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    Clinical Trial Results:
    A Long-Term, Open-Label Follow-Up Study of Tofacitinib (CP-690,550) for Treatment of Rheumatoid Arthritis

    Summary
    EudraCT number
    		 2006-005035-19
    Trial protocol
    		 BE   ES   AT   SE   IT   HU   CZ   GR   DE   SK   GB   BG   FI   DK   IE  
    Global end of trial date
    26 Oct 2017

    Results information
    Results version number
    		 v2(current)
    This version publication date
    21 Oct 2018
    First version publication date
    03 Dec 2017
    Other versions
    		 v1
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    A3921024
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00413699
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pfizer Inc.
    Sponsor organisation address
    235 East 42nd Street, New York, United States, NY 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 1800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 1800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.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
    25 Apr 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Oct 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the long-term safety and tolerability of 5mg twice daily and 10mg twice daily of tofacitinib for treatment of the signs and symptoms of rheumatoid arthritis.
    Protection of trial subjects
    The study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. In addition, all local and regulatory requirements were followed, in particular, those affording greater protection to the safety of trial subjects.
    Background therapy
    		 The following DMARDs were allowed in doses consistent with local standards of care: Auranofin (oral gold), aurothioglucose (injectable gold), aurothiomalate (injectable gold); Sulfasalazine, chloroquine, hydroxychloroquine, leflunomide (Arava®), and methotrexate, d-penicillamine and tetracyclines. In Ireland, methotrexate doses higher than 20 mg weekly were not permitted under any circumstances.
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    05 Feb 2007
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 60
    Country: Number of subjects enrolled
    Australia: 99
    Country: Number of subjects enrolled
    Austria: 31
    Country: Number of subjects enrolled
    Belgium: 11
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 5
    Country: Number of subjects enrolled
    Brazil: 237
    Country: Number of subjects enrolled
    Bulgaria: 110
    Country: Number of subjects enrolled
    Canada: 70
    Country: Number of subjects enrolled
    Chile: 133
    Country: Number of subjects enrolled
    China: 192
    Country: Number of subjects enrolled
    Colombia: 97
    Country: Number of subjects enrolled
    Costa Rica: 10
    Country: Number of subjects enrolled
    Croatia: 20
    Country: Number of subjects enrolled
    Czech Republic: 364
    Country: Number of subjects enrolled
    Denmark: 3
    Country: Number of subjects enrolled
    Dominican Republic: 22
    Country: Number of subjects enrolled
    Finland: 10
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    Germany: 193
    Country: Number of subjects enrolled
    Greece: 7
    Country: Number of subjects enrolled
    Hungary: 10
    Country: Number of subjects enrolled
    India: 115
    Country: Number of subjects enrolled
    Ireland: 3
    Country: Number of subjects enrolled
    Italy: 14
    Country: Number of subjects enrolled
    Korea, Republic of: 210
    Country: Number of subjects enrolled
    Malaysia: 41
    Country: Number of subjects enrolled
    Mexico: 212
    Country: Number of subjects enrolled
    New Zealand: 8
    Country: Number of subjects enrolled
    Peru: 9
    Country: Number of subjects enrolled
    Philippines: 44
    Country: Number of subjects enrolled
    Poland: 267
    Country: Number of subjects enrolled
    Puerto Rico: 7
    Country: Number of subjects enrolled
    Romania: 7
    Country: Number of subjects enrolled
    Russian Federation: 140
    Country: Number of subjects enrolled
    Slovakia: 90
    Country: Number of subjects enrolled
    Spain: 117
    Country: Number of subjects enrolled
    Sweden: 15
    Country: Number of subjects enrolled
    Taiwan: 28
    Country: Number of subjects enrolled
    Thailand: 55
    Country: Number of subjects enrolled
    Turkey: 3
    Country: Number of subjects enrolled
    Ukraine: 201
    Country: Number of subjects enrolled
    United Kingdom: 14
    Country: Number of subjects enrolled
    United States: 1190
    Worldwide total number of subjects
    4481
    EEA total number of subjects
    1293
    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)
    3754
    From 65 to 84 years
    724
    85 years and over
    3

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Initial period (IP): conducted at multiple sites, subjects were assigned to Tofacitinib 5 mg and 10 mg BID. Extension period (EP): subjects who took part initially in IP, completed 2 years of lymphocyte assessment in IP, given consent, were enrolled in EP and assigned to “Extension Period: Tofacitinib 5 mg”. EP was conducted in 2 countries.

    Pre-assignment
    Screening details
    		 Subjects had previously participated in qualifying studies (A3921019, A3921025, A3921032, A3921035, A3921044, A3921045, A3921046, A3921064, A3921068, A3921069, A3921073, A3921109, A3921129, A3921130, A3921152, A3921237) prior to enrollment in initial period.

    Period 1
    Period 1 title
    Initial Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Initial Period: Tofacitinib 5 milligram(mg) twice daily (BID)
    Arm description
    		 Tofacitinib 5 mg BID. Participants with non-zero average total daily dose across study <15 were assigned to 5 mg BID. avg=average; BID=twice daily; mg=milligram; ppts=participants; tofa=tofacitinib
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tofacitinib
    Investigational medicinal product code
    CP-690550-10
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    5 mg BID

    Arm title
    		 Initial Period: Tofacitinib 10 mg BID
    Arm description
    		 Tofacitinib 10 mg BID. Participants with non-zero average total daily dose across study ≥15 were assigned to 10 mg BID. avg=average; BID=twice daily; mg=milligram; ppts=participants; tofa=tofacitinib
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tofacitinib
    Investigational medicinal product code
    CP-690550-10
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg BID

    Number of subjects in period 1
    		Initial Period: Tofacitinib 5 milligram(mg) twice daily (BID) Initial Period: Tofacitinib 10 mg BID
    Started
    1123
    3358
    Completed
    484
    1653
    Not completed
    639
    1705
         Adverse event, serious fatal
    25
    30
         Did not meet entrance criteria
    2
    2
         Study terminated by Sponsor
    -
    1
         Not specified
    67
    211
         Missing end of study page
    -
    4
         Medication error without adverse event
    -
    1
         No longer willing to participate
    116
    368
         Adverse event not related to study drug
    113
    248
         Pregnancy
    10
    8
         Lost to follow-up
    31
    101
         Adverse event related to study drug
    178
    527
         Lack of efficacy
    59
    115
         Protocol deviation
    38
    89
    Period 2
    Period 2 title
    Extension Period
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Extension Period: Tofacitinib 5 mg
    Arm description
    		 Subjects who completed 2 years of lymphocyte assessment in Initial period and enrolled for Extension period received Tofacitinib (CP-690,550) 5 mg orally, twice daily up to 12 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tofacitinib
    Investigational medicinal product code
    CP-690,550
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Tofacitinib (CP-690,550) 5 mg orally, twice daily up to 12 months.

    Number of subjects in period 2 [1]
    		Extension Period: Tofacitinib 5 mg
    Started
    48
    Completed
    43
    Not completed
    5
         Adverse Event
    2
         No longer willing to participate
    2
         Protocol deviation
    1
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Only those subjects who enrolled in extension period are reported

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Initial Period: Tofacitinib 5 milligram(mg) twice daily (BID)
    Reporting group description
    		 Tofacitinib 5 mg BID. Participants with non-zero average total daily dose across study <15 were assigned to 5 mg BID. avg=average; BID=twice daily; mg=milligram; ppts=participants; tofa=tofacitinib

    Reporting group title
    Initial Period: Tofacitinib 10 mg BID
    Reporting group description
    		 Tofacitinib 10 mg BID. Participants with non-zero average total daily dose across study ≥15 were assigned to 10 mg BID. avg=average; BID=twice daily; mg=milligram; ppts=participants; tofa=tofacitinib

    Reporting group values
    		 Initial Period: Tofacitinib 5 milligram(mg) twice daily (BID) Initial Period: Tofacitinib 10 mg BID Total
    Number of subjects
    		 1123 3358 4481
    Age Categorical
    The subject analysis set groups for tofacitinib 10mg BID continuous and interrupted are from the vaccine sub-study. Age and gender characteristics are presented for the main study only.
    Units: Subjects
        <18 years
    		 0 0 0
        18 to 64 years
    		 916 2838 3754
        >=65 years
    		 207 520 727
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 54.0 ± 12.1 53.0 ± 11.5 -
    Gender, Male/Female
    The subject analysis set groups for tofacitinib 10mg BID continuous and interrupted are from the vaccine sub-study. Age and gender characteristics are presented for the main study only.
    Units: Subjects
        Female
    		 927 2744 3671
        Male
    		 196 614 810
    Subject analysis sets

    Subject analysis set title
    All Tofacitinib
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All participants treated with tofacitinib from 5 mg BID and 10 mg BID groups

    Subject analysis set title
    Tofacitinib 5 milligram (mg) twice daily (BID)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with non-zero average total daily dose across study <15 were assigned to 5 mg BID

    Subject analysis set title
    Tofacitinib 10 mg BID
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with non-zero average total daily dose across study ≥15 were assigned to 10 mg BID

    Subject analysis set title
    Tofacitinib 10 mg BID Continuous Visit 3
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants receiving continuous tofacitinib treatment

    Subject analysis set title
    Tofacitinib 10 mg BID Interrupted Visit 3
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants whose treatment with tofacitinib was interrupted for 2 weeks post-randomization

    Subject analysis set title
    Tofacitinib 10 mg BID Continuous Visit 4
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants receiving continuous tofacitinib treatment

    Subject analysis set title
    Tofacitinib 10 mg BID Interrupted Visit 4
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants whose treatment with tofacitinib was interrupted for 2 weeks post-randomization

    Subject analysis set title
    Tofacitinib 10 mg BID Continuous
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants receiving continuous tofacitinib treatment

    Subject analysis set title
    Tofacitinib 10 mg BID Interrupted
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants whose treatment with tofacitinib was interrupted for 2 weeks post-randomization

    Subject analysis set title
    Tofacitinib 10 mg Continuous
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants receiving continuous tofacitinib treatment

    Subject analysis set title
    Tofacitinib 10 mg BID Continuous Visit 2
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants receiving continuous tofacitinib treatment

    Subject analysis set title
    Tofacitinib 10 mg BID Interrupted Visit 2
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants whose treatment with tofacitinib was interrupted for 2 weeks post-randomization

    Subject analysis set title
    Tofacitinib 10 mg BID Continuous Visit 3
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants receiving continuous tofacitinib treatment

    Subject analysis set title
    Tofacitinib 10 mg BID Interrupted Visit 4
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients whose treatment with tofacitinib was interrupted for 2 weeks post-randomization

