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    Clinical Trial Results:
    (OSKIRA-X): A Long-term Extension Study to Assess the Safety and Efficacy of Fostamatinib Disodium in the Treatment of Rheumatoid Arthritis

    These results have been removed from public view whilst they are reviewed and may need to be corrected before being returned to public view
    Summary
    EudraCT number
    2010-020892-22
    Trial protocol
    BE   GB   DE   SK   HU   LV   EE   LT   CZ   PT   ES   BG   IT   NL  
    Global end of trial date
    18 Sep 2013

    Results information
    Results version number
    v1(current)
    This version publication date
    23 Dec 2016
    First version publication date
    23 Dec 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D4300C00005
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01242514
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    AstraZeneca Pharmaceuticals
    Sponsor organisation address
    Alderley Park, Macclesfield, United Kingdom, SK10 4TG
    Public contact
    Neil Mackillop, AstraZeneca, information.center@astrazeneca.com
    Scientific contact
    Neil Mackillop, AstraZeneca, neil.mackillop@astrazeneca.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    07 Oct 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Sep 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Sep 2013
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the long-term safety and tolerability of fostamatinib in patients with active RA by assessment of adverse event (AE) reports, laboratory safety data, vital signs, electrocardiograms (ECGs) and physical examination.
    Protection of trial subjects
    This study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with International Conference on Harmonisation/Good Clinical Practice (GCP) and applicable regulatory requirements and the AstraZeneca policy on Bioethics and Human Biological Samples. Before enrolment of any patient into the study, the final clinical study protocol, including the final version of the informed consent form, was approved by the national regulatory authority or a notification to the national regulatory authority was done, according to local regulations. The study was approved or given a favourable opinion in writing by an Independent Ethics Committee (IEC) for each study centre. The investigator(s) at each centre ensured that the patient was given full and adequate oral and written information about the nature, purpose, possible risk and benefit of the study. Patients were also notified that they were free to discontinue investigational product (IP) and/or withdraw from the study at any time. The patient was given the opportunity to ask questions and allowed time to consider the information provided.The patient’s signed and dated informed consent was obtained before conducting any procedure specifically for the study.
    Background therapy
    Patients entering from qualifying studies D4300C00001, D4300C00002, D4300C00003 and D4300C00033 were to continue taking their study treatment in combination with their regular DMARD therapy, at the discretion of the investigator. Depending on the qualifying study, this could be methotrexate, sulfasalazine, hydroxychloroquine or chloroquine. Patients entering from qualifying study D4300C00004 were to continue taking IP as monotherapy, though it was acceptable to initiate an allowed DMARD, at the discretion of the investigator.
    Evidence for comparator
    -
    Actual start date of recruitment
    10 Jan 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Scientific research
    Long term follow-up duration
    4 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Slovakia: 11
    Country: Number of subjects enrolled
    South Africa: 103
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    Ukraine: 201
    Country: Number of subjects enrolled
    United Kingdom: 30
    Country: Number of subjects enrolled
    United States: 453
    Country: Number of subjects enrolled
    Argentina: 133
    Country: Number of subjects enrolled
    Australia: 9
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    Brazil: 20
    Country: Number of subjects enrolled
    Bulgaria: 50
    Country: Number of subjects enrolled
    Canada: 24
    Country: Number of subjects enrolled
    Chile: 4
    Country: Number of subjects enrolled
    Czech Republic: 165
    Country: Number of subjects enrolled
    Estonia: 21
    Country: Number of subjects enrolled
    France: 12
    Country: Number of subjects enrolled
    Germany: 20
    Country: Number of subjects enrolled
    Hungary: 38
    Country: Number of subjects enrolled
    India: 124
    Country: Number of subjects enrolled
    Israel: 19
    Country: Number of subjects enrolled
    Italy: 4
    Country: Number of subjects enrolled
    Latvia: 13
    Country: Number of subjects enrolled
    Lithuania: 16
    Country: Number of subjects enrolled
    Mexico: 76
    Country: Number of subjects enrolled
    Peru: 116
    Country: Number of subjects enrolled
    Poland: 120
    Country: Number of subjects enrolled
    Portugal: 6
    Country: Number of subjects enrolled
    Romania: 3
    Country: Number of subjects enrolled
    Russian Federation: 30
    Country: Number of subjects enrolled
    Serbia: 81
    Worldwide total number of subjects
    1912
    EEA total number of subjects
    519
    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)
    1617
    From 65 to 84 years
    294
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    Total of 1917 enrolled patients: 1346, 357 & 214 were allocated to the 100 mg twice daily (bid), 150 mg once daily (qd) and 100 mg qd groups, respectively (1343, 357 & 212 received at least 1 dose of investigational product). As this was a long-term extension study no specific end date was given. As such no patients were recorded as completers.

