    Country: Number of subjects enrolled
    Russian Federation: 34
    Country: Number of subjects enrolled
    Saudi Arabia: 8
    Country: Number of subjects enrolled
    South Africa: 29
    Country: Number of subjects enrolled
    Thailand: 19
    Country: Number of subjects enrolled
    Tunisia: 27
    Country: Number of subjects enrolled
    Israel: 20
    Worldwide total number of subjects
    2233
    EEA total number of subjects
    1831
    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)
    899
    From 65 to 84 years
    1312
    85 years and over
    22

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was an expanded access study intended to provide an access path to ruxolitinib for patients with Myelofibrosis (MF) and to allow for collection of additional safety and efficacy data for ruxolitinib.

    Pre-assignment
    Screening details
    		 All patients were to be screened for inclusion and exclusion criteria within 28 days prior to the first dose of ruxolitinib.

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

    Arms
    Arm title
    		 INC424
    Arm description
    		 5 - 25 mg twice a day (BID) INC424: All patients enrolled into the study will receive INC424 (ruxolitinib). Starting dose is based on baseline platelet counts, with doses ranging from 5 to 20 mg twice a day. No INC424 dose will exceed 25 mg BID orally.
    Arm type
    		 Experimental

    Investigational medicinal product name
    INC424
    Investigational medicinal product code
    Other name
    Ruxolitinib
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    All patients enrolled into the study will receive INC424 (ruxolitinib). Starting dose is based on baseline platelet counts, with doses ranging from 5 to 20 mg twice a day. No INC424 dose will exceed 25 mg BID orally.

    Number of subjects in period 1
    		INC424
    Started
    2233
    Completed
    1283
    Not completed
    950
         Physician decision
    93
         Consent withdrawn by subject
    79
         Disease progression
    204
         Adverse Event
    405
         Death
    101
         Administrative problems
    25
         Lost to follow-up
    16
         Protocol deviation
    27

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    INC424
    Reporting group description
    		 5 - 25 mg twice a day (BID) INC424: All patients enrolled into the study will receive INC424 (ruxolitinib). Starting dose is based on baseline platelet counts, with doses ranging from 5 to 20 mg twice a day. No INC424 dose will exceed 25 mg BID orally.

    Reporting group values
    		 INC424 Total
    Number of subjects
    		 2233 2233
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 899 899
        From 65-84 years
    		 1312 1312
        85 years and over
    		 22 22
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 65.6 ( 10.50 ) -
    Gender categorical
    Units: Subjects
        Female
    		 1016 1016
        Male
    		 1217 1217
    ECOG score
    Units: Subjects
        00
    		 1061 1061
        01
    		 960 960
        02
    		 197 197
        03
    		 1 1
        04
    		 0 0
        Missing
    		 14 14

    End points

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    End points reporting groups
    Reporting group title
    INC424
    Reporting group description
    		 5 - 25 mg twice a day (BID) INC424: All patients enrolled into the study will receive INC424 (ruxolitinib). Starting dose is based on baseline platelet counts, with doses ranging from 5 to 20 mg twice a day. No INC424 dose will exceed 25 mg BID orally.

    Subject analysis set title
    INC424 - Responders
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Responders with spleen length between 5 and 10 cm=non palpable spleen. Responders with spleen length more than 10 cm=Spleen reduction of 50% from baseline. 5 - 25 mg twice a day (BID) INC424: All patients enrolled into the study will receive INC424 (ruxolitinib). Starting dose is based on baseline platelet counts, with doses ranging from 5 to 20 mg twice a day. No INC424 dose will exceed 25 mg BID orally.

    Subject analysis set title
    INC424 - Stable Disease
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants with Stable Disease with spleen length between 5 and 10 cm=does not meet criteria for response or disease progression. Participants with Stable Disease with spleen length more than 10 cm=does not meet criteria for response or disease progression. 5 - 25 mg twice a day (BID) INC424: All patients enrolled into the study will receive INC424 (ruxolitinib). Starting dose is based on baseline platelet counts, with doses ranging from 5 to 20 mg twice a day. No INC424 dose will exceed 25 mg BID orally.

    Subject analysis set title
    INC424 - Progressive Disease
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants with Progressive Disease with spleen length between 5 and 10 cm=increase of 100% from baseline in spleen length. Participants with Progressive Disease with spleen length more than 10 cm=increase of 50% from baseline in spleen length. 5 - 25 mg twice a day (BID) INC424: All patients enrolled into the study will receive INC424 (ruxolitinib). Starting dose is based on baseline platelet counts, with doses ranging from 5 to 20 mg twice a day. No INC424 dose will exceed 25 mg BID orally.

    Subject analysis set title
    INC424 - Missing
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Missing values. 5 - 25 mg twice a day (BID) INC424: All patients enrolled into the study will receive INC424 (ruxolitinib). Starting dose is based on baseline platelet counts, with doses ranging from 5 to 20 mg twice a day. No INC424 dose will exceed 25 mg BID orally.