    Subject analysis sets values
    		 All Tofacitinib Tofacitinib 5 milligram (mg) twice daily (BID) Tofacitinib 10 mg BID Tofacitinib 10 mg BID Continuous Visit 3 Tofacitinib 10 mg BID Interrupted Visit 3 Tofacitinib 10 mg BID Continuous Visit 4 Tofacitinib 10 mg BID Interrupted Visit 4 Tofacitinib 10 mg BID Continuous Tofacitinib 10 mg BID Interrupted Tofacitinib 10 mg Continuous Tofacitinib 10 mg BID Continuous Visit 2 Tofacitinib 10 mg BID Interrupted Visit 2 Tofacitinib 10 mg BID Continuous Visit 3 Tofacitinib 10 mg BID Interrupted Visit 4
    Number of subjects
    4481
    1123
    3358
    91
    91
    92
    91
    92
    91
    92
    92
    91
    92
    91
    Age Categorical
    The subject analysis set groups for tofacitinib 10mg BID continuous and interrupted are from the vaccine sub-study. Age and gender characteristics are presented for the main study only.
    Units: Subjects
        <18 years
    0
    0
    0
        18 to 64 years
    3754
    916
    2838
        >=65 years
    727
    207
    520
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    53.3 ± 11.6
    54.0 ± 12.1
    53.0 ± 11.5
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    Gender, Male/Female
    The subject analysis set groups for tofacitinib 10mg BID continuous and interrupted are from the vaccine sub-study. Age and gender characteristics are presented for the main study only.
    Units: Subjects
        Female
    3671
    927
    2744
        Male
    810
    196
    614

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Initial Period: Tofacitinib 5 milligram(mg) twice daily (BID)
    Reporting group description
    		 Tofacitinib 5 mg BID. Participants with non-zero average total daily dose across study <15 were assigned to 5 mg BID. avg=average; BID=twice daily; mg=milligram; ppts=participants; tofa=tofacitinib

    Reporting group title
    Initial Period: Tofacitinib 10 mg BID
    Reporting group description
    		 Tofacitinib 10 mg BID. Participants with non-zero average total daily dose across study ≥15 were assigned to 10 mg BID. avg=average; BID=twice daily; mg=milligram; ppts=participants; tofa=tofacitinib
    Reporting group title
    Extension Period: Tofacitinib 5 mg
    Reporting group description
    		 Subjects who completed 2 years of lymphocyte assessment in Initial period and enrolled for Extension period received Tofacitinib (CP-690,550) 5 mg orally, twice daily up to 12 months.

    Subject analysis set title
    All Tofacitinib
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All participants treated with tofacitinib from 5 mg BID and 10 mg BID groups

    Subject analysis set title
    Tofacitinib 5 milligram (mg) twice daily (BID)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with non-zero average total daily dose across study <15 were assigned to 5 mg BID

    Subject analysis set title
    Tofacitinib 10 mg BID
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with non-zero average total daily dose across study ≥15 were assigned to 10 mg BID

    Subject analysis set title
    Tofacitinib 10 mg BID Continuous Visit 3
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants receiving continuous tofacitinib treatment

    Subject analysis set title
    Tofacitinib 10 mg BID Interrupted Visit 3
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants whose treatment with tofacitinib was interrupted for 2 weeks post-randomization

    Subject analysis set title
    Tofacitinib 10 mg BID Continuous Visit 4
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants receiving continuous tofacitinib treatment

    Subject analysis set title
    Tofacitinib 10 mg BID Interrupted Visit 4
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants whose treatment with tofacitinib was interrupted for 2 weeks post-randomization

    Subject analysis set title
    Tofacitinib 10 mg BID Continuous
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants receiving continuous tofacitinib treatment

    Subject analysis set title
    Tofacitinib 10 mg BID Interrupted
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants whose treatment with tofacitinib was interrupted for 2 weeks post-randomization

    Subject analysis set title
    Tofacitinib 10 mg Continuous
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants receiving continuous tofacitinib treatment

    Subject analysis set title
    Tofacitinib 10 mg BID Continuous Visit 2
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants receiving continuous tofacitinib treatment

    Subject analysis set title
    Tofacitinib 10 mg BID Interrupted Visit 2
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants whose treatment with tofacitinib was interrupted for 2 weeks post-randomization

    Subject analysis set title
    Tofacitinib 10 mg BID Continuous Visit 3
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants receiving continuous tofacitinib treatment

    Subject analysis set title
    Tofacitinib 10 mg BID Interrupted Visit 4
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients whose treatment with tofacitinib was interrupted for 2 weeks post-randomization

    Primary: Initial Period: Primary endpoints were standard laboratory safety data (chemistry, hematology, etc.) and adverse event (AE) reports

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    End point title
    		 Initial Period: Primary endpoints were standard laboratory safety data (chemistry, hematology, etc.) and adverse event (AE) reports
    End point description
    Treatment-emergent non serious AEs by System Organ Class (SOC) (all causalities) and Laboratory Test Abnormalities (without regard to baseline). The stated number of participants analyzed was the total number of participants in each group. The actual number of participants analyzed for each laboratory parameter varied, and is provided for each. Abs=absolute; ALT=alanine aminotransferase; AST=aspartate aminotransferase; ESR=erythrocyte sedimentation rate; GGT=gamma glutamyl transferase; hgb=hemoglobin; HDL=high density lipids; LDL=low density lipids; LLN=lower limit of normal; qual=qualitative; Tot=total; ULN=upper limit of normal; WBC=white blood cell
    End point type
    Primary
    End point timeframe
    Includes laboratory test abnormality data for all visits and AE data up to 999 days after last dose of study drug
    End point values
    		 Initial Period: Tofacitinib 5 milligram(mg) twice daily (BID) Initial Period: Tofacitinib 10 mg BID All Tofacitinib
    Number of subjects analysed
    1123
    3358
    4481
    Units: Number of participants
        Participants with non-serious AEs
    991
    2963
    3954
        Blood and lymphatic system disorders
    159
    395
    554
        Cardiac disorders
    93
    185
    278
        Congenital, familial and genetic disorders
    6
    16
    22
        Ear and labyrinth disorders
    67
    138
    205
        Endocrine disorders
    29
    94
    123
        Eye disorders
    117
    259
    376
        Gastrointestinal disorders
    393
    1011
    1404
        General disorders and admin site conditions
    169
    477
    646
        Hepatobiliary disorders
    60
    176
    236
        Immune system disorders
    18
    87
    105
        Infections and infestations
    704
    2200
    2904
        Injury, poisoning and procedural complications
    244
    721
    965
        Investigations
    402
    995
    1397
        Metabolism and nutrition disorders
    184
    562
    746
        Musculoskeletal and connective tissue disorders
    425
    1314
    1739
        Neoplasms benign, malignant and unspecified
    80
    219
    299
        Nervous system disorders
    222
    639
    861
        Pregnancy, puerperium and perinatal conditions
    1
    0
    1
        Product issues
    2
    8
    10
        Psychiatric disorders
    97
    280
    377
        Renal and urinary disorders
    123
    265
    388
        Reproductive system and breast disorders
    89
    206
    295
        Respiratory, thoracic and mediastinal disorders
    208
    634
    842
        Skin and subcutaneous tissue disorders
    201
    682
    883
        Social circumstances
    1
    5
    6
        Surgical and medical procedures
    2
    4
    6
        Vascular disorders
    207
    468
    675
        Participants evaluable for lab abnormalities
    1118
    3346
    4464
        Participants with laboratory abnormalities
    1095
    3208
    4303
        Hemoglobin <0.8x LLN (N=1117,3343,4460)
    57
    148
    205
        Hematocrit <0.8x LLN (N=1117,3343,4460)
    29
    67
    96
        Red blood cell count <0.8x LLN (N=1049,3343,4392)
    32
    142
    174
        Reticulocytes (Abs) <0.5x LLN (N=570, 75,645)
    44
    5
    49
        Reticulocytes (Abs) >1.5x ULN (N=570,75,645)
    49
    9
    58
        Platelets <0.5x LLN (N=1116,3343,4459)
    5
    2
    7
        Platelets >1.75x ULN (N=1116,3343,4459)
    5
    25
    30
        Reticulocyte count (%) <0.5x LLN (N=46,34,80)
    1
    1
    2
        Reticulocyte count (%) >1.5x ULN (N=46,34,80)
    24
    17
    41
        WBC count <0.6x LLN (N=1117,3343,4460)
    21
    33
    54
        WBC count >1.5x ULN (N=1117,3343,4460)
    29
    71
    100
        Lymphocytes (Abs) <0.8x LLN (N=1117,3343,4460)
    254
    789
    1043
        Lymphocytes (Abs) >1.2x ULN (N=1117,3343,4460)
    23
    94
    117
        Lymphocytes (%) <0.8x LLN (N=1043,3343,4386)
    401
    1267
    1668
        Lymphocytes (%) >1.2x ULN (N=1043,3343,4386)
    23
    75
    98
        Tot neutrophils (Abs) <0.8x LLN (N=1117,3343,4460)
    105
    305
    410
        Tot neutrophils (Abs) >1.2x ULN (N=1117,3343,4460)
    239
    617
    856
        Neutrophils (%) <0.8x LLN (N=1042,3343,4385)
    23
    75
    98
        Neutrophils (%) >1.2x ULN (N=1042,3343,4385)
    29
    93
    122
        Basophils (Abs) >1.2x ULN (N=1117,3343,4460)
    19
    10
    29
        Basophils (%) >1.2x ULN (N=1043,3343,4386)
    76
    221
    297
        Eosinophils (Abs) >1.2x ULN (N=1117,3343,4460)
    24
    58
    82
        Eosinophils (%) >1.2x ULN (N=1043,3343,4386)
    36
    118
    154
        Monocytes (Abs) >1.2x ULN (N=1117,3343,4460)
    65
    107
    172
        Monocytes (%) >1.2x ULN (N=1043,3343,4386)
    128
    405
    533
        ESR >1.5x ULN (N=1113,3343,4456)
    872
    2411
    3283
        Total bilirubin >1.5x ULN (N=1117,3345,4462)
    18
    38
    56
        Direct bilirubin >1.5x ULN (N=1088,3344,4432)
    5
    14
    19
        Indirect bilirubin >1.5x ULN (N=1041,3344,4385)
    4
    18
    22
        AST >3.0x ULN (N=1117,3343,4461)
    52
    111
    163
        ALT >3.0x ULN (N=1117,3345,4462)
    87
    189
    276
        GGT >3.0x ULN (N=1118,3345,4463)
    82
    239
    321
        Alkaline phosphatase >3.0x ULN (N=1118,3345,4463)
    3
    10
    13
        Total protein <0.8x LLN (N=1118,3345,4463)
    1
    0
    1
        Total protein >1.2x ULN (N=1118,3345,4463)
    2
    4
    6
        Albumin <0.8x LLN (N=1118,3345,4463)
    11
    28
    39
        Albumin >1.2x ULN (N=1118,3345,4463)
    0
    0
    0
        Blood urea nitrogen >1.3x ULN (N=1118,3345,4463)
    87
    126
    213
        Creatinine >1.3x ULN (N=1118,3345,4463)
    52
    95
    147
        Cholesterol >1.3x ULN (N=1104,3345,4449)
    42
    130
    172
        HDL Cholesterol <0.8x LLN (N=1097,3301,4398)
    32
    59
    91
        LDL Cholesterol >1.2x ULN (N=1094,3293,4387)
    69
    145
    214
        Triglycerides >1.3x ULN (N=1096,3300,4396)
    196
    373
    569
        Sodium <0.95x LLN (N=1118,3345,4463)
    6
    19
    25
        Sodium >1.05x ULN (N=1118,3345,4463)
    11
    18
    29
        Potassium <0.9x LLN (N=1118,3345,4463)
    28
    62
    90
        Potassium >1.1x ULN (N=1118,3345,4463)
    11
    25
    36
        Chloride <0.9x LLN (N=1118,3345,4463)
    3
    5
    8
        Chloride >1.1x ULN (N=1118,3345,4463)
    0
    1
    1
        Calcium <0.9x LLN (N=1041,3345,4386)
    2
    8
    10
        Calcium >1.1x ULN (N=1041,3345,4386)
    6
    9
    15
        Bicarbonate (venous) <0.9x LLN (N=1117,3345,4462)
    106
    277
    383
        Bicarbonate (venous) >1.1x ULN (N=1117,3345,4462)
    1
    5
    6
        Glucose <0.6x LLN (N=1118,3345,4463)
    3
    4
    7
        Glucose >1.5x ULN (N=1118,3345,4463)
    125
    345
    470
        Creatine Kinase >2.0x ULN (N=1041,3345,4386)
    203
    908
    1111
        C-reactive protein >1.25x ULN (N=697,242,939)
    365
    106
    471
        Urine specific gravity <1.003 (N=1098,3319,4417)
    2
    7
    9
        Urine specific gravity >1.030 (N=1098,3319,4417)
    203
    303
    506
        Urine pH <4.5 (N=1098,3319,4417)
    0
    0
    0
        Urine pH >8 (N=1098,3319,4417)
    20
    17
    37
        Urine glucose (qual) ≥1 (N=1095,3319,4414)
    60
    148
    208
        Urine ketones (qual) ≥1 (N=686,103,789)
    2
    1
    3
        Urine protein (qual) ≥1 (N=1097,3319,4416)
    65
    222
    287
        Urine blood/hgb (qual) ≥1 (N=1098,3319,4417)
    444
    1260
    1704
        Urine leukocyte esterase ≥1 (N=687,132,819)
    158
    23
    181
        Urine red blood cells ≥20 (N=678,1498,2176)
    198
    491
    689
        Urine WBC ≥20 (N=689,1603,2292)
    219
    507
    726
        Urine epithelial cells ≥6 (N=422,38,460)
    205
    20
    225
        Urine casts >1 (N=420,38,458)
    0
    0
    0
        Urine granular casts >1 (N=0,2,2)
    0
    0
    0
        Urine hyaline casts >1 (N=14,60,74)
    0
    0
    0
        Urine bacteria >20 (N=384,35,419)
    0
    0
    0
    Statistical analysis title
    		 Descriptive statistics only performed
    Comparison groups
    Initial Period: Tofacitinib 5 milligram(mg) twice daily (BID) v Initial Period: Tofacitinib 10 mg BID
    Number of subjects included in analysis
    4481
    Analysis specification
    Post-hoc
    Analysis type
    		 other [1]
    P-value
    		 = 0
    Method
    		 Not applicable
    Parameter type
    		 Not applicable
    Confidence interval
    Notes
    [1] - Arbitrary analysis specification entered as only descriptive statistics performed for this endpoint