    Pre-assignment
    Screening details
    A total of 5 patients did not receive treatment.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    Blinding of the treatment regimens was necessary initially, since the randomised, double-blind, placebo-controlled qualifying studies were ongoing when this extension study commenced. Once the qualifying studies were completed and database was locked, the treatment allocation could be considered open-label.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Fostamatinib 100 mg bid
    Arm description
    Oral treatment
    Arm type
    Experimental

    Investigational medicinal product name
    Fostamatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100mg twice daily

    Arm title
    Fostamatinib 150 mg qd
    Arm description
    Oral treatment
    Arm type
    Experimental

    Investigational medicinal product name
    Fostamatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    150mg once daily

    Arm title
    Fostamatinib 100 mg qd
    Arm description
    Oral treatment
    Arm type
    Experimental

    Investigational medicinal product name
    Fostamatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100mg once daily

    Number of subjects in period 1
    Fostamatinib 100 mg bid Fostamatinib 150 mg qd Fostamatinib 100 mg qd
    Started
    1343
    357
    212
    Completed
    985
    303
    162
    Not completed
    358
    54
    50
         Dev. of study specific discont. criteria
    21
    3
    5
         Lack of therapeutic response
    99
    16
    10
         Adverse event, non-fatal
    129
    18
    19
         Severe non-compliance to protocol
    5
    2
    1
         Other eg Subject decision
    90
    10
    11
         Lost to follow-up
    14
    5
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Fostamatinib 100 mg bid
    Reporting group description
    Oral treatment

    Reporting group title
    Fostamatinib 150 mg qd
    Reporting group description
    Oral treatment

    Reporting group title
    Fostamatinib 100 mg qd
    Reporting group description
    Oral treatment

    Reporting group values
    Fostamatinib 100 mg bid Fostamatinib 150 mg qd Fostamatinib 100 mg qd Total
    Number of subjects
    1343 357 212 1912
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0
        Newborns (0-27 days)
    0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0
        Children (2-11 years)
    0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0
        Adults (18-64 years)
    1138 295 184 1617
        From 65-84 years
    204 62 28 294
        85 years and over
    1 0 0 1
    Age Continuous |
    Units: years
        arithmetic mean (standard deviation)
    53 ± 12 53 ± 11.6 53 ± 11.3 -
    Gender, Male/Female
    Units: Participants
        Female
    1086 297 193 1576
        Male
    257 60 19 336
    Race/Ethnicity, Customized
    Units: Subjects
        White
    1092 278 141 1511
        Black or African American
    63 11 6 80
        Asian
    40 12 7 59
        American Indian or Alaska Native
    20 11 6 37
        Indian or Pakistani
    54 15 22 91
        Other
    74 30 30 134
    Subject analysis sets

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All patients who receive at least 1 dose of study drug and summarised according to treatment first received in this study.

    Subject analysis sets values
    Full Analysis Set
    Number of subjects
    1912
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    1617
        From 65-84 years
    294
        85 years and over
    1
    Age Continuous |
    Units: years
        arithmetic mean (standard deviation)
    53 ± 11.8
    Gender, Male/Female
    Units: Participants
        Female
    1576
        Male
    336
    Race/Ethnicity, Customized
    Units: Subjects
        White
    1511
        Black or African American
    80
        Asian
    59
        American Indian or Alaska Native
    37
        Indian or Pakistani
    91
        Other
    134

    End points

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    End points reporting groups
    Reporting group title
    Fostamatinib 100 mg bid
    Reporting group description
    Oral treatment

    Reporting group title
    Fostamatinib 150 mg qd
    Reporting group description
    Oral treatment

    Reporting group title
    Fostamatinib 100 mg qd
    Reporting group description
    Oral treatment

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All patients who receive at least 1 dose of study drug and summarised according to treatment first received in this study.