    Primary: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) up to 5 Years

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    End point title
    		 Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) up to 5 Years [1]
    End point description
    An adverse event (AE) is any untoward medical occurrence in a clinical trial participant regardless of causal relationship to study drug and regardless whether study drug has been administered. A serious adverse event (SAE) is any untoward medical occurrence or effect that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability / incapacity, is a congenital anomaly / birth defect or is medically important due to other reasons than the above mentioned criteria. A non-serious AE is any AE that does not meet the criteria above. The occurrence of adverse events may be volunteered by the patient or obtained by non-directive questioning at each visit during the study or through physical examination, laboratory test, or other assessments.
    End point type
    Primary
    End point timeframe
    Baseline up to approximately 5 years
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses were completed for this primary end point.
    End point values
    		 INC424
    Number of subjects analysed
    2233 [2]
    Units: Count of Participants
    number (not applicable)
        Adverse Events
    2153
        Serious adverse events
    830
    Notes
    [2] - Safety set-all patients who received one dose of study drug and one post-baseline safety assessment
    No statistical analyses for this end point

    Secondary: Percentage of Participants With at Least 50% Reduction in Spleen Length

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    End point title
    		 Percentage of Participants With at Least 50% Reduction in Spleen Length
    End point description
    Spleen length was assessed by manual palpation. Assessment of spleen response was repeated until early discontinuation of the study drug and also at study completion (28 days post end of treatment visit).
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 5 years
    End point values
    		 INC424
    Number of subjects analysed
    2049 [3]
    Units: participants
        number (confidence interval 95%)
    71.7 (69.7 to 73.7)
    Notes
    [3] - Full analysis set includes all patients who received at least one administration of study drug.
    No statistical analyses for this end point

    Secondary: Best Overall Response (BOR) up to 5 Years

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    End point title
    		 Best Overall Response (BOR) up to 5 Years
    End point description
    Overall response is analyzed using the spleen response, as assessed by the investigator and also by deriving the response using International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria. Subjects with spleen length of less than 5 cm are not evaluable and do not appear in table.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 5 years
    End point values
    		 INC424 - Responders INC424 - Stable Disease INC424 - Progressive Disease INC424 - Missing
    Number of subjects analysed
    2233 [4]
    2233 [5]
    2233 [6]
    2233 [7]
    Units: Participants
    number (not applicable)
        Between 5 and 10 cm (N = 765)
    421
    334
    1
    9
        More than 10 cm (N = 1224)
    742
    463
    0
    19
    Notes
    [4] - FAS
    [5] - FAS
    [6] - FAS
    [7] - FAS
    No statistical analyses for this end point

    Secondary: Time to First Improvement in FACT-Lym, FACIT-Fatigue Score and ECOG Performance Status

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    End point title
    		 Time to First Improvement in FACT-Lym, FACIT-Fatigue Score and ECOG Performance Status
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 5 years
    End point values
    		 INC424
    Number of subjects analysed
    2233 [8]
    Units: weeks
    median (confidence interval 95%)
        FACT-Lym Total score median time to improvement
    10.9 (5.1 to 11.6)
        FACIT – Fatigue score median time to improvement
    4.6 (4.4 to 4.6)
        ECOG score median time to improvement
    63.1 (61.1 to 65.0)
    Notes
    [8] - Full analysis set includes all patients who received at least one administration of study drug.
    No statistical analyses for this end point

    Secondary: Change in Eastern Cooperative Oncology Group (ECOG) Performance Status up to 5 Years

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    End point title
    		 Change in Eastern Cooperative Oncology Group (ECOG) Performance Status up to 5 Years
    End point description
    ECOG Performance Score has 4 grades. 0 = Fully active, able to carry out all pre-disease activities; 1 = Restricted in strenuous activity but ambulatory and able to carry out work of light or sedentary nature; 2 = Ambulatory and capable of all self-care but unable to carry out work activities. Active about 50% of waking hours; 3 = Capable of limited self-care, confined to bed/chair more than 50% of waking hours; 4 = Completely disabled; cannot carry on self-care. Totally confined to bed/chair.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 5 years
    End point values
    		 INC424
    Number of subjects analysed
    2233 [9]
    Units: participants
    number (not applicable)
        Baseline - Grade 0:Worst post-baseline: Grade 0
    598
        Baseline - Grade 0:Worst post-baseline: Grade 1
    377
        Baseline - Grade 0:Worst post-baseline: Grade 2
    62
        Baseline - Grade 0:Worst post-baseline: Grade 3
    12
        Baseline - Grade 0:Worst post-baseline: Grade 4
    7
        Baseline - Grade 0:Worst post-baseline: Grade 5
    0
        Baseline - Grade 0:Worst post-baseline: Missing
    5
        Baseline - Grade 1:Worst post-baseline: Grade 0
    89
        Baseline - Grade 1:Worst post-baseline: Grade 1
    629
        Baseline - Grade 1:Worst post-baseline: Grade 2
    187
        Baseline - Grade 1:Worst post-baseline: Grade 3
    26
        Baseline - Grade 1:Worst post-baseline: Grade 4
    12
        Baseline - Grade 1:Worst post-baseline: Grade 5
    1
        Baseline - Grade 1:Worst post-baseline: Missing
    16
        Baseline - Grade 2:Worst post-baseline: Grade 0
    3
        Baseline - Grade 2:Worst post-baseline: Grade 1
    43
        Baseline - Grade 2:Worst post-baseline: Grade 2
    111
        Baseline - Grade 2:Worst post-baseline: Grade 3
    20
        Baseline - Grade 2:Worst post-baseline: Grade 4
    12
        Baseline - Grade 2:Worst post-baseline: Grade 5
    1
        Baseline - Grade 2:Worst post-baseline: Missing
    7
        Baseline - Grade 3:Worst post-baseline: Grade 0
    0
        Baseline - Grade 3:Worst post-baseline: Grade 1
    0
        Baseline - Grade 3:Worst post-baseline: Grade 2
    0
        Baseline - Grade 3:Worst post-baseline: Grade 3
    1
        Baseline - Grade 3:Worst post-baseline: Grade 4
    0
        Baseline - Grade 3:Worst post-baseline: Grade 5
    0
        Baseline - Grade 3:Worst post-baseline: Missing
    0
        Baseline - Grade 4:Worst post-baseline: Grade 0
    0
        Baseline - Grade 4:Worst post-baseline: Grade 1
    0
        Baseline - Grade 4:Worst post-baseline: Grade 2
    0
        Baseline - Grade 4:Worst post-baseline: Grade 3
    0
        Baseline - Grade 4:Worst post-baseline: Grade 4
    0
        Baseline - Grade 4:Worst post-baseline: Grade 5
    0
        Baseline - Grade 4:Worst post-baseline: Missing
    0
        Baseline - Missing:Worst post-baseline: Grade 0
    1
        Baseline - Missing:Worst post-baseline: Grade 1
    8
        Baseline - Missing:Worst post-baseline: Grade 2
    4
        Baseline - Missing:Worst post-baseline: Grade 3
    1
        Baseline - Missing:Worst post-baseline: Grade 4
    0
        Baseline - Missing:Worst post-baseline: Grade 5
    0
        Baseline - Missing:Worst post-baseline: Missing
    0
    Notes
    [9] - FAS N= G0 1061, Baseline - G1 960,Baseline - G2 197, Baseline - G3 1, Baseline - G4 0, GMissing 14
    No statistical analyses for this end point