    Primary: Extension Period: Number of Subjects with Treatment Emergent Adverse Events (AEs), Serious Adverse Events (SAEs)

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    End point title
    		 Extension Period: Number of Subjects with Treatment Emergent Adverse Events (AEs), Serious Adverse Events (SAEs) [2]
    End point description
    An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. A treatment emergent AE was defined as an event that emerged during the treatment period that was absent before treatment, or worsened during the treatment period relative to the pretreatment state. AEs included both serious and non-serious adverse events. Safety analysis set included all subjects who enrolled for extension period and received at least 1 dose of open label study medication in extension period.
    End point type
    Primary
    End point timeframe
    Baseline (Entry of Extension Period) up to 28 days after last study drug dose in Extension Period (13 Months)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint
    End point values
    		 Extension Period: Tofacitinib 5 mg
    Number of subjects analysed
    48
    Units: Subjects
        Subjects with AEs
    16
        Subjects with SAEs
    5
    No statistical analyses for this end point

    Primary: Extension Period: Number of Subjects with Laboratory Test Abnormalities

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    End point title
    		 Extension Period: Number of Subjects with Laboratory Test Abnormalities [3]
    End point description
    Criteria for laboratory abnormalities: hemoglobin (Hg), hematocrit, red blood cell (RBC), high density lipoprotein (HDL) cholesterol:<0.8*lower limit of normal (LLN), platelet<0.5*LLN/>1.75*upper limit of normal (ULN), white blood cell (WBC)<0.6*LLN/>1.5*ULN, lymphocyte, neutrophil, protein, albumin <0.8*LLN/>1.2*ULN, basophil, eosinophil, monocyte, low density lipoprotein (LDL) cholesterol: >1.2*ULN; bilirubin>1.5*ULN, aspartate amino transferase(AT), alanine AT, gammaglutamyl transferase, alkaline phosphatase:>3.0*ULN; blood urea nitrogen, creatinine, cholesterol, triglyceride:>1.3*ULN; sodium <0.95*LLN/>1.05*ULN, potassium, chloride, calcium, bicarbonate: <0.9*LLN/>1.1*ULN; glucose<0.6*LLN/>1.5*ULN; Urine (specific gravity<1.003/>1.030, pH<4.5/>8, glucose, ketone, protein, blood/Hg(>=1; RBC, WBC>=20; creatinine kinase>2*ULN). Safety analysis set included all subjects who enrolled for extension period and received at least 1 dose of open label study medication in extension period.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1 at Entry of Extension Period) up to 28 days after last study drug dose in Extension Period (13 Months)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint
    End point values
    		 Extension Period: Tofacitinib 5 mg
    Number of subjects analysed
    48
    Units: Subjects
    30
    No statistical analyses for this end point

    Primary: Initial Period: The long-term safety and tolerability of CP-690,550 5 milligrams (mg) twice daily (BID) and 10 mg BID for the treatment of rheumatoid arthritis

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    End point title
    		 Initial Period: The long-term safety and tolerability of CP-690,550 5 milligrams (mg) twice daily (BID) and 10 mg BID for the treatment of rheumatoid arthritis
    End point description
    Treatment-emergent AEs by SOC (all causalities) - all patients, by time. Data presented for Post Month 96 includes data up to and including Month 114.
    End point type
    Primary
    End point timeframe
    Every visit until last observation
    End point values
    		 Initial Period: Tofacitinib 5 milligram(mg) twice daily (BID) Initial Period: Tofacitinib 10 mg BID All Tofacitinib
    Number of subjects analysed
    1123
    3358
    4481
    Units: Number of participants
    number (not applicable)
        Evaluable for AEs at Months 0 to 6
    1123
    3358
    4481
        Percent with AEs at Months 0 to 6
    59.4
    61.8
    61.2
        Percent discontinued due to AEs at Months 0 to 6
    4.2
    4.0
    4.0
        Evaluable for AEs at Months 6 to 12
    1033
    3121
    4154
        Percent with AEs at Months 6 to 12
    45.1
    47.7
    47.1
        Percent discontinued due to AEs at Months 6 to 12
    2.1
    3.7
    3.3
        Evaluable for AEs at Months 12 to 18
    969
    2865
    3834
        Percent with AEs at Months 12 to 18
    41.2
    46.8
    45.4
        Percent discontinued due to AEs at Months 12 to 18
    3.2
    3.4
    3.3
        Evaluable at Months 18 to 24
    896
    2660
    3556
        Percent with AEs at Months 18 to 24
    38.1
    43.2
    41.9
        Percent discontinued due to AEs at Months 18 to 24
    2.8
    2.9
    2.9
        Evaluable for AEs at Months 24 to 30
    820
    2461
    3281
        Percent with AEs at Months 24 to 30
    40.7
    44.5
    43.5
        Percent discontinued due to AEs at Months 24 to 30
    3.2
    2.8
    2.9
        Evaluable for AEs at Months 30 to 36
    774
    2288
    3062
        Percent with AEs at Months 30 to 36
    39.0
    40.7
    40.3
        Percent discontinued due to AEs at Months 30 to 36
    2.6
    2.5
    2.5
        Evaluable for AEs at Months 36 to 42
    729
    2162
    2891
        Percent with AEs at Months 36 to 42
    38.1
    37.5
    37.6
        Percent discontinued due to AEs at Months 36 to 42
    2.5
    2.5
    2.5
        Evaluable for AEs at Months 42 to 48
    652
    1843
    2495
        Percent with AEs at Months 42 to 48
    37.9
    34.3
    35.3
        Percent discontinued due to AEs at Months 42 to 48
    2.8
    2.9
    2.9
        Evaluable for AEs at Months 48 to 54
    558
    1471
    2029
        Percent with AEs at Months 48 to 54
    36.0
    36.4
    36.3
        Percent discontinued due to AEs at Months 48 to 54
    2.0
    2.5
    2.4
        Evaluable for AEs at Months 54 to 60
    466
    1172
    1638
        Percent with AEs at Months 54 to 60
    37.1
    35.4
    35.9
        Percent discontinued due to AEs at Months 54 to 60
    3.6
    2.7
    3.0
        Evaluable for AEs at Months 60 to 66
    414
    918
    1332
        Percent with AEs at Months 60 to 66
    33.8
    31.4
    32.1
        Percent discontinued due to AEs at Months 60 to 66
    2.4
    1.9
    2.0
        Evaluable for AEs at Months 66 to 72
    379
    670
    1049
        Percent with AEs at Months 66 to 72
    33.5
    21.6
    25.9
        Percent discontinued due to AEs at Months 66 to 72
    3.2
    0.7
    1.6
        Evaluable for AEs at Months 72 to 78
    336
    262
    598
        Percent with AEs at Months 72 to 78
    33.6
    22.5
    28.8
        Percent discontinued due to AEs at Months 72 to 78
    0.9
    0.4
    0.7
        Evaluable for AEs at Months 78 to 84
    302
    86
    388
        Percent with AEs at Months 78 to 84
    36.8
    26.7
    34.5
        Percent discontinued due to AEs at Months 78 to 84
    3.3
    1.2
    2.8
        Evaluable for AEs at Months 84 to 90
    273
    42
    315
        Percent with AEs at Months 84 to 90
    30.8
    35.7
    31.4
        Percent discontinued due to AEs at Months 84 to 90
    1.8
    0
    1.6
        Evaluable for AEs at Months 90 to 96
    234
    34
    268
        Percent with AEs at Months 90 to 96
    21.8
    29.4
    22.8
        Percent discontinued due to AEs at Months 90 to 96
    0.9
    0
    0.7
        Evaluable for AEs post Month 96
    130
    15
    145
        Percent with AEs post Month 96
    20.8
    46.7
    23.4
        Percent discontinued due to AEs post Month 96
    1.5
    0
    1.4
    Statistical analysis title
    		 Descriptive statistics only performed
    Comparison groups
    Initial Period: Tofacitinib 5 milligram(mg) twice daily (BID) v Initial Period: Tofacitinib 10 mg BID
    Number of subjects included in analysis
    4481
    Analysis specification
    Post-hoc
    Analysis type
    		 other [4]
    P-value
    		 = 0
    Method
    		 Not applicable
    Parameter type
    		 Not applicable
    Confidence interval
    Notes
    [4] - Arbitrary analysis specification entered as descriptive statistics only performed for this endpoint