    Primary: Percentage of patients who had at least 1 adverse event in any category

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    End point title
    Percentage of patients who had at least 1 adverse event in any category [1]
    End point description
    AE = adverse event, bid = twice daily, IP = investigational product, qd = once daily, SAE = serious adverse event
    End point type
    Primary
    End point timeframe
    Entry in extension to end of study (variable duration; maximum 109 weeks)
    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 - observational study.
    End point values
    Fostamatinib 100 mg bid Fostamatinib 150 mg qd Fostamatinib 100 mg qd
    Number of subjects analysed
    1343
    357
    212
    Units: Percentage of patients
    number (not applicable)
        Any AE
    74.4
    70.3
    69.8
        Any AE with outcome of death
    0.7
    0.3
    0.5
        Any SAE (including events with outcome of death)
    11.4
    8.7
    5.7
        Any AE leading to discontinuation of IP
    10.5
    5.9
    9.9
    No statistical analyses for this end point

    Secondary: Mean DAS28-CRP score

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    End point title
    Mean DAS28-CRP score
    End point description
    DAS28-CRP: Disease Activity Score based on a count of swollen and tender joints (out of 28 joints), blood test measures of inflammation (CRP) and the patient's own assessment. Scores can take any positive value with a lower value indicating a better clinical condition. Number of participants are those with data at entry to this study (Week 0). As no imputation was applied, the numbers at subsequent visits are lower. bid = twice daily, CRP = C-reactive protein, qd = once daily
    End point type
    Secondary
    End point timeframe
    Weeks 0, 12, 24, 36 and 52
    End point values
    Fostamatinib 100 mg bid Fostamatinib 150 mg qd Fostamatinib 100 mg qd
    Number of subjects analysed
    1247
    336
    198
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Week 0 (n=1247, 336, 198)
    4.5 ± 1.58
    3.8 ± 1.24
    3.9 ± 1.27
        Week 12 (n=1018, 288, 160)
    3.8 ± 1.34
    3.6 ± 1.19
    3.7 ± 1.21
        Week 24 (n=800, 230 126)
    3.8 ± 1.3
    3.7 ± 1.24
    3.6 ± 1.19
        Week 36 (n=581, 148, 68)
    3.9 ± 1.32
    3.7 ± 1.24
    3.9 ± 1.07
        Week 52 (n=290, 28, 14)
    4 ± 1.25
    3.8 ± 1.37
    3.6 ± 1.22
    No statistical analyses for this end point

    Secondary: Mean mTSS score

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    End point title
    Mean mTSS score
    End point description
    mTSS: modified total sharp score, a measure of structural progression based upon X-rays. Hand and foot joints are scored for erosions and joint space narrowing and the results summed to give a value between 0 and 488. A higher value represents more serious progression of the disease. Number of participants are those with data at entry to this study (Week 0). As no imputation was applied, the numbers at subsequent visits are lower. bid = twice daily, N/A = not applicable, qd = once daily
    End point type
    Secondary
    End point timeframe
    Weeks 0 and 52
    End point values
    Fostamatinib 100 mg bid Fostamatinib 150 mg qd Fostamatinib 100 mg qd
    Number of subjects analysed
    480
    73 [2]
    37
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Week 0 (n=480, 73, 37)
    30.5 ± 47.73
    22.2 ± 32.89
    20.8 ± 46.6
        Week 52 (n=223, 1, 6)
    30.1 ± 46.83
    0.5 ± 0
    37.3 ± 67.7
    Notes
    [2] - 0 entered for standard deviation, although not defined for a single patient
    No statistical analyses for this end point