    Secondary: Change in Functional Assessment of Cancer Therapy (FACT-TOI, FACT-G) and FACT-Lymphoma (FACT-Lym) Total Scores up to Week 48

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    End point title
    		 Change in Functional Assessment of Cancer Therapy (FACT-TOI, FACT-G) and FACT-Lymphoma (FACT-Lym) Total Scores up to Week 48
    End point description
    The FACT-Lym questionnaire consists of a total of 42 questions divided between five subscales (i.e., physical well-being, social/family well-being, emotional well-being, functional well-being and lymphoma subscale) which in turn contribute to three total sum scores, namely FACT-Lym Trial Outcome Index (TOI), FACT-General (FACT-G) total score and FACT- Lym total score.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 48
    End point values
    		 INC424
    Number of subjects analysed
    2233 [10]
    Units: scores on a scale
    arithmetic mean (standard deviation)
        FACT-Lymphoma Baseline
    42.3 ( 10.20 )
        FACT-Lymphoma Week 48
    47.9 ( 8.47 )
        FACT-Lymphoma TOI Baseline
    77.9 ( 18.99 )
        FACT-Lymphoma TOI Week 48
    86.8 ( 16.42 )
        FACT-Lymphoma total score Baseline
    113.9 ( 24.01 )
        FACT-Lymphoma total score Week 48
    123.3 ( 22.34 )
        FACT-G Baseline
    71.6 ( 15.98 )
        FACT-G Week 48
    75.5 ( 15.59 )
    Notes
    [10] - FAS; N= 2065, 952, 2034, 940, 2029, 937, 2050, 950
    No statistical analyses for this end point

    Secondary: Medical Resource Utilization up to 5 Years

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    End point title
    		 Medical Resource Utilization up to 5 Years
    End point description
    Percentage of patients requiring medical resources (blood transfusions, hospitalization, emergency room visits, general practitioners or specialists consultations, urgent care or splenic irradiation) up to 5 years.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 5 years.
    End point values
    		 INC424
    Number of subjects analysed
    2233 [11]
    Units: participants
    number (not applicable)
        Baseline- Dependency vs End of Study - Dependency
    129
        Baseline- Dependency vs End of Study-Independency
    29
        Baseline- Independency vs End of Study-Dependency
    480
        Baseline-Independency vs End of Study-Idependency
    1595
    Notes
    [11] - FAS Baseline- Dependency n= 158 Baseline- Independency n =2075
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events (AEs) were collected up to 24-months after last patient first visit (LPFV) for each participant, up to approximately 5 years.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    INC424
    Reporting group description
    		 5 - 25 mg twice a day (BID) INC424: All patients enrolled into the study will receive INC424 (ruxolitinib). Starting dose is based on baseline platelet counts, with doses ranging from 5 to 20 mg twice a day. No INC424 dose will exceed 25 mg BID orally.