    Primary: Extension Period: Percentage of Subjects With Adverse Events and who Discontinued Treatment Due to Adverse Events to Assess Long-term Safety and Tolerability of Tofacitinib

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    End point title
    		 Extension Period: Percentage of Subjects With Adverse Events and who Discontinued Treatment Due to Adverse Events to Assess Long-term Safety and Tolerability of Tofacitinib [5]
    End point description
    Long term safety and tolerability of Tofacitinib was measured as following: percentage (%) of subjects with AEs, percentage of subjects who discontinued due to AEs. An AE is any untoward medical occurrence in subject who received study drug without regard to possibility of causal relationship. Safety analysis set included all subjects who enrolled for extension period and received at least 1 dose of open label study medication in extension period. Here, “n” signifies number of subjects evaluable for specified categories.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1 at Entry of Extension Period) up to Month 6 of Extension Period; Month 6 of Extension Period to Month 12 of Extension Period
    Notes
    [5] - 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: Only descriptive data was planned to be analyzed for this endpoint
    End point values
    		 Extension Period: Tofacitinib 5 mg
    Number of subjects analysed
    48
    Units: Percentage of subjects
    number (not applicable)
        Baseline to Month 6: % of Subjects with AEs (n=48)
    31.3
        Baseline-Month 6:%of Subjects Discontinued(n=48)
    4.2
        Month 6 to 12: % of Subjects with AEs (n=17)
    17.6
        Month 6 to 12: % of Subjects Discontinued (n=17)
    0.0
    No statistical analyses for this end point

    Secondary: Initial Period: Percent of patients with American College of Rheumatology (ACR) 20, 50, and 70 responses

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    End point title
    		 Initial Period: Percent of patients with American College of Rheumatology (ACR) 20, 50, and 70 responses
    End point description
    The stated number of participants analyzed was the total number of participants in each group. The actual number of participants analyzed on each occasion varied, and is provided for each visit presented.
    End point type
    Secondary
    End point timeframe
    Every visit until last observation
    End point values
    		 Initial Period: Tofacitinib 5 milligram(mg) twice daily (BID) Initial Period: Tofacitinib 10 mg BID All Tofacitinib
    Number of subjects analysed
    1123
    3358
    4481
    Units: Percent of participants
    number (not applicable)
        ACR20 at Month 1 (N=1114,3307,4421)
    70.65
    73.60
    72.86
        ACR20 at Month 2 (N=1080,3254,4334)
    74.81
    76.06
    75.75
        ACR20 at Month 3 (N=1069, 3228,4297)
    75.68
    78.00
    77.43
        ACR20 at Month 6 (N=1040,3132,4172)
    75.58
    77.36
    76.92
        ACR20 at Month 9 (N=1003,3022,4025)
    76.57
    77.53
    77.29
        ACR20 at Month 12 (N=972,2891,3863)
    77.88
    78.24
    78.15
        ACR20 at Month 15 (N=938,2775,3713)
    76.76
    78.67
    78.18
        ACR20 at Month 18 (N=910,2665,3575)
    77.91
    78.46
    78.32
        ACR20 at Month 21 (N=860,2565,3425)
    77.91
    79.42
    79.04
        ACR20 at Month 24 (N=824, 2464, 3288)
    79.61
    78.37
    78.68
        ACR20 at Month 27 (N=796,2361,3157)
    79.15
    79.16
    79.16
        ACR20 at Month 30 (N=770,2288,3058)
    80.00
    79.90
    79.92
        ACR20 at Month 33 (N=749,2219,2968)
    80.51
    79.81
    79.99
        ACR20 at Month 36 (N=730, 2157, 2887)
    81.78
    79.37
    79.98
        ACR20 at Month 39 (N=690,2073,2763)
    78.55
    81.23
    80.56
        ACR20 at Month 42 (N=657,1907,2564)
    78.69
    80.49
    80.03
        ACR20 at Month 45 (N=616,1658,2274)
    82.14
    79.55
    80.26
        ACR20 at Month 48 (N=581,1486,2067)
    78.31
    80.69
    80.02
        ACR20 at Month 51 (N=490,1355,1845)
    83.47
    80.30
    81.14
        ACR20 at Month 54 (N=471,1208,1679)
    79.19
    78.97
    79.04
        ACR20 at Month 57 (N=441,1021,1462)
    80.73
    82.37
    81.87
        ACR20 at Month 60 (N=411,920,1331)
    81.75
    82.39
    82.19
        ACR20 at Month 63 (N=396,692,1010)
    80.30
    82.97
    82.11
        ACR20 at Month 66 (N=382,705,1087)
    79.84
    81.42
    80.86
        ACR20 at Month 69 (N=358,486,844)
    82.68
    83.54
    83.18
        ACR20 at Month 72 (N=339, 287, 626)
    82.01
    82.58
    82.27
        ACR20 at Month 75 (N=309,171,480)
    82.20
    78.95
    81.04
        ACR20 at Month 78 (N=295,91,386)
    81.69
    80.22
    81.35
        ACR20 at Month 81 (N=286,54,340)
    82.52
    79.63
    82.06
        ACR20 at Month 84 (N=271,44,315)
    82.66
    81.82
    82.54
        ACR20 at Month 87 (N=264,41,305)
    84.47
    70.73
    82.62
        ACR20 at Month 90 (N=241,39,280)
    82.57
    74.36
    81.43
        ACR20 at Month 93 (N=196,28,224)
    82.14
    78.57
    81.70
        ACR20 at Month 96 (N=144,16,160)
    78.47
    81.25
    78.75
        ACR20 at Month 99 (N=65,11,76)
    83.08
    90.91
    84.21
        ACR20 at Month 102 (N=22,4,26)
    77.27
    50.00
    73.08
        ACR20 at Month 105 (N=15,3,18)
    73.33
    66.67
    72.22
        ACR20 at Month 108 (N=8,1,9)
    62.50
    100.00
    66.67
        ACR20 at Month 111 (N=3,1,4)
    100.00
    100.00
    100.00
        ACR20 at Month 114 (N=1,0,1)
    100.00
    0
    100.00
        ACR50 at Month 1 (N=1114,3307,4421)
    47.67
    49.56
    49.08
        ACR50 at Month 2 (N=1080,3254,4334)
    50.19
    53.29
    52.51
        ACR50 at Month 3 (N=1069,3228,4297)
    51.45
    54.52
    53.76
        ACR50 at Month 6 (N=1040,3132,4172)
    52.79
    55.75
    55.01
        ACR50 at Month 9 (N=1003,3022,4025)
    53.24
    55.96
    55.28
        ACR50 at Month 12 (N=972,2891,3863)
    52.98
    56.73
    55.79
        ACR50 at Month 15 (N=938,2775,3713)
    55.76
    56.61
    56.40
        ACR50 at Month 18 (N=910,2665,3575)
    55.16
    57.30
    56.76
        ACR50 at Month 21 (N=860,2565,3425)
    54.77
    59.10
    58.01
        ACR50 at Month 24 (N=824,2464,3288)
    57.77
    57.67
    57.69
        ACR50 at Month 27 (N=796,2361,3157)
    56.91
    58.58
    58.16
        ACR50 at Month 30 (N=770,2288,3058)
    58.83
    58.65
    58.70
        ACR50 at Month 33 (N=749,2219,2968)
    57.68
    59.31
    58.89
        ACR50 at Month 36 (N=730,2157,2887)
    58.49
    58.51
    58.50
        ACR50 at Month 39 (N=690,2073,2763)
    59.28
    59.29
    59.28
        ACR50 at Month 42 (N=657,1907,2564)
    58.60
    59.99
    59.63
        ACR50 at Month 45 (N=616,1658,2274)
    59.42
    60.07
    59.89
        ACR50 at Month 48 (N=581,1486,2067)
    58.00
    57.60
    57.72
        ACR50 at Month 51 (N=490,1355,1845)
    62.45
    59.19
    60.05
        ACR50 at Month 54 (N=471,1355,1845)
    58.60
    59.44
    59.20
        ACR50 at Month 57 (N=441,1021,1462)
    61.45
    61.12
    61.22
        ACR50 at Month 60 (N=411,920,1331)
    62.53
    60.65
    61.23
        ACR50 at Month 63 (N=396,834,1230)
    64.39
    61.99
    62.76
        ACR50 at Month 66 (N=382,705,1087)
    60.73
    60.85
    60.81
        ACR50 at Month 69 (N=358,486,844)
    58.10
    61.11
    59.83
        ACR50 at Month 72 (N=339,287,626)
    62.54
    59.93
    61.34
        ACR50 at Month 75 (N=309,171,480)
    61.49
    56.14
    59.58
        ACR50 at Month 78 (N=295,91,386)
    60.00
    58.24
    59.59
        ACR50 at Month 81 (N=286,54,340)
    63.99
    51.85
    62.06
        ACR50 at Month 84 (N=271,44,315)
    63.10
    54.55
    61.90
        ACR50 at Month 87 (N=264,41,305)
    67.05
    43.90
    63.93
        ACR50 at Month 90 (N=241,39,280)
    61.00
    46.15
    58.93
        ACR50 at Month 93 (N=196,28,224)
    61.22
    57.14
    60.71
        ACR50 at Month 96 (N=144,16,160)
    61.11
    56.25
    60.63
        ACR50 at Month 99 (N=65,11,76)
    53.85
    54.55
    53.95
        ACR50 at Month 102 (N=22,4,26)
    54.55
    25.00
    50.00
        ACR50 at Month 105 (N=15,3,18)
    66.67
    33.33
    61.11
        ACR50 at Month 108 (N=8,1,9)
    50.00
    0.00
    44.44
        ACR50 at Month 111 (N=3,1,4)
    100.00
    0.00
    75.00
        ACR50 at Month 114 (N=1,0,1)
    100.00
    0.00
    100.00
        ACR70 at Month 1 (N=1114,3307,4421)
    26.66
    28.82
    28.27
        ACR70 at Month 2 (N=1080,3254,4334)
    27.78
    31.53
    30.60
        ACR70 at Month 3 (N=1069,3228,4297)
    29.37
    33.09
    32.16
        ACR70 at Month 6 (N=1040,3132,4172)
    31.06
    33.75
    33.08
        ACR70 at Month 9 (N=1003,3022,4025)
    31.80
    34.91
    34.14
        ACR70 at Month 12 (N=972,2891,3863)
    31.38
    35.84
    34.71
        ACR70 at Month 15 (N=937,2775,3713)
    32.94
    36.54
    35.63
        ACR70 at Month 18 (N=910,2665,3575)
    35.82
    36.40
    36.25
        ACR70 at Month 21 (N=860,2565,3425)
    33.49
    37.66
    36.61
        ACR70 at Month 24 (N=824,2464,3288)
    35.44
    38.15
    37.47
        ACR70 at Month 27 (N=796,2361,3157)
    36.06
    38.33
    37.76
        ACR70 at Month 30 (N=770,2288,3058)
    37.27
    38.99
    38.55
        ACR70 at Month 33 (N=749,2219,2968)
    33.64
    38.26
    37.10
        ACR70 at Month 36 (N=730,2157,2887)
    36.71
    37.41
    37.24
        ACR70 at Month 39 (N=690,2073,2763)
    38.41
    38.88
    38.76
        ACR70 at Month 42 (N=657,1907,2564)
    35.77
    38.91
    38.10
        ACR70 at Month 45 (N=616,1658,2274)
    36.69
    38.18
    37.77
        ACR70 at Month 48 (N=581,1486,2067)
    35.97
    37.01
    36.72
        ACR70 at Month 51 (N=490,1355,1845)
    39.59
    37.34
    37.94
        ACR70 at Month 54 (N=471,1208,1679)
    36.73
    39.32
    38.59
        ACR70 at Month 57 (N=441,1021,1462)
    38.78
    39.47
    39.26
        ACR70 at Month 60 (N=411,920,1331)
    37.96
    38.91
    38.62
        ACR70 at Month 63 (N=396,834,1230)
    38.64
    39.33
    39.11
        ACR70 at Month 66 (N=.146,283,429)
    38.22
    40.14
    39.47
        ACR70 at Month 69 (N=358,486,844)
    38.55
    41.56
    40.28
        ACR70 at Month 72 (N=339,287,626)
    40.12
    36.59
    38.50
        ACR70 at Month 75 (N=309,171,480)
    40.13
    36.84
    38.96
        ACR70 at Month 78 (N=295,91,386)
    42.37
    32.97
    40.16
        ACR70 at Month 81 (N=286,54,340)
    41.26
    35.19
    40.29
        ACR70 at Month 84 (N=271,44,315)
    42.07
    31.82
    40.63
        ACR70 at Month 87 (N=264,41,305)
    42.80
    21.95
    40.00
        ACR70 at Month 90 (N=241,39,280)
    38.17
    25.64
    36.43
        ACR70 at Month 93 (N=196,28,224)
    41.84
    39.29
    41.52
        ACR70 at Month 96 (N=144,16,160)
    43.75
    31.25
    42.50
        ACR70 at Month 99 (N=65,11,76)
    40.00
    18.18
    36.84
        ACR70 at Month 102 (N=22,4,26)
    40.91
    25.00
    38.46
        ACR70 at Month 105 (N=15,3,18)
    46.67
    33.33
    44.44
        ACR70 at Month 108 (N=8,1,9)
    25.00
    0.00
    22.22
        ACR70 at Month 111 (N=3,1,4)
    100.00
    0.00
    75.00
        ACR70 at Month 114 (N=1,0,1)
    100.00
    0.00
    100.00
    No statistical analyses for this end point