    Secondary: Mean HAQ-DI score

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    End point title
    Mean HAQ-DI score
    End point description
    HAQ-DI: Health Assessment Questionnaire - Disability Index, a measure of physical function. The HAQ-DI score is then calculated by summing the category scores from 8 sub-categories (ie, scores for patient ability in dressing and grooming, rising, eating, walking, hygiene, reach, grip and common daily activities) and dividing by the number of categories completed. The HAQ-DI score takes values between 0 and 3, with a higher score indicating greater disability. Number of participants are those with data at entry to this study (Week 0). As no imputation was applied, the numbers at subsequent visits are lower. bid = twice daily, qd = once daily
    End point type
    Secondary
    End point timeframe
    Weeks 0, 12, 24, 36 and 52
    End point values
    Fostamatinib 100 mg bid Fostamatinib 150 mg qd Fostamatinib 100 mg qd
    Number of subjects analysed
    1271
    342
    201
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Week 0 (n=1271, 342, 201)
    1.2 ± 0.69
    1 ± 0.64
    1 ± 0.62
        Week 12 (n=1061, 298, 166)
    1.1 ± 0.68
    1 ± 0.63
    1 ± 0.63
        Week 24 (n=817, 238, 132)
    1.1 ± 0.68
    1 ± 0.67
    0.9 ± 0.55
        Week 36 (n=587, 149, 71)
    1.1 ± 0.67
    1 ± 0.65
    1.1 ± 0.62
        Week 52 (n=296, 28, 14)
    1.2 ± 0.68
    1.1 ± 0.64
    1 ± 0.73
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    As this was an ongoing long term extension study the timeframe for adverse event reporting was from the start of the study (January 2011) to study termination (September 2013).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    FOSTA 100 MG BID
    Reporting group description
    Fostamatinib 100mg twice daily

    Reporting group title
    FOSTA 150 MG QD
    Reporting group description
    Fostmatinib 150mg once daily

    Reporting group title
    FOSTA 100 MG QD
    Reporting group description
    Fostamatinib 100mg once daily