    Serious adverse events
    		 INC424
    Total subjects affected by serious adverse events
         subjects affected / exposed
    830 / 2233 (37.17%)
         number of deaths (all causes)
    205
         number of deaths resulting from adverse events
    20
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acrochordon
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Acute leukaemia
         subjects affected / exposed
    13 / 2233 (0.58%)
         occurrences causally related to treatment / all
    0 / 13
         deaths causally related to treatment / all
    0 / 2
    Adenocarcinoma pancreas
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Acute myeloid leukaemia
         subjects affected / exposed
    18 / 2233 (0.81%)
         occurrences causally related to treatment / all
    2 / 18
         deaths causally related to treatment / all
    0 / 4
    B-cell lymphoma
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    10 / 2233 (0.45%)
         occurrences causally related to treatment / all
    1 / 10
         deaths causally related to treatment / all
    0 / 0
    Bladder transitional cell carcinoma
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blast cell crisis
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Chloroma
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cholangiocarcinoma
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Chronic lymphocytic leukaemia
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Chronic myeloid leukaemia
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Chronic myeloid leukaemia transformation
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Chronic myelomonocytic leukaemia
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intestinal adenocarcinoma
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Leukaemia
         subjects affected / exposed
    7 / 2233 (0.31%)
         occurrences causally related to treatment / all
    2 / 7
         deaths causally related to treatment / all
    0 / 1
    Lung neoplasm malignant
         subjects affected / exposed
    4 / 2233 (0.18%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    Lymphangioma
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Metastases to liver
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metastases to lung
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Monoclonal gammopathy
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Myelofibrosis
         subjects affected / exposed
    5 / 2233 (0.22%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Myeloid metaplasia
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Neoplasm
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Neoplasm skin
         subjects affected / exposed
    3 / 2233 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Neuroendocrine carcinoma
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neuroendocrine tumour
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Non-Hodgkin's lymphoma
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Pelvic neoplasm
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Prostate cancer
         subjects affected / exposed
    4 / 2233 (0.18%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    Rectal adenocarcinoma
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Second primary malignancy
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Squamous cell carcinoma
         subjects affected / exposed
    9 / 2233 (0.40%)
         occurrences causally related to treatment / all
    1 / 14
         deaths causally related to treatment / all
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    6 / 2233 (0.27%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Squamous cell carcinoma of the vagina
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tumour thrombosis
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Aortic rupture
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Aortic stenosis
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Arterial disorder
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Arterial haemorrhage
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    10 / 2233 (0.45%)
         occurrences causally related to treatment / all
    0 / 10
         deaths causally related to treatment / all
    0 / 1
    Embolism
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haematoma
         subjects affected / exposed
    9 / 2233 (0.40%)
         occurrences causally related to treatment / all
    2 / 10
         deaths causally related to treatment / all
    0 / 0
    Hyperaemia
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypertension
         subjects affected / exposed
    3 / 2233 (0.13%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypotension
         subjects affected / exposed
    7 / 2233 (0.31%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    Pallor
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Peripheral artery occlusion
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Peripheral artery stenosis
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    3 / 2233 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Phlebitis
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Shock
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Thrombophlebitis superficial
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Surgical and medical procedures
    Stem cell transplant
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    14 / 2233 (0.63%)
         occurrences causally related to treatment / all
    4 / 15
         deaths causally related to treatment / all
    0 / 0
    Chest pain
         subjects affected / exposed
    8 / 2233 (0.36%)
         occurrences causally related to treatment / all
    1 / 8
         deaths causally related to treatment / all
    0 / 0
    Death
         subjects affected / exposed
    12 / 2233 (0.54%)
         occurrences causally related to treatment / all
    1 / 12
         deaths causally related to treatment / all
    1 / 10
    Disease progression
         subjects affected / exposed
    4 / 2233 (0.18%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Drug withdrawal syndrome
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Face oedema
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fatigue
         subjects affected / exposed
    11 / 2233 (0.49%)
         occurrences causally related to treatment / all
    1 / 13
         deaths causally related to treatment / all
    0 / 1
    Gait disturbance
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    19 / 2233 (0.85%)
         occurrences causally related to treatment / all
    2 / 19
         deaths causally related to treatment / all
    0 / 1
    Generalised oedema
         subjects affected / exposed
    5 / 2233 (0.22%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Hernia
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyperpyrexia
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    11 / 2233 (0.49%)
         occurrences causally related to treatment / all
    3 / 11
         deaths causally related to treatment / all
    1 / 7
    Nodule
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    10 / 2233 (0.45%)
         occurrences causally related to treatment / all
    1 / 10
         deaths causally related to treatment / all
    0 / 0
    Pain
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Peripheral swelling
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Polyp
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pseudocyst
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyrexia
         subjects affected / exposed
    79 / 2233 (3.54%)
         occurrences causally related to treatment / all
    11 / 85
         deaths causally related to treatment / all
    0 / 1
    Sudden death
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    1 / 2
    Immune system disorders
    Cytokine release syndrome
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Immunosuppression
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cervical dysplasia
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Menometrorrhagia
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Postmenopausal haemorrhage
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Prostatitis
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Testicular pain
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    4 / 2233 (0.18%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    1 / 2
    Acute respiratory distress syndrome
         subjects affected / exposed
    7 / 2233 (0.31%)
         occurrences causally related to treatment / all
    1 / 7
         deaths causally related to treatment / all
    0 / 4
    Acute respiratory failure
         subjects affected / exposed
    7 / 2233 (0.31%)
         occurrences causally related to treatment / all
    0 / 8
         deaths causally related to treatment / all
    0 / 1
    Alveolitis
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Asthma
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchospasm
         subjects affected / exposed
    3 / 2233 (0.13%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    3 / 2233 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Chronic respiratory failure
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cough
         subjects affected / exposed
    6 / 2233 (0.27%)
         occurrences causally related to treatment / all
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    Dyspnoea
         subjects affected / exposed
    36 / 2233 (1.61%)
         occurrences causally related to treatment / all
    7 / 39
         deaths causally related to treatment / all
    0 / 1
    Emphysema
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Epistaxis
         subjects affected / exposed
    10 / 2233 (0.45%)
         occurrences causally related to treatment / all
    1 / 10
         deaths causally related to treatment / all
    0 / 0
    Haemoptysis
         subjects affected / exposed
    4 / 2233 (0.18%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Haemothorax
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hydrothorax
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung infiltration
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    3 / 2233 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pleural effusion
         subjects affected / exposed
    13 / 2233 (0.58%)
         occurrences causally related to treatment / all
    1 / 13
         deaths causally related to treatment / all
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonitis
         subjects affected / exposed
    5 / 2233 (0.22%)
         occurrences causally related to treatment / all
    3 / 6
         deaths causally related to treatment / all
    0 / 1
    Pneumothorax
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Productive cough
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    18 / 2233 (0.81%)
         occurrences causally related to treatment / all
    2 / 18
         deaths causally related to treatment / all
    1 / 5
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    8 / 2233 (0.36%)
         occurrences causally related to treatment / all
    2 / 9
         deaths causally related to treatment / all
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    5 / 2233 (0.22%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 2
    Respiratory distress
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Respiratory failure
         subjects affected / exposed
    26 / 2233 (1.16%)
         occurrences causally related to treatment / all
    2 / 27
         deaths causally related to treatment / all
    0 / 7
    Thoracic haemorrhage