    Secondary: Extension Period: Percentage of Subjects With American College of Rheumatology (ACR) 20, 50, and 70 Responses

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    End point title
    		 Extension Period: Percentage of Subjects With American College of Rheumatology (ACR) 20, 50, and 70 Responses
    End point description
    ACR20=20 percent (%) improvement from baseline (Month 0 at entry of Initial Period) in tender/painful joint count (JC), swollen JC, and in at least 3 of 5 variables: subject’s global assessment of arthritis (SGA), physician's global assessment of arthritis (PGA), subject’s assessment of arthritis pain (SA), HAQ-DI, CRP. ACR50 is a 50% improvement and ACR70 a 70% improvement in these variables. SGA:subject assessed overall disease activity, score: 0 (no arthritis) to 10 (extreme arthritis), higher score=more arthritis. PGA: physician judged subject’s overall disease activity, score: 0 (no arthritis) to 10 (extreme arthritis), higher score=more arthritis. SA: subject assessed arthritis pain by 100 millimeter (mm) visual analogue scale, score: 0 mm (no pain) to 100 mm (extreme pain), higher score=more pain. HAQ-DI:functional disability evaluation, score: 0 (no difficulty) to 3 (extreme difficulty), higher score=more disability. FAS for extension. “n”=subjects evaluable for categories.
    End point type
    Secondary
    End point timeframe
    Month 3, 6, 9 and 12 of Extension Period
    End point values
    		 Extension Period: Tofacitinib 5 mg
    Number of subjects analysed
    48
    Units: Percentage of subjects
    number (not applicable)
        ACR20 at Month 3 (n =47)
    70.21
        ACR20 at Month 6 (n =36)
    66.67
        ACR20 at Month 9 (n =15)
    86.67
        ACR20 at Month 12 (n =2)
    50.00
        ACR50 at Month 3 (n =47)
    48.94
        ACR50 at Month 6 (n =36)
    55.56
        ACR50 at Month 9 (n =15)
    60.00
        ACR50 at Month 12 (n =2)
    50.00
        ACR70 at Month 3 (n =47)
    23.40
        ACR70 at Month 6 (n =36)
    36.11
        ACR70 at Month 9 (n =15)
    40.00
        ACR70 at Month 12 (n =2)
    50.00
    No statistical analyses for this end point

    Secondary: Area under American College of Rheumatology (ACR) n curve

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    End point title
    		 Area under American College of Rheumatology (ACR) n curve
    End point description
    No data was analyzed for this endpoint because it was removed from the protocol in a previous amendment.
    End point type
    Secondary
    End point timeframe
    Every visit until last observation
    End point values
    		 Initial Period: Tofacitinib 5 milligram(mg) twice daily (BID) Initial Period: Tofacitinib 10 mg BID
    Number of subjects analysed
    0 [6]
    0 [7]
    Units: Not applicable
        arithmetic mean (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [6] - No data analyzed for this endpoint as it was removed in a previous protocol amendment.
    [7] - No data analyzed for this endpoint as it was removed in a previous protocol amendment.
    No statistical analyses for this end point

    Secondary: Initial Period: Disease Activity Score (DAS)28 (C-reactive protein [CRP]) and DAS28 (erythrocyte sedimentation rate [ESR])