    Serious adverse events
    FOSTA 100 MG BID FOSTA 150 MG QD FOSTA 100 MG QD
    Total subjects affected by serious adverse events
         subjects affected / exposed
    153 / 1343 (11.39%)
    31 / 357 (8.68%)
    12 / 212 (5.66%)
         number of deaths (all causes)
    9
    1
    1
         number of deaths resulting from adverse events
    2
    0
    0
    Vascular disorders
    AORTIC ANEURYSM RUPTURE
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    AORTIC STENOSIS
         subjects affected / exposed
    0 / 1343 (0.00%)
    0 / 357 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    AORTIC THROMBOSIS
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ARTERIAL THROMBOSIS
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    FEMORAL ARTERY OCCLUSION
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PERIPHERAL ISCHAEMIA
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    THROMBOPHLEBITIS SUPERFICIAL
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    BASAL CELL CARCINOMA
         subjects affected / exposed
    2 / 1343 (0.15%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BENIGN NEOPLASM OF PROSTATE
         subjects affected / exposed
    0 / 1343 (0.00%)
    1 / 357 (0.28%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BENIGN SOFT TISSUE NEOPLASM
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BREAST CANCER
         subjects affected / exposed
    2 / 1343 (0.15%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CERVIX CARCINOMA
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COLORECTAL CANCER
         subjects affected / exposed
    0 / 1343 (0.00%)
    1 / 357 (0.28%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GASTRIC CANCER
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    LIPOMA
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    LUNG SQUAMOUS CELL CARCINOMA STAGE UNSPECIFIED
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    MALIGNANT MELANOMA
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PANCREATIC NEUROENDOCRINE TUMOUR
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PROSTATE CANCER
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    RECTAL CANCER
         subjects affected / exposed
    0 / 1343 (0.00%)
    1 / 357 (0.28%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    RENAL CANCER METASTATIC
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    RENAL CELL CARCINOMA
         subjects affected / exposed
    0 / 1343 (0.00%)
    1 / 357 (0.28%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    UTERINE LEIOMYOMA
         subjects affected / exposed
    2 / 1343 (0.15%)
    1 / 357 (0.28%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    VAGINAL CANCER
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    ANAPHYLACTIC SHOCK
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    FOOD ALLERGY
         subjects affected / exposed
    0 / 1343 (0.00%)
    1 / 357 (0.28%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPERSENSITIVITY
         subjects affected / exposed
    2 / 1343 (0.15%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    DEVICE DISLOCATION
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GENERAL PHYSICAL HEALTH DETERIORATION
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    NON-CARDIAC CHEST PAIN
         subjects affected / exposed
    3 / 1343 (0.22%)
    0 / 357 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    ADJUSTMENT DISORDER
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ALCOHOL ABUSE
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DEPRESSION
         subjects affected / exposed
    2 / 1343 (0.15%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    ADENOMYOSIS
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BENIGN PROSTATIC HYPERPLASIA
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    OVARIAN CYST
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    UTERINE POLYP
         subjects affected / exposed
    0 / 1343 (0.00%)
    1 / 357 (0.28%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    ACCIDENTAL OVERDOSE
         subjects affected / exposed
    0 / 1343 (0.00%)
    2 / 357 (0.56%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    FACIAL BONES FRACTURE
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    FEMORAL NECK FRACTURE
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    FEMUR FRACTURE
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    FIBULA FRACTURE
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HUMERUS FRACTURE
         subjects affected / exposed
    2 / 1343 (0.15%)
    1 / 357 (0.28%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    JOINT DISLOCATION
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    JOINT INJURY
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PATELLA FRACTURE
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    TENDON RUPTURE
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    TIBIA FRACTURE
         subjects affected / exposed
    0 / 1343 (0.00%)
    0 / 357 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ULNA FRACTURE
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    UPPER LIMB FRACTURE
         subjects affected / exposed
    0 / 1343 (0.00%)
    1 / 357 (0.28%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    WOUND DEHISCENCE
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    WRIST FRACTURE
         subjects affected / exposed
    0 / 1343 (0.00%)
    1 / 357 (0.28%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    LIVER FUNCTION TEST ABNORMAL
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    ACUTE MYOCARDIAL INFARCTION
         subjects affected / exposed
    0 / 1343 (0.00%)
    1 / 357 (0.28%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ANGINA UNSTABLE
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ATRIAL FIBRILLATION
         subjects affected / exposed
    2 / 1343 (0.15%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BRADYCARDIA
         subjects affected / exposed
    0 / 1343 (0.00%)
    0 / 357 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CARDIAC FAILURE CHRONIC
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CARDIAC FAILURE CONGESTIVE
         subjects affected / exposed
    2 / 1343 (0.15%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CARDIO-RESPIRATORY ARREST
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CARDIOMYOPATHY
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    MYOCARDIAL INFARCTION
         subjects affected / exposed
    2 / 1343 (0.15%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    MYOCARDIAL ISCHAEMIA
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    ACUTE RESPIRATORY FAILURE
         subjects affected / exposed
    2 / 1343 (0.15%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    CHRONIC OBSTRUCTIVE PULMONARY DISEASE
         subjects affected / exposed