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Anxiety disorder
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Confusional state
         subjects affected / exposed
    3 / 2233 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Delirium
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Depression
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Disorientation
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Product issues
    Device leakage
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Biliary colic
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cholangitis chronic
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cholecystitis
         subjects affected / exposed
    3 / 2233 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    3 / 2233 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    5 / 2233 (0.22%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Hepatitis
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatorenal syndrome
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Jaundice
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Portal hypertension
         subjects affected / exposed
    3 / 2233 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Portal vein thrombosis
         subjects affected / exposed
    5 / 2233 (0.22%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Blast cell count increased
         subjects affected / exposed
    3 / 2233 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Body temperature increased
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cardioactive drug level increased
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Electrocardiogram T wave abnormal
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Electrocardiogram T wave amplitude increased
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Epstein-Barr virus antigen positive
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General physical condition abnormal
         subjects affected / exposed
    4 / 2233 (0.18%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    Haemoglobin decreased
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Heart rate irregular
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lipase increased
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Myeloblast count increased
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Portal vein pressure increased
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sensory level abnormal
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Troponin I increased
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    White blood cell count increased
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Anastomotic leak
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ankle fracture
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Arterial injury
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Brain contusion
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Crush injury
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Face injury
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fall
         subjects affected / exposed
    6 / 2233 (0.27%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Femur fracture
         subjects affected / exposed
    6 / 2233 (0.27%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Foot fracture
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Fractured sacrum
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Head injury
         subjects affected / exposed
    4 / 2233 (0.18%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    Heart injury
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Humerus fracture
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Joint injury
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Limb injury
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Meniscus injury
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Patella fracture
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    4 / 2233 (0.18%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Rib fracture
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal fracture
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Splenic injury
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Splenic rupture
         subjects affected / exposed
    7 / 2233 (0.31%)
         occurrences causally related to treatment / all
    3 / 7
         deaths causally related to treatment / all
    0 / 1
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Subdural haemorrhage
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Tendon rupture
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Transfusion reaction
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Traumatic fracture
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Traumatic haemorrhage
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Upper limb fracture
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Congenital, familial and genetic disorders
    Hydrocele
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    9 / 2233 (0.40%)
         occurrences causally related to treatment / all
    1 / 9
         deaths causally related to treatment / all
    0 / 0
    Angina pectoris
         subjects affected / exposed
    8 / 2233 (0.36%)
         occurrences causally related to treatment / all
    1 / 9
         deaths causally related to treatment / all
    0 / 0
    Aortic valve incompetence
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    21 / 2233 (0.94%)
         occurrences causally related to treatment / all
    1 / 24
         deaths causally related to treatment / all
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Atrioventricular block first degree
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bradycardia
         subjects affected / exposed
    4 / 2233 (0.18%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    16 / 2233 (0.72%)
         occurrences causally related to treatment / all
    4 / 16
         deaths causally related to treatment / all
    4 / 11
    Cardiac disorder
         subjects affected / exposed
    3 / 2233 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    Cardiac failure
         subjects affected / exposed
    43 / 2233 (1.93%)
         occurrences causally related to treatment / all
    7 / 45
         deaths causally related to treatment / all
    0 / 10
    Cardiac failure acute
         subjects affected / exposed
    5 / 2233 (0.22%)
         occurrences causally related to treatment / all
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    7 / 2233 (0.31%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 1
    Cardiac tamponade
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    9 / 2233 (0.40%)
         occurrences causally related to treatment / all
    0 / 9
         deaths causally related to treatment / all
    0 / 5
    Cardiogenic shock
         subjects affected / exposed
    5 / 2233 (0.22%)
         occurrences causally related to treatment / all
    1 / 5
         deaths causally related to treatment / all
    0 / 4
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Conduction disorder
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Congestive cardiomyopathy
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cor pulmonale
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    5 / 2233 (0.22%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypertensive heart disease
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intracardiac thrombus
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Left ventricular hypertrophy
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    5 / 2233 (0.22%)
         occurrences causally related to treatment / all
    1 / 5
         deaths causally related to treatment / all
    1 / 3
    Myocardial ischaemia
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Palpitations
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    3 / 2233 (0.13%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Pericardial haemorrhage
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pericarditis
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Right ventricular dysfunction
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Stress cardiomyopathy
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    3 / 2233 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Tachyarrhythmia
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tricuspid valve incompetence
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ventricular dysfunction
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ventricular hypokinesia
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Basilar artery aneurysm
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Central nervous system haemorrhage
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Central nervous system lesion
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Cerebral haemorrhage
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Cerebral ischaemia
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    4 / 2233 (0.18%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Coma
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cranial nerve paralysis
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dizziness
         subjects affected / exposed
    5 / 2233 (0.22%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Drop attacks
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Dysarthria
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Embolic stroke
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Encephalopathy
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Extrapyramidal disorder
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Headache
         subjects affected / exposed
    3 / 2233 (0.13%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyperaesthesia
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Muscle contractions involuntary
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Myoclonus
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neuralgia
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neurological decompensation
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Osmotic demyelination syndrome
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    3 / 2233 (0.13%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Paraesthesia
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Parkinson's disease
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Posterior reversible encephalopathy syndrome
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyramidal tract syndrome
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Seizure
         subjects affected / exposed
    3 / 2233 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Somnolence
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Speech disorder
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Syncope
         subjects affected / exposed
    11 / 2233 (0.49%)
         occurrences causally related to treatment / all
    1 / 12
         deaths causally related to treatment / all
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    5 / 2233 (0.22%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Agranulocytosis
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Anaemia
         subjects affected / exposed
    94 / 2233 (4.21%)
         occurrences causally related to treatment / all
    52 / 104
         deaths causally related to treatment / all
    1 / 1
    Autoimmune haemolytic anaemia
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bone marrow oedema
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Coagulopathy