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    End point title
    		 Initial Period: Disease Activity Score (DAS)28 (C-reactive protein [CRP]) and DAS28 (erythrocyte sedimentation rate [ESR])
    End point description
    Descriptive statistics for DAS28-3 (CRP) and DAS28-4 (ESR). The stated number of participants analyzed was the total number of participants in each group. The actual number of participants analyzed on each occasion varied, and is provided for each visit presented.
    End point type
    Secondary
    End point timeframe
    Every visit until last observation
    End point values
    		 Initial Period: Tofacitinib 5 milligram(mg) twice daily (BID) Initial Period: Tofacitinib 10 mg BID All Tofacitinib
    Number of subjects analysed
    1123
    3358
    4481
    Units: Score
    arithmetic mean (standard deviation)
        DAS28-4 (ESR) Baseline (N=1002,3296,4298)
    6.27 ± 1.02
    6.39 ± 1.04
    6.36 ± 1.04
        DAS28-4 (ESR) Month 1 (N=1036,3254,4290)
    3.81 ± 1.32
    3.78 ± 1.36
    3.79 ± 1.35
        DAS28-4 (ESR) Month 2 (N=1026,3222,4248)
    3.72 ± 1.27
    3.66 ± 1.32
    3.68 ± 1.31
        DAS28-4 (ESR) Month 3 (N=1033,3203,4236)
    3.75 ± 1.32
    3.61 ± 1.30
    3.65 ± 1.31
        DAS28-4 (ESR) Month 6 (N=1015,3110,4125)
    3.67 ± 1.33
    3.61 ± 1.30
    3.62 ± 1.31
        DAS28-4 (ESR) Month 9 (N=992,3003,3995)
    3.60 ± 1.31
    3.58 ± 1.32
    3.59 ± 1.31
        DAS28-4 (ESR) Month 12 (N=967,2862,3829)
    3.61 ± 1.26
    3.56 ± 1.30
    3.57 ± 1.29
        DAS28-4 (ESR) Month 15 (N=922,2759,3681)
    3.54 ± 1.26
    3.53 ± 1.30
    3.53 ± 1.29
        DAS28-4 (ESR) Month 18 (N=899,2655,3554)
    3.57 ± 1.26
    3.50 ± 1.28
    3.52 ± 1.28
        DAS28-4 (ESR) Month 21 (N=850,2547,3397)
    3.58 ± 1.25
    3.45 ± 1.27
    3.48 ± 1.26
        DAS28-4 (ESR) Month 24 (N=818,2441,3259)
    3.54 ± 1.21
    3.46 ± 1.26
    3.48 ± 1.25
        DAS28-4 (ESR) Month 27 (N=787,2343,3130)
    3.52 ± 1.20
    3.44 ± 1.25
    3.46 ± 1.24
        DAS28-4 (ESR) Month 30 (N=764,2257,3021)
    3.54 ± 1.23
    3.43 ± 1.25
    3.46 ± 1.24
        DAS28-4 (ESR) Month 33 (N=746,2199,2945)
    3.51 ± 1.22
    3.42 ± 1.27
    3.45 ± 1.26
        DAS28-4 (ESR) Month 36 (N=720,2141,2861)
    3.51 ± 1.23
    3.42 ± 1.27
    3.44 ± 1.26
        DAS28-4 (ESR) Month 39 (N=679,2056,2735)
    3.56 ± 1.27
    3.39 ± 1.24
    3.43 ± 1.25
        DAS28-4 (ESR) Month 42 (N=642,1890,2532)
    3.53 ± 1.26
    3.40 ± 1.26
    3.43 ± 1.26
        DAS28-4 (ESR) Month 45 (N=609,1641,2250)
    3.45 ± 1.20
    3.37 ± 1.21
    3.39 ± 1.20
        DAS28-4 (ESR) Month 48 (N=570,1471,2041)
    3.46 ± 1.16
    3.36 ± 1.21
    3.39 ± 1.20
        DAS28-4 (ESR) Month 51 (N=481,1344,1825)
    3.43 ± 1.20
    3.39 ± 1.24
    3.40 ± 1.23
        DAS28-4 (ESR) Month 54 (N=467,1194,1661)
    3.54 ± 1.23
    3.38 ± 1.25
    3.42 ± 1.25
        DAS28-4 (ESR) Month 57 (N=438,1006,1444)
    3.48 ± 1.19
    3.36 ± 1.21
    3.40 ± 1.20
        DAS28-4 (ESR) Month 60 (N=408,908,1316)
    3.51 ± 1.27
    3.34 ± 1.20
    3.39 ± 1.22
        DAS28-4 (ESR) Month 63 (N=388,825,1213)
    3.51 ± 1.15
    3.30 ± 1.16
    3.37 ± 1.16
        DAS28-4 (ESR) Month 66 (N=379,700,1079)
    3.58 ± 1.12
    3.34 ± 1.17
    3.42 ± 1.15
        DAS28-4 (ESR) Month 69 (N=355,483,838)
    3.51 ± 1.18
    3.35 ± 1.20
    3.41 ± 1.19
        DAS28-4 (ESR) Month 72 (N=338,284,622)
    3.45 ± 1.20
    3.42 ± 1.19
    3.44 ± 1.20
        DAS28-4 (ESR) Month 75 (N=299,169,468)
    3.43 ± 1.11
    3.41 ± 1.14
    3.43 ± 1.12
        DAS28-4 (ESR) Month 78 (N=291,91,382)
    3.44 ± 1.14
    3.32 ± 1.20
    3.41 ± 1.16
        DAS28-4 (ESR) Month 81 (N=284,54,338)
    3.40 ± 1.11
    3.56 ± 1.24
    3.42 ± 1.13
        DAS28-4 (ESR) Month 84 (N=271,44,315)
    3.32 ± 1.13
    3.42 ± 1.37
    3.34 ± 1.16
        DAS28-4 (ESR) Month 87 (N=263,41,304)
    3.33 ± 1.13
    3.19 ± 1.15
    3.31 ± 1.13
        DAS28-4 (ESR) Month 90 (N=237,39,276)
    3.34 ± 1.14
    3.28 ± 1.10
    3.33 ± 1.13
        DAS28-4 (ESR) Month 93 (N=191,28,219)
    3.33 ± 1.14
    3.23 ± 1.12
    3.32 ± 1.13
        DAS28-4 (ESR) Month 96 (N=142,16,158)
    3.30 ± 1.12
    3.48 ± 1.06
    3.32 ± 1.11
        DAS28-4 (ESR) Month 99 (N=65,11,76)
    3.26 ± 1.07
    3.04 ± 1.24
    3.23 ± 1.09
        DAS28-4 (ESR) Month 102 (N=22,4,26)
    3.34 ± 1.47
    3.10 ± 1.76
    3.30 ± 1.48
        DAS28-4 (ESR) Month 105 (N=14,3,17)
    3.64 ± 1.52
    2.65 ± 0.97
    3.46 ± 1.46
        DAS28-4 (ESR) Month 108 (N=8,1,9)
    3.36 ± 1.76
    4.65 ± 0
    3.51 ± 1.70
        DAS28-4 (ESR) Month 111 (N=3,1,4)
    2.03 ± 0.69
    3.59 ± 0
    2.42 ± 0.96
        DAS28-4 (ESR) Month 114 (N=1,0,1)
    1.28 ± 0
    0 ± 0
    1.28 ± 0
        DAS28-3 (CRP) Baseline (N=1112,3340,4452)
    5.31 ± 0.95
    5.34 ± 0.98
    5.33 ± 0.97
        DAS28-3 (CRP) Month 1 (N=1096,3234,4330)
    3.10 ± 1.19
    2.96 ± 1.22
    2.99 ± 1.21
        DAS28-3 (CRP) Month 2 (N=1070,3180,4250)
    3.01 ± 1.15
    2.87 ± 1.17
    2.90 ± 1.17
        DAS28-3 (CRP) Month 3 (N=1057,3190,4247)
    2.98 ± 1.15
    2.81 ± 1.15
    2.85 ± 1.15
        DAS28-3 (CRP) Month 6 (N=1026,3106,4132)
    2.89 ± 1.16
    2.79 ± 1.15
    2.81 ± 1.16
        DAS28-3 (CRP) Month 9 (N=993,3008,4001)
    2.82 ± 1.12
    2.74 ± 1.16
    2.76 ± 1.15
        DAS28-3 (CRP) Month 12 (N=962,2874,3836)
    2.81 ± 1.11
    2.72 ± 1.13
    2.74 ± 1.13
        DAS28-3 (CRP) Month 15 (N=923,2761,3684)
    2.73 ± 1.10
    2.69 ± 1.13
    2.70 ± 1.12
        DAS28-3 (CRP) Month 18 (N=899,2654,3553)
    2.72 ± 1.11
    2.66 ± 1.11
    2.68 ± 1.11
        DAS28-3 (CRP) Month 21 (N=856,2556,3412)
    2.75 ± 1.12
    2.62 ± 1.09
    2.65 ± 1.09
        DAS28-3 (CRP) Month 24 (N=813,2456,3269)
    2.96 ± 1.07
    2.63 ± 1.11
    2.64 ± 1.10
        DAS28-3 (CRP) Month 27 (N=793,2345,3138)
    2.66 ± 1.06
    2.60 ± 1.09
    2.62 ± 1.08
        DAS28-3 (CRP) Month 30 (N=766,2271,3037)
    2.65 ± 1.07
    2.59 ± 1.09
    2.60 ± 1.08
        DAS28-3 (CRP) Month 33 (N=745,2209,2954)
    2.64 ± 1.06
    2.58 ± 1.10
    2.60 ± 1.09
        DAS28-3 (CRP) Month 36 (N=724,2142,2866)
    2.64 ± 1.07
    2.59 ± 1.08
    2.60 ± 1.08
        DAS28-3 (CRP) Month 39 (N=686,2057,2743)
    2.65 ± 1.10
    2.57 ± 1.07
    2.59 ± 1.08
        DAS28-3 (CRP) Month 42 (N=653,1893,2546)
    2.63 ± 1.09
    2.57 ± 1.09
    2.59 ± 1.09
        DAS28-3 (CRP) Month 45 (N=611,1644,2255)
    2.57 ± 1.04
    2.53 ± 1.03
    2.54 ± 1.03
        DAS28-3 (CRP) Month 48 (N=579,1469,2048)
    2.59 ± 1.03
    2.54 ± 1.05
    2.56 ± 1.04
        DAS28-3 (CRP) Month 51 (N=487,1348,1835)
    2.59 ± 0.99
    2.57 ± 1.07
    2.57 ± 1.05
        DAS28-3 (CRP) Month 54 (N=468,1198,1666)
    2.68 ± 1.07
    2.56 ± 1.05
    2.59 ± 1.06
        DAS28-3 (CRP) Month 57 (N=439,1011,1450)
    2.63 ± 1.03
    2.54 ± 1.04
    2.56 ± 1.03
        DAS28-3 (CRP) Month 60 (N=407,913,1320)
    2.66 ± 1.09
    2.53 ± 1.03
    2.57 ± 1.05
        DAS28-3 (CRP) Month 63 (N=390,824,1214)
    2.67 ± 1.01
    2.51 ± 0.98
    2.56 ± 0.99
        DAS28-3 (CRP) Month 66 (N=376,702,1078)
    2.70 ± 1.02
    2.53 ± 1.01
    2.59 ± 1.02
        DAS28-3 (CRP) Month 69 (N=355,483,838)
    2.67 ± 1.06
    2.55 ± 1.00
    2.60 ± 1.03
        DAS28-3 (CRP) Month 72 (N=337,285,622)
    2.65 ± 1.04
    2.64 ± 1.03
    2.64 ± 1.04
        DAS28-3 (CRP) Month 75 (N=304,170,474)
    2.63 ± 1.05
    2.59 ± 1.02
    2.61 ± 1.04
        DAS28-3 (CRP) Month 78 (N=292,91,383)
    2.59 ± 1.02
    2.68 ± 1.01
    2.61 ± 1.02
        DAS28-3 (CRP) Month 81 (N=285,54,339)
    2.54 ± 0.96
    2.82 ± 1.13
    2.59 ± 0.99
        DAS28-3 (CRP) Month 84 (N=269,44,313)
    2.49 ± 0.94
    2.84 ± 1.20
    2.54 ± 0.99
        DAS28-3 (CRP) Month 87 (N=264,41,305)
    2.52 ± 0.97
    2.56 ± 0.91
    2.52 ± 0.96
        DAS28-3 (CRP) Month 90 (N=240,39,279)
    2.55 ± 1.00
    2.58 ± 0.95
    2.55 ± 0.99
        DAS28-3 (CRP) Month 93 (N=196,28,224)
    2.59 ± 1.00
    2.59 ± 0.85
    2.59 ± 0.98
        DAS28-3 (CRP) Month 96 (N=144,16,160)
    2.59 ± 0.93
    2.68 ± 0.80
    2.60 ± 0.92
        DAS28-3 (CRP) Month 99 (N=64,11,75)
    2.58 ± 0.89
    2.49 ± 1.12
    2.57 ± 0.92
        DAS28-3 (CRP) Month 102 (N=13,3,16)
    2.66 ± 0.78
    2.29 ± 1.01
    2.59 ± 0.81
        DAS28-3 (CRP) Month 105 (N=12,2,14)
    3.31 ± 1.23
    1.76 ± 0.34
    3.09 ± 1.26
        DAS28-3 (CRP) Month 108 (N=7,1,8)
    3.46 ± 1.59
    3.70 ± 0
    3.49 ± 1.47
        DAS28-3 (CRP) Month 111 (N=3,1,4)
    1.82 ± 0.50
    2.49 ± 0
    1.98 ± 0.53
        DAS28-3 (CRP) Month 114 (N=1,0,1)
    2.67 ± 0
    0 ± 0
    2.67 ± 0
    No statistical analyses for this end point

    Secondary: Extension Period: Change From Baseline in Disease Activity Score (DAS) 28-3 C-reactive Protein [CRP](DAS28-3 CRP) and DAS28-4 Erythrocyte Sedimentation Rate (ESR)(DAS28-4 ESR) at Month 3, 6, 9 and 12

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    End point title
    		 Extension Period: Change From Baseline in Disease Activity Score (DAS) 28-3 C-reactive Protein [CRP](DAS28-3 CRP) and DAS28-4 Erythrocyte Sedimentation Rate (ESR)(DAS28-4 ESR) at Month 3, 6, 9 and 12
    End point description
    DAS28 is composite score, derived from: 1) tender/painful joints count, out of 28 joints (TJC28), 2) swollen joints count, out of 28 joints (SJC28), 3) blood marker of inflammation (ESR [millimeter per hour] or CRP [milligram per liter]). DAS28-4 also include score of general health (GH). GH is general health or subjects’ global assessment of disease activity on 100 mm VAS (score: 0 mm=very well to 100 mm=extremely bad, higher scores=worse health condition). DAS28-3(CRP) = (0.56*sqrt[TJC28] + 0.28*sqrt[SJC28] + 0.36*ln[CRP+1])*1.10 + 1.15) and DAS28-4(ESR) = (0.56*sqrt[TJC28] + 0.28*sqrt[SJC28] + 0.70*ln[ESR] + 0.014*GH), where sqrt=square root, ln=natural logarithm. DAS28-4 ESR and DAS28-3 CRP:score range is 0 (none) to 9.4 (extreme disease activity), higher score = more disease activity. Score of <=3.2: low disease activity; score of <2.6: disease remission. FAS. "n"=subjects evaluable for specified categories. 99999=standard deviation not estimable as 1 subject evaluable.
    End point type
    Secondary
    End point timeframe
    Baseline (Month 0 at the entry of Initial period); Month 3, 6, 9 and 12 of Extension Period
    End point values
    		 Extension Period: Tofacitinib 5 mg
    Number of subjects analysed
    48
    Units: units on score
    arithmetic mean (standard deviation)
        DAS28-4 (ESR) Baseline (n =47)
    5.68 ± 1.26
        DAS28-4 (ESR): Change at Month 3 (n =43)
    -2.82 ± 1.52
        DAS28-4 (ESR): Change at Month 6 (n =34)
    -3.02 ± 1.50
        DAS28-4 (ESR): Change at Month 9 (n =15)
    -3.13 ± 1.66
        DAS28-4 (ESR): Change at Month 12 (n =2)
    -2.55 ± 3.70
        DAS28-3 (CRP): Baseline (n =48)
    4.67 ± 1.24
        DAS28-3 (CRP): Change at Month 3 (n =42)
    -2.36 ± 1.25
        DAS28-3 (CRP): Change at Month 6 (n =34)
    -2.49 ± 1.30
        DAS28-3 (CRP): Change at Month 9 (n =15)
    -3.04 ± 1.49
        DAS28-3 (CRP): Change at Month 12 (n =1)
    0.29 ± 99999
    No statistical analyses for this end point