    1 / 1343 (0.07%)
    1 / 357 (0.28%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPERVENTILATION
         subjects affected / exposed
    0 / 1343 (0.00%)
    1 / 357 (0.28%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PNEUMONIA ASPIRATION
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    PULMONARY EMBOLISM
         subjects affected / exposed
    4 / 1343 (0.30%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    RESPIRATORY FAILURE
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    SPLENIC INFARCTION
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    APHASIA
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CAROTID ARTERY STENOSIS
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CONVULSION
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DYSARTHRIA
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HAEMORRHAGIC STROKE
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    HYPERTENSIVE ENCEPHALOPATHY
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPOGLYCAEMIC COMA
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ISCHAEMIC STROKE
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    LUMBAR RADICULOPATHY
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    RADICULITIS LUMBOSACRAL
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SCIATICA
         subjects affected / exposed
    0 / 1343 (0.00%)
    0 / 357 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SYNCOPE
         subjects affected / exposed
    3 / 1343 (0.22%)
    2 / 357 (0.56%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    TENSION HEADACHE
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    TRANSIENT ISCHAEMIC ATTACK
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    VITH NERVE PARALYSIS
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    RETINAL DETACHMENT
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    0 / 1343 (0.00%)
    0 / 357 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ACUTE ABDOMEN
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    BARRETT'S OESOPHAGUS
         subjects affected / exposed
    0 / 1343 (0.00%)
    1 / 357 (0.28%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COLITIS
         subjects affected / exposed
    2 / 1343 (0.15%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COLITIS MICROSCOPIC
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COLONIC STENOSIS
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DIARRHOEA
         subjects affected / exposed
    4 / 1343 (0.30%)
    0 / 357 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DYSPEPSIA
         subjects affected / exposed
    0 / 1343 (0.00%)
    1 / 357 (0.28%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GASTRIC ULCER
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GASTRITIS
         subjects affected / exposed
    2 / 1343 (0.15%)
    1 / 357 (0.28%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GASTRITIS EROSIVE
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HAEMATEMESIS
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ILEITIS
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ILEUS
         subjects affected / exposed
    2 / 1343 (0.15%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    INGUINAL HERNIA
         subjects affected / exposed
    2 / 1343 (0.15%)
    1 / 357 (0.28%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    INTESTINAL HAEMORRHAGE
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    INTESTINAL ISCHAEMIA
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    INTESTINAL OBSTRUCTION
         subjects affected / exposed
    0 / 1343 (0.00%)
    1 / 357 (0.28%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    OESOPHAGEAL ACHALASIA
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PANCREATIC PSEUDOCYST
         subjects affected / exposed
    0 / 1343 (0.00%)
    0 / 357 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PANCREATITIS
         subjects affected / exposed
    3 / 1343 (0.22%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PANCREATITIS ACUTE
         subjects affected / exposed
    3 / 1343 (0.22%)
    0 / 357 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Renal and urinary disorders
    CALCULUS URETERIC
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CALCULUS URINARY
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    NEPHROLITHIASIS
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    RENAL FAILURE ACUTE
         subjects affected / exposed
    3 / 1343 (0.22%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    RENAL IMPAIRMENT
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    URINARY BLADDER POLYP
         subjects affected / exposed
    0 / 1343 (0.00%)
    1 / 357 (0.28%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    BILE DUCT OBSTRUCTION
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BILIARY COLIC
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CHOLECYSTITIS
         subjects affected / exposed
    2 / 1343 (0.15%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CHOLECYSTITIS ACUTE
         subjects affected / exposed
    0 / 1343 (0.00%)
    1 / 357 (0.28%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CHOLECYSTITIS CHRONIC
         subjects affected / exposed
    0 / 1343 (0.00%)
    1 / 357 (0.28%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CHOLELITHIASIS
         subjects affected / exposed
    4 / 1343 (0.30%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GALLBLADDER POLYP
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    POST CHOLECYSTECTOMY SYNDROME
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    DIGITAL ULCER
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ERYTHEMA MULTIFORME
         subjects affected / exposed
    0 / 1343 (0.00%)
    1 / 357 (0.28%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    TOXIC EPIDERMAL NECROLYSIS
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    ARTHRITIS
         subjects affected / exposed
    2 / 1343 (0.15%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BACK PAIN
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HIP DEFORMITY
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    INTERVERTEBRAL DISC DISORDER
         subjects affected / exposed
    0 / 1343 (0.00%)
    1 / 357 (0.28%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    INTERVERTEBRAL DISC DISPLACEMENT
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    INTERVERTEBRAL DISC PROTRUSION
         subjects affected / exposed
    4 / 1343 (0.30%)
    0 / 357 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    LUMBAR SPINAL STENOSIS
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    MUSCULOSKELETAL CHEST PAIN
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    OSTEITIS
         subjects affected / exposed
    0 / 1343 (0.00%)
    0 / 357 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    OSTEOARTHRITIS