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    8 / 2233 (0.36%)
         occurrences causally related to treatment / all
    4 / 9
         deaths causally related to treatment / all
    0 / 0
    Haemolytic anaemia
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Histiocytosis haematophagic
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypercoagulation
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Leukocytosis
         subjects affected / exposed
    8 / 2233 (0.36%)
         occurrences causally related to treatment / all
    1 / 8
         deaths causally related to treatment / all
    0 / 0
    Leukostasis syndrome
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lymphocytosis
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Monoclonal B-cell lymphocytosis
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neutropenia
         subjects affected / exposed
    10 / 2233 (0.45%)
         occurrences causally related to treatment / all
    5 / 10
         deaths causally related to treatment / all
    0 / 0
    Pancytopenia
         subjects affected / exposed
    3 / 2233 (0.13%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Polycythaemia
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Splenic haematoma
         subjects affected / exposed
    3 / 2233 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Splenic infarction
         subjects affected / exposed
    4 / 2233 (0.18%)
         occurrences causally related to treatment / all
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    Splenomegaly
         subjects affected / exposed
    8 / 2233 (0.36%)
         occurrences causally related to treatment / all
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    Spontaneous haematoma
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    24 / 2233 (1.07%)
         occurrences causally related to treatment / all
    9 / 24
         deaths causally related to treatment / all
    0 / 0
    Thrombocytosis
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ear and labyrinth disorders
    Hypoacusis
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Vertigo
         subjects affected / exposed
    5 / 2233 (0.22%)
         occurrences causally related to treatment / all
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    3 / 2233 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Corneal oedema
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diplopia
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Macular degeneration
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Optic ischaemic neuropathy
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Uveitis
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Abdominal mass
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Abdominal pain
         subjects affected / exposed
    28 / 2233 (1.25%)
         occurrences causally related to treatment / all
    3 / 30
         deaths causally related to treatment / all
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    5 / 2233 (0.22%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Abdominal tenderness
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Abdominal wall haematoma
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Anal fissure
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Anal prolapse
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Anal ulcer
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ascites
         subjects affected / exposed
    14 / 2233 (0.63%)
         occurrences causally related to treatment / all
    3 / 14
         deaths causally related to treatment / all
    0 / 0
    Barrett's oesophagus
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Colitis
         subjects affected / exposed
    3 / 2233 (0.13%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
         subjects affected / exposed
    17 / 2233 (0.76%)
         occurrences causally related to treatment / all
    1 / 18
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea haemorrhagic
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Diverticulum intestinal haemorrhagic
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Enterovesical fistula
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Faecaloma
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Femoral hernia
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    4 / 2233 (0.18%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    Gastric stenosis
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastric varices haemorrhage
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    21 / 2233 (0.94%)
         occurrences causally related to treatment / all
    2 / 23
         deaths causally related to treatment / all
    0 / 1
    Haematemesis
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Haematochezia
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    3 / 2233 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Inguinal hernia
         subjects affected / exposed
    5 / 2233 (0.22%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Inguinal hernia strangulated
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intestinal haemorrhage
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Intestinal infarction
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Mallory-Weiss syndrome
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Melaena
         subjects affected / exposed
    4 / 2233 (0.18%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    Mesenteric haemorrhage
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Mesenteric vein thrombosis
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Mouth haemorrhage
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nausea
         subjects affected / exposed
    5 / 2233 (0.22%)
         occurrences causally related to treatment / all
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    Oesophageal haemorrhage
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Oesophageal rupture
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Oesophageal varices haemorrhage
         subjects affected / exposed
    10 / 2233 (0.45%)
         occurrences causally related to treatment / all
    1 / 11
         deaths causally related to treatment / all
    0 / 1
    Pancreatitis
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Peritoneal haemorrhage
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pneumoperitoneum
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    3 / 2233 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Rectal polyp
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Retroperitoneal haematoma
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Retroperitoneal haemorrhage
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Small intestinal stenosis
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Splenic artery aneurysm
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Subileus
         subjects affected / exposed
    3 / 2233 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Tooth loss
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Toothache
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    5 / 2233 (0.22%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Varices oesophageal
         subjects affected / exposed
    5 / 2233 (0.22%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    16 / 2233 (0.72%)
         occurrences causally related to treatment / all
    3 / 17
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermal cyst
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dermatitis
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Erythema nodosum
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyperhidrosis
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Panniculitis
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pruritus
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Skin lesion
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin mass
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin ulcer
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    19 / 2233 (0.85%)
         occurrences causally related to treatment / all
    4 / 21
         deaths causally related to treatment / all
    0 / 3
    Acute prerenal failure
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Anuria
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Calculus bladder
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    6 / 2233 (0.27%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Dysuria
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haematuria
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    6 / 2233 (0.27%)
         occurrences causally related to treatment / all
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    Nephropathy
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nephrotic syndrome
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal colic
         subjects affected / exposed
    3 / 2233 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Renal failure
         subjects affected / exposed
    12 / 2233 (0.54%)
         occurrences causally related to treatment / all
    2 / 12
         deaths causally related to treatment / all
    0 / 1
    Renal impairment
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Renal infarct
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Tubulointerstitial nephritis
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Arthritis
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Arthropathy
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Back pain
         subjects affected / exposed
    8 / 2233 (0.36%)
         occurrences causally related to treatment / all
    2 / 8
         deaths causally related to treatment / all
    0 / 0
    Bone pain
         subjects affected / exposed
    11 / 2233 (0.49%)
         occurrences causally related to treatment / all
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    Chondrocalcinosis pyrophosphate
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Compartment syndrome
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Crystal arthropathy
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Flank pain
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gouty arthritis
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Haemarthrosis
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Meniscal degeneration
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Muscle haemorrhage
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Muscle tightness
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Muscular weakness
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Myalgia
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Neck pain
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Osteolysis
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Osteoporotic fracture
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pain in extremity
         subjects affected / exposed
    4 / 2233 (0.18%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Soft tissue necrosis
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Actinomycosis
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Anal abscess
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Appendicitis
         subjects affected / exposed
    5 / 2233 (0.22%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    Aspergillus infection
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bacterial infection
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Biliary sepsis
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bone tuberculosis
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchitis
         subjects affected / exposed