    Secondary: Initial Period: Number (%) of participants with DAS28-4 (ESR) and DAS28-3 (CRP) <2.6 and ≤3.2

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    End point title
    		 Initial Period: Number (%) of participants with DAS28-4 (ESR) and DAS28-3 (CRP) <2.6 and ≤3.2
    End point description
    Percent participants with DAS28-4 (ESR) <2.6 and ≤3.2 and percent participants with DAS28-3 (CRP) <2.6 and ≤3.2. The stated number of participants analyzed was the total number of participants in each group. The actual number of participants analyzed on each occasion varied, and is provided for each visit presented.
    End point type
    Secondary
    End point timeframe
    Every visit until last observation
    End point values
    		 Initial Period: Tofacitinib 5 milligram(mg) twice daily (BID) Initial Period: Tofacitinib 10 mg BID All Tofacitinib
    Number of subjects analysed
    1123
    3358
    4481
    Units: Percent of participants
    number (not applicable)
        DAS28-4 (ESR) <2.6 Baseline (N=1002,3296,4298)
    0.2
    0.3
    0.3
        DAS28-4 (ESR) <2.6 Month 1 (N=1036,3254,4290)
    19.9
    20.4
    20.3
        DAS28-4 (ESR) <2.6 Month 2 (N=1026,3222,4248)
    20.5
    22.5
    22.0
        DAS28-4 (ESR) <2.6 Month 3 (N=1033,3203,4236)
    20.0
    22.9
    22.2
        DAS28-4 (ESR) <2.6 Month 6 (N=1015,3110,4125)
    22.9
    23.4
    23.3
        DAS28-4 (ESR) <2.6 Month 9 (N=992,3003,3995)
    24.4
    25.1
    24.9
        DAS28-4 (ESR) <2.6 Month 12 (N=967,2862,3829)
    22.3
    24.4
    23.9
        DAS28-4 (ESR) <2.6 Month 15 (N=922,2759,3681)
    23.8
    25.7
    25.2
        DAS28-4 (ESR) <2.6 Month 18 (N=899,2655,3554)
    25.3
    26.9
    26.4
        DAS28-4 (ESR) <2.6 Month 21 (N=850,2547,3397)
    22.2
    27.1
    25.9
        DAS28-4 (ESR) <2.6 Month 24 (N=818,2441,3259)
    22.7
    26.8
    25.8
        DAS28-4 (ESR) <2.6 Month 27 (N=787,2343,3130)
    22.6
    27.9
    26.5
        DAS28-4 (ESR) <2.6 Month 30 (N=764,2257,3021)
    24.6
    27.7
    26.9
        DAS28-4 (ESR) <2.6 Month 33 (N=746,2199,2945)
    23.7
    28.3
    27.1
        DAS28-4 (ESR) <2.6 Month 36 (N=720,2141,2861)
    25.6
    28.9
    28.1
        DAS28-4 (ESR) <2.6 Month 39 (N=679,2056,2735)
    23.9
    28.4
    27.3
        DAS28-4 (ESR) <2.6 Month 42 (N=642,1890,2532)
    24.3
    27.9
    27.0
        DAS28-4 (ESR) <2.6 Month 45 (N=609,1641,2250)
    24.1
    27.5
    26.6
        DAS28-4 (ESR) <2.6 Month 48 (N=570,1471,2041)
    23.5
    28.0
    26.8
        DAS28-4 (ESR) <2.6 Month 51 (N=481,1344,1825)
    28.3
    27.3
    27.6
        DAS28-4 (ESR) <2.6 Month 54 (N=467,1194,1661)
    21.4
    28.3
    26.4
        DAS28-4 (ESR) <2.6 Month 57 (N=438,1006,1444)
    23.1
    28.0
    26.5
        DAS28-4 (ESR) <2.6 Month 60 (N=408,908,1316)
    24.0
    28.6
    27.2
        DAS28-4 (ESR) <2.6 Month 63 (N=388,825,1213)
    22.4
    29.5
    27.2
        DAS28-4 (ESR) <2.6 Month 66 (N=379,700,1079)
    19.5
    26.9
    24.3
        DAS28-4 (ESR) <2.6 Month 69 (N=355,483,838)
    23.9
    26.3
    25.3
        DAS28-4 (ESR) <2.6 Month 72 (N=338,284,622)
    25.7
    25.0
    25.4
        DAS28-4 (ESR) <2.6 Month 75 (N=299,169,468)
    23.7
    26.0
    24.6
        DAS28-4 (ESR) <2.6 Month 78 (N=291,91,382)
    24.7
    33.0
    26.7
        DAS28-4 (ESR) <2.6 Month 81 (N=284,54,338)
    24.6
    22.2
    24.3
        DAS28-4 (ESR) <2.6 Month 84 (N=271,44,315)
    27.3
    27.3
    27.3
        DAS28-4 (ESR) <2.6 Month 87 (N=263,41,304)
    31.2
    31.7
    31.3
        DAS28-4 (ESR) <2.6 Month 90 (N=237,39,276)
    28.7
    25.6
    28.3
        DAS28-4 (ESR) <2.6 Month 93 (N=191,28,219)
    28.3
    28.6
    28.3
        DAS28-4 (ESR) <2.6 Month 96 (N=142,16,158)
    25.4
    18.8
    24.7
        DAS28-4 (ESR) <2.6 Month 99 (N=65,11,76)
    27.7
    36.4
    28.9
        DAS28-4 (ESR) <2.6 Month 102 (N=22,4,26)
    31.8
    50.0
    34.6
        DAS28-4 (ESR) <2.6 Month 105 (N=14,3,17)
    28.6
    33.3
    29.4
        DAS28-4 (ESR) <2.6 Month 108 (N=8,1,9)
    25.0
    0
    22.2
        DAS28-4 (ESR) </=3.2 Baseline (N=1002,3296,4298)
    0.4
    0.7
    0.6
        DAS28-4 (ESR) </=3.2 Month 1 (N=1036,3254,4290)
    34.2
    37.6
    36.8
        DAS28-4 (ESR) </=3.2 Month 2 (N=1026,3222,4248)
    36.7
    40.5
    39.6
        DAS28-4 (ESR) </=3.2 Month 3 (N=1033,3203,4236)
    36.6
    41.6
    40.4
        DAS28-4 (ESR) </=3.2 Month 6 (N=1015,3110,4125)
    39.8
    42.5
    41.9
        DAS28-4 (ESR) </=3.2 Month 9 (N=992,3003,3995)
    41.3
    43.8
    43.2
        DAS28-4 (ESR) </=3.2 Month 12 (N=967,2862,3829)
    42.1
    42.5
    42.4
        DAS28-4 (ESR) </=3.2 Month 18 (N=899,2655,3554)
    42.7
    45.0
    44.4
        DAS28-4 (ESR) </=3.2 Month 21 (N=850,2547,3397)
    41.9
    47.2
    45.9
        DAS28-4 (ESR) </=3.2 Month 24 (N=818,2441,3259)
    42.5
    46.5
    45.5
        DAS28-4 (ESR) </=3.2 Month 27 (N=787,2343,3130)
    44.9
    46.9
    46.4
        DAS28-4 (ESR) </=3.2 Month 30 (N=764,2257,3021)
    42.8
    47.4
    46.2
        DAS28-4 (ESR) </=3.2 Month 33 (N=746,2199,2945)
    42.8
    47.5
    46.3
        DAS28-4 (ESR) </=3.2 Month 36 (N=720,2141,2861)
    44.6
    48.4
    47.5
        DAS28-4 (ESR) </=3.2 Month 39 (N=679,2056,2735)
    42.6
    48.3
    46.9
        DAS28-4 (ESR) </=3.2 Month 42 (N=642,1890,2532)
    45.8
    49.2
    48.3
        DAS28-4 (ESR) </=3.2 Month 45 (N=609,1641,2250)
    45.3
    48.4
    47.6
        DAS28-4 (ESR) </=3.2 Month 48 (N=570,1471,2041)
    46.1
    49.4
    48.5
        DAS28-4 (ESR) </=3.2 Month 51 (N=481,1344,1825)
    44.9
    49.0
    47.9
        DAS28-4 (ESR) </=3.2 Month 54 (N=467,1194,1661)
    43.7
    49.4
    47.8
        DAS28-4 (ESR) </=3.2 Month 57 (N=438,1006,1444)
    45.2
    50.3
    48.8
        DAS28-4 (ESR) </=3.2 Month 60 (N=408,908,1316)
    46.3
    49.9
    48.8
        DAS28-4 (ESR) </=3.2 Month 63 (N=388,825,1213)
    41.0
    49.9
    47.1
        DAS28-4 (ESR) </=3.2 Month 66 (N=379,700,1079)
    38.8
    49.7
    45.9
        DAS28-4 (ESR) </=3.2 Month 69 (N=355,483,838)
    45.6
    50.3
    48.3
        DAS28-4 (ESR) </=3.2 Month 72 (N=338,284,622)
    44.7
    48.2
    46.3
        DAS28-4 (ESR) </=3.2 Month 75 (N=299,169,458)
    43.1
    48.5
    45.1
        DAS28-4 (ESR) </=3.2 Month 78 (N=291,91,382)
    44.7
    45.1
    44.8
        DAS28-4 (ESR) </=3.2 Month 81 (N=284,54,338)
    49.3
    48.1
    49.1
        DAS28-4 (ESR) </=3.2 Month 84 (N=271,44,315)
    47.2
    45.5
    47.0
        DAS28-4 (ESR) </=3.2 Month 87 (N=263,41,304)
    47.9
    46.3
    47.7
        DAS28-4 (ESR) </=3.2 Month 90 (N=237,39,276)
    46.0
    46.2
    46.0
        DAS28-4 (ESR) </=3.2 Month 93 (N=191,28,219)
    48.2
    50.0
    48.4
        DAS28-4 (ESR) </=3.2 Month 96 (N=142,16,158)
    47.2
    43.8
    46.8
        DAS28-4 (ESR) </=3.2 Month 99 (N=142,16,158)
    43.1
    54.5
    44.7
        DAS28-4 (ESR) </=3.2 Month 102 (N=22,4,26)
    45.5
    50.0
    46.2
        DAS28-4 (ESR) </=3.2 Month 105 (N=14,3,17)
    42.9
    66.7
    47.1
        DAS28-4 (ESR) </=3.2 Month 108 (N=8,1,9)
    50.0
    0
    44.4
        DAS28-3 (CRP) <2.6 Baseline 1 (N=1112,3340,4452)
    0.5
    0.9
    0.8
        DAS28-3 (CRP) <2.6 Month 1 (N=1096,3234,4330)
    38.0
    43.0
    41.7
        DAS28-3 (CRP) <2.6 Month 2 (N=1070,3180,4250)
    39.7
    47.1
    45.2
        DAS28-3 (CRP) <2.6 Month 3 (N=1057,3190,4247)
    42.3
    47.5
    46.2
        DAS28-3 (CRP) <2.6 Month 6 (N=1026,3106,4132)
    45.2
    49.0
    48.1
        DAS28-3 (CRP) <2.6 Month 9 (N=993,3008,4001)
    47.1
    50.7
    49.8
        DAS28-3 (CRP) <2.6 Month 12 (N=962,2874,3836)
    47.8
    51.8
    50.8
        DAS28-3 (CRP) <2.6 Month 15 (N=923,2761,3684)
    50.6
    52.3
    51.9
        DAS28-3 (CRP) <2.6 Month 18 (N=899,2654,3553)
    51.3
    54.1
    53.4
        DAS28-3 (CRP) <2.6 Month 21 (N=856,2556,3412)
    51.1
    55.5
    54.4
        DAS28-3 (CRP) <2.6 Month 24 (N=813,2456,3269)
    51.9
    55.3
    54.4
        DAS28-3 (CRP) <2.6 Month 27 (N=793,2345,3138)
    53.2
    55.8
    55.2
        DAS28-3 (CRP) <2.6 Month 30 (N=766,2271,3037)
    53.3
    56.8
    55.9
        DAS28-3 (CRP) <2.6 Month 33 (N=745,2209,2954)
    54.1
    56.0
    55.6
        DAS28-3 (CRP) <2.6 Month 36 (N=724,2142,2866)
    52.9
    55.6
    54.9
        DAS28-3 (CRP) <2.6 Month 39 (N=686,2057,2743)
    54.2
    56.9
    56.2
        DAS28-3 (CRP) <2.6 Month 42 (N=653,1893,2546)
    54.2
    56.8
    56.2
        DAS28-3 (CRP) <2.6 Month 45 (N=611,1644,2255)
    56.3
    58.6
    58.0
        DAS28-3 (CRP) <2.6 Month 48 (N=579,1469,2048)
    55.4
    59.3
    58.2
        DAS28-3 (CRP) <2.6 Month 51 (N=487,1348,1835)
    56.1
    57.3
    56.9
        DAS28-3 (CRP) <2.6 Month 54 (N=468,1198,1666)
    52.6
    57.8
    56.3
        DAS28-3 (CRP) <2.6 Month 57 (N=439,1011,1450)
    55.6
    57.7
    57.0
        DAS28-3 (CRP) <2.6 Month 60 (N=407,913,1320)
    55.0
    57.9
    57.0
        DAS28-3 (CRP) <2.6 Month 63 (N=390,824,1214)
    51.0
    58.1
    55.8
        DAS28-3 (CRP) <2.6 Month 66 (N=376,702,1078)
    51.9
    59.3
    56.7
        DAS28-3 (CRP) <2.6 Month 69 (N=355,483,838)
    53.5
    57.8
    56.0
        DAS28-3 (CRP) <2.6 Month 72 (N=337,285,622)
    52.2
    55.4
    53.7
        DAS28-3 (CRP) <2.6 Month 75 (N=304,170,474)
    53.9
    53.5
    53.8
        DAS28-3 (CRP) <2.6 Month 78 (N=292,91,383)
    58.2
    51.6
    56.7
        DAS28-3 (CRP) <2.6 Month 81 (N=285,54,339)
    58.6
    51.9
    57.5
        DAS28-3 (CRP) <2.6 Month 84 (N=269,44,313)
    61.7
    43.2
    59.1
        DAS28-3 (CRP) <2.6 Month 87 (N=264,41,305)
    60.2
    48.8
    58.7
        DAS28-3 (CRP) <2.6 Month 90 (N=240,39,279)
    60.8
    46.2
    58.8
        DAS28-3 (CRP) <2.6 Month 93 (N=196,28,224)
    56.1
    53.6
    55.8
        DAS28-3 (CRP) <2.6 Month 96 (N=144,16,160)
    56.3
    37.5
    54.4
        DAS28-3 (CRP) <2.6 Month 99 (N=64,11,75)
    50.0
    63.6
    52.0
        DAS28-3 (CRP) <2.6 Month 102 (N=13,3,16)
    46.2
    66.7
    50.0
        DAS28-3 (CRP) <2.6 Month 105 (N=12,2,14)
    33.3
    100
    42.9
        DAS28-3 (CRP) <2.6 Month 108 (N=7,1,8)
    42.9
    0
    37.5
        DAS28-3 (CRP) <2.6 Month 111 (N=3,1,4)
    100
    100
    100
        DAS28-3 (CRP) </=3.2 Month 1 (N=1096,3234,4330)
    55.3
    61.9
    60.2
        DAS28-3 (CRP) </=3.2 Month 2 (N=1070,3180,4250)
    60.7
    64.5
    63.6
        DAS28-3 (CRP) </=3.2 Month 3 (N=1057,3190,4247)
    60.6
    66.3
    64.9
        DAS28-3 (CRP) </=3.2 Month 6 (N=1026,3106,4132)
    64.4
    67.1
    66.4
        DAS28-3 (CRP) </=3.2 Month 9 (N=993,3008,4001)
    66.4
    68.3
    67.8
        DAS28-3 (CRP) </=3.2 Month 12 (N=962,2874,3836)
    66.1
    70.0
    69.0
        DAS28-3 (CRP) </=3.2 Month 15 (N=923,2761,3684)
    70.0
    70.0
    70.0
        DAS28-3 (CRP) </=3.2 Month 18 (N=899,2654,3553)
    69.2
    71.7
    71.1
        DAS28-3 (CRP) </=3.2 Month 21 (N=856,2556,3412)
    69.5
    72.5
    71.8
        DAS28-3 (CRP) </=3.2 Month 24 (N=813,2456,3269)
    71.7
    72.5
    72.3
        DAS28-3 (CRP) </=3.2 Month 27 (N=793,2345,3138)
    72.6
    73.0
    72.9
        DAS28-3 (CRP) </=3.2 Month 30 (N=766,2271,3037)
    73.0
    73.8
    73.6
        DAS28-3 (CRP) </=3.2 Month 33 (N=745,2209,2954)
    72.2
    74.5
    73.9
        DAS28-3 (CRP) </=3.2 Month 36 (N=724,2142,2866)
    73.8
    73.4
    73.5
        DAS28-3 (CRP) </=3.2 Month 39 (N=686,2057,2743)
    73.2
    74.6
    74.2
        DAS28-3 (CRP) </=3.2 Month 42 (N=653,1893,2546)
    73.8
    74.7
    74.5
        DAS28-3 (CRP) </=3.2 Month 45 (N=611,1644,2255)
    74.6
    75.2
    75.1
        DAS28-3 (CRP) </=3.2 Month 48 (N=579,1469,2048)
    74.6
    75.0
    74.9
        DAS28-3 (CRP) </=3.2 Month 51 (N=487,1348,1835)
    74.3
    75.1
    74.9
        DAS28-3 (CRP) </=3.2 Month 54 (N=468,1198,1666)
    71.4
    76.4
    75.0
        DAS28-3 (CRP) </=3.2 Month 57 (N=439,1011,1450)
    73.6
    75.2
    74.7
        DAS28-3 (CRP) </=3.2 Month 60 (N=407,913,1320)
    72.5
    77.0
    75.6
        DAS28-3 (CRP) </=3.2 Month 63 (N=390,824,1214)
    72.8
    76.5
    75.3
        DAS28-3 (CRP) </=3.2 Month 66 (N=376,702,1078)
    71.5
    78.1
    75.8
        DAS28-3 (CRP) </=3.2 Month 69 (N=355,483,838)
    69.9
    77.0
    74.0
        DAS28-3 (CRP) </=3.2 Month 72 (N=337,285,622)
    74.8
    73.3
    74.1
        DAS28-3 (CRP) </=3.2 Month 75 (N=304,170,474)
    77.0
    72.9
    75.5
        DAS28-3 (CRP) </=3.2 Month 78 (N=292,91,383)
    74.3
    70.3
    73.4
        DAS28-3 (CRP) </=3.2 Month 81 (N=285,54,339)
    75.8
    68.5
    74.6
        DAS28-3 (CRP) </=3.2 Month 84 (N=269,44,313)
    79.2
    68.2
    77.6
        DAS28-4 (CRP) </=3.2 Month 87 (N=264,41,305)
    81.1
    70.7
    79.7
        DAS28-3 (CRP) </=3.2 Month 90 (N=240,39,279)
    77.1
    74.4
    76.7
        DAS28-3 (CRP) </=3.2 Month 93 (N=196,28,224)
    75.0
    67.9
    74.1
        DAS28-3 (CRP) </=3.2 Month 96 (N=144,16,160)
    77.1
    87.5
    78.1
        DAS28-3 (CRP) </=3.2 Month 99 (N=64,11,75)
    76.6
    81.8
    77.3
        DAS28-3 (CRP) </=3.2 Month 102 (N=13,3,16)
    84.6
    66.7
    81.3
        DAS28-3 (CRP) </=3.2 Month 105 (N=12,2,14)
    50.0
    100
    57.1
        DAS28-3 (CRP) </=3.2 Month 108 (N=7,1,8)
    42.9
    0
    37.5
    No statistical analyses for this end point