         subjects affected / exposed
    6 / 1343 (0.45%)
    2 / 357 (0.56%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    OSTEONECROSIS
         subjects affected / exposed
    0 / 1343 (0.00%)
    1 / 357 (0.28%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PATHOLOGICAL FRACTURE
         subjects affected / exposed
    2 / 1343 (0.15%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    RHEUMATOID ARTHRITIS
         subjects affected / exposed
    9 / 1343 (0.67%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SJOGREN'S SYNDROME
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SPONDYLOLISTHESIS
         subjects affected / exposed
    0 / 1343 (0.00%)
    1 / 357 (0.28%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SYNOVITIS
         subjects affected / exposed
    0 / 1343 (0.00%)
    1 / 357 (0.28%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    GOITRE
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    DEHYDRATION
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPOKALAEMIA
         subjects affected / exposed
    1 / 1343 (0.07%)
    1 / 357 (0.28%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPONATRAEMIA
         subjects affected / exposed
    1 / 1343 (0.07%)
    1 / 357 (0.28%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    TYPE 2 DIABETES MELLITUS
         subjects affected / exposed
    0 / 1343 (0.00%)
    0 / 357 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    ABSCESS LIMB
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    APPENDICITIS
         subjects affected / exposed
    4 / 1343 (0.30%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ARTHRITIS BACTERIAL
         subjects affected / exposed
    0 / 1343 (0.00%)
    0 / 357 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BACTERAEMIA
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BACTERIAL PYELONEPHRITIS
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BACTERIAL SEPSIS
         subjects affected / exposed
    2 / 1343 (0.15%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BRONCHITIS
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BRONCHOPNEUMONIA
         subjects affected / exposed
    0 / 1343 (0.00%)
    1 / 357 (0.28%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CELLULITIS
         subjects affected / exposed
    6 / 1343 (0.45%)
    0 / 357 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    2 / 7
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CYTOMEGALOVIRUS INFECTION
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DIVERTICULITIS
         subjects affected / exposed
    0 / 1343 (0.00%)
    1 / 357 (0.28%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ENTEROCOLITIS BACTERIAL
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ENTEROCOLITIS VIRAL
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ERYSIPELAS
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ESCHERICHIA URINARY TRACT INFECTION
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GANGRENE
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GASTROENTERITIS
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GASTROENTERITIS BACTERIAL
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GASTROENTERITIS VIRAL
         subjects affected / exposed
    1 / 1343 (0.07%)
    1 / 357 (0.28%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HERPES ZOSTER
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    INTERVERTEBRAL DISCITIS
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    LIVER ABSCESS
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    LUNG ABSCESS
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    OSTEOMYELITIS
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    OTITIS EXTERNA
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PANCREATITIS VIRAL
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PERITONITIS
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    5 / 1343 (0.37%)
    1 / 357 (0.28%)
    1 / 212 (0.47%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PNEUMONIA BACTERIAL
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PNEUMONIA VIRAL
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    PULMONARY TUBERCULOSIS
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    STAPHYLOCOCCAL SEPSIS
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SUBCUTANEOUS ABSCESS
         subjects affected / exposed
    0 / 1343 (0.00%)
    1 / 357 (0.28%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    URINARY TRACT INFECTION
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    URINARY TRACT INFECTION BACTERIAL
         subjects affected / exposed
    2 / 1343 (0.15%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    UROSEPSIS
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    VIRAL UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    WOUND INFECTION BACTERIAL
         subjects affected / exposed
    0 / 1343 (0.00%)
    1 / 357 (0.28%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    WOUND SEPSIS
         subjects affected / exposed
    1 / 1343 (0.07%)
    0 / 357 (0.00%)
    0 / 212 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    FOSTA 100 MG BID FOSTA 150 MG QD FOSTA 100 MG QD
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    466 / 1343 (34.70%)
    98 / 357 (27.45%)
    68 / 212 (32.08%)
    Vascular disorders
    HYPERTENSION
         subjects affected / exposed
    166 / 1343 (12.36%)
    20 / 357 (5.60%)
    14 / 212 (6.60%)
         occurrences all number
    197
    23
    15
    Gastrointestinal disorders
    DIARRHOEA
         subjects affected / exposed
    202 / 1343 (15.04%)
    43 / 357 (12.04%)
    28 / 212 (13.21%)
         occurrences all number
    268
    61
    40
    Musculoskeletal and connective tissue disorders
    RHEUMATOID ARTHRITIS
         subjects affected / exposed
    116 / 1343 (8.64%)
    30 / 357 (8.40%)
    19 / 212 (8.96%)
         occurrences all number
    155
    35
    22
    Infections and infestations
    NASOPHARYNGITIS
         subjects affected / exposed
    86 / 1343 (6.40%)
    28 / 357 (7.84%)
    15 / 212 (7.08%)
         occurrences all number
    102
    31
    16

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Mar 2011
    Restrictions for male patients entering the study who wished to father a child or donate sperm were removed.
    04 Oct 2011
    If in the investigator's opinion the patient had achieved sustained stable RA disease activity then reduction of NSAIDs / steroids was permitted.
    17 Jan 2012
    The addition of patients who could enter from qualifying study D4300C00033 with an exploratory objective to describe the effects on blood pressure in these patients.

    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
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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