    9 / 2233 (0.40%)
         occurrences causally related to treatment / all
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    Bronchitis bacterial
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    Campylobacter infection
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cellulitis
         subjects affected / exposed
    8 / 2233 (0.36%)
         occurrences causally related to treatment / all
    0 / 8
         deaths causally related to treatment / all
    0 / 1
    Cerebral toxoplasmosis
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Community acquired infection
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Corneal abscess
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Dengue fever
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dermo-hypodermitis
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Device related infection
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Device related sepsis
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diverticulitis
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Endocarditis
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Enterococcal infection
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Enterococcal sepsis
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Epididymitis
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Erysipelas
         subjects affected / exposed
    3 / 2233 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Escherichia infection
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    6 / 2233 (0.27%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gangrene
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    11 / 2233 (0.49%)
         occurrences causally related to treatment / all
    5 / 12
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis norovirus
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis salmonella
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    3 / 2233 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Genital herpes
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    H1N1 influenza
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatic echinococciasis
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatitis B
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatitis E
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatitis infectious
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Herpes simplex
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Herpes simplex pneumonia
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Herpes zoster
         subjects affected / exposed
    5 / 2233 (0.22%)
         occurrences causally related to treatment / all
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    Herpes zoster infection neurological
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infection
         subjects affected / exposed
    3 / 2233 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Influenza
         subjects affected / exposed
    5 / 2233 (0.22%)
         occurrences causally related to treatment / all
    2 / 5
         deaths causally related to treatment / all
    1 / 1
    Klebsiella infection
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Localised infection
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    3 / 2233 (0.13%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Lung abscess
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung infection
         subjects affected / exposed
    11 / 2233 (0.49%)
         occurrences causally related to treatment / all
    2 / 11
         deaths causally related to treatment / all
    0 / 0
    Lymph node tuberculosis
         subjects affected / exposed
    3 / 2233 (0.13%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Meningitis
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Mycobacterial infection
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Neurocryptococcosis
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Ophthalmic herpes zoster
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pelvic inflammatory disease
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Perirectal abscess
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Peritoneal tuberculosis
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Peritonitis
         subjects affected / exposed
    4 / 2233 (0.18%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    Peritonitis bacterial
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    Pharyngitis
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pneumococcal infection
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumocystis jirovecii infection
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    123 / 2233 (5.51%)
         occurrences causally related to treatment / all
    24 / 140
         deaths causally related to treatment / all
    1 / 16
    Pneumonia bacterial
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pseudomonal sepsis
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psoas abscess
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Pulpitis dental
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Q fever
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    19 / 2233 (0.85%)
         occurrences causally related to treatment / all
    2 / 20
         deaths causally related to treatment / all
    1 / 2
    Sepsis
         subjects affected / exposed
    31 / 2233 (1.39%)
         occurrences causally related to treatment / all
    5 / 33
         deaths causally related to treatment / all
    0 / 10
    Septic shock
         subjects affected / exposed
    21 / 2233 (0.94%)
         occurrences causally related to treatment / all
    3 / 21
         deaths causally related to treatment / all
    2 / 12
    Sinusitis
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Skin infection
         subjects affected / exposed
    6 / 2233 (0.27%)
         occurrences causally related to treatment / all
    2 / 7
         deaths causally related to treatment / all
    0 / 1
    Soft tissue infection
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    3 / 2233 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Streptococcal sepsis
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tooth abscess
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tracheitis
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tuberculosis
         subjects affected / exposed
    5 / 2233 (0.22%)
         occurrences causally related to treatment / all
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    Tubo-ovarian abscess
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 2233 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    23 / 2233 (1.03%)
         occurrences causally related to treatment / all
    3 / 25
         deaths causally related to treatment / all
    0 / 1
    Urinary tract infection bacterial
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urosepsis
         subjects affected / exposed
    8 / 2233 (0.36%)
         occurrences causally related to treatment / all
    1 / 8
         deaths causally related to treatment / all
    0 / 0
    Vestibular neuronitis
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    3 / 2233 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Decreased appetite
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dehydration
         subjects affected / exposed
    8 / 2233 (0.36%)
         occurrences causally related to treatment / all
    3 / 9
         deaths causally related to treatment / all
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    3 / 2233 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Diabetic metabolic decompensation
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fluid retention
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gout
         subjects affected / exposed
    3 / 2233 (0.13%)
         occurrences causally related to treatment / all
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    8 / 2233 (0.36%)
         occurrences causally related to treatment / all
    2 / 8
         deaths causally related to treatment / all
    0 / 0
    Hyperlactacidaemia
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyperuricaemia
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    2 / 2233 (0.09%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    3 / 2233 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    3 / 2233 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    1 / 2233 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    3 / 2233 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    4 / 2233 (0.18%)
         occurrences causally related to treatment / all
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 INC424
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2008 / 2233 (89.92%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    134 / 2233 (6.00%)
         occurrences all number
    166
    Platelet count decreased
         subjects affected / exposed
    198 / 2233 (8.87%)
         occurrences all number
    323
    Weight increased
         subjects affected / exposed
    140 / 2233 (6.27%)
         occurrences all number
    152
    Nervous system disorders
    Headache
         subjects affected / exposed
    191 / 2233 (8.55%)
         occurrences all number
    231
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1300 / 2233 (58.22%)
         occurrences all number
    2207
    Neutropenia
         subjects affected / exposed
    146 / 2233 (6.54%)
         occurrences all number
    219
    Thrombocytopenia
         subjects affected / exposed
    990 / 2233 (44.33%)
         occurrences all number
    1775
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    331 / 2233 (14.82%)
         occurrences all number
    423
    Fatigue
         subjects affected / exposed
    215 / 2233 (9.63%)
         occurrences all number
    253
    Oedema peripheral
         subjects affected / exposed
    182 / 2233 (8.15%)
         occurrences all number
    210
    Pyrexia
         subjects affected / exposed
    310 / 2233 (13.88%)
         occurrences all number
    422
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    149 / 2233 (6.67%)
         occurrences all number
    174
    Constipation
         subjects affected / exposed
    121 / 2233 (5.42%)
         occurrences all number
    134
    Diarrhoea
         subjects affected / exposed
    267 / 2233 (11.96%)
         occurrences all number
    358
    Nausea
         subjects affected / exposed
    128 / 2233 (5.73%)
         occurrences all number
    147
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    186 / 2233 (8.33%)
         occurrences all number
    206
    Dyspnoea
         subjects affected / exposed
    155 / 2233 (6.94%)
         occurrences all number
    172
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    131 / 2233 (5.87%)
         occurrences all number
    149
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    176 / 2233 (7.88%)
         occurrences all number
    218
    Back pain
         subjects affected / exposed
    115 / 2233 (5.15%)
         occurrences all number
    125
    Pain in extremity
         subjects affected / exposed
    147 / 2233 (6.58%)
         occurrences all number
    168
    Infections and infestations
    Herpes zoster
         subjects affected / exposed
    112 / 2233 (5.02%)
         occurrences all number
    125
    Nasopharyngitis
         subjects affected / exposed
    115 / 2233 (5.15%)
         occurrences all number
    140
    Urinary tract infection
         subjects affected / exposed
    114 / 2233 (5.11%)
         occurrences all number
    162

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Aug 2012
    1. To re-evaluate the inclusion and exclusion criteria to the study 2. Increase the enrollment sample size from 950 to 1600 patients plus a 20% attrition rate 3. Addition of interim analyses
    11 Sep 2013
    1. Addition of inclusion criteria for patients having a 50000 to 75000/ μL baseline platelet count if all other inclusion/exclusion criteria are met, and addition of dosing instructions for those patients for an initial dose of 5 mg po bid. 2. The sample size is to be increased up to a maximum of 2484. 3. Enrollment to the study will complete when the maximum number of patients has been enrolled or December 31, 2014, whichever comes first. 4. The decision regarding end of treatment will now include physician decision. 5. Data analysis will no longer be performed annually, but may be performed if needed to fulfill regulatory request or publication purpose. 6. Where Country-specific local Health Authority approval is in process, drug supply is updated to take into account that drug may be supplied centrally, or locally if deemed necessary after local Health Authority approval have been granted. 7. Statistical analysis reflecting updates in estimated end of enrollment and end of treatment, with inclusion of patients with baseline platelet count of 50000 to 75000/μL in the pool of patients with low platelet counts. 8. Update AE definition and processing. 9. Update reference list.
    17 Dec 2013
    1. Addition of inclusion criteria to allow fedratinib pretreated patients to be included in the trial as long as clinical, laboratory and image assessments are properly documented. 2. Update of visit schedule and assessments.
    21 Mar 2016
    The primary purpose of the amendment was to align this protocol with the latest modified Novartis standard language for clinical study protocols: *Updated highly effective contraception method The “contraception use” wording has been updated to provide clarification and implement latest available guidelines as to highly effective contraception. Since all patients are enrolled, the clarification does not apply per se to exclusion criteria but may be used as needed for female of childbearing potential currently enrolled in the trial, *Updates to concomitant therapy and prohibited concomitant therapy Clarifications to concomitant therapy and prohibited concomitant therapy is also updated in appendix. *Additional changes: Reticulocytes count and coagulation parameters determination may or may not be part of the standard evaluation performed in clinical practice at different health care centers. As this study aims to resemble the use of ruxolitinib in patients with myelofibrosis in the clinical practice setting, we will allow optional collection and results reporting in the CRF when collected and deemed clinically relevant on a patient basis.

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

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