    Secondary: Extension Period: Percentage of Subjects With DAS28-4 (ESR) and DAS28-3 (CRP) Less Than (<) 2.6 and Less Than or (<=) 3.2

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    End point title
    		 Extension Period: Percentage of Subjects With DAS28-4 (ESR) and DAS28-3 (CRP) Less Than (<) 2.6 and Less Than or (<=) 3.2
    End point description
    DAS28 is composite score, derived from: 1) tender/painful joints count, out of 28 joints (TJC28), 2) swollen joints count, out of 28 joints (SJC28), 3) blood marker of inflammation (ESR [millimeter per hour] or CRP [milligram per liter]). DAS28-4 also include score of GH. GH is general health or subjects’ global assessment of disease activity on 100 mm VAS (score: 0 mm=very well to 100 mm=extremely bad, higher scores=worse health condition). DAS28-3(CRP) = (0.56*sqrt[TJC28] + 0.28*sqrt[SJC28] + 0.36*ln[CRP+1])*1.10 + 1.15) and DAS28-4(ESR) = (0.56*sqrt[TJC28] + 0.28*sqrt[SJC28] + 0.70*ln[ESR] + 0.014*GH), where sqrt=square root, ln=natural logarithm. DAS28-4 ESR and DAS28-3 CRP:score range is 0 (none) to 9.4 (extreme disease activity), higher score = more disease activity. Score of <=3.2: low disease activity; score of <2.6: disease remission. FAS analysis set. "n"=subjects evaluable for specified categories.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1 at the entry of Extension period); Month 3, 6, 9 and 12 of Extension Period
    End point values
    		 Extension Period: Tofacitinib 5 mg
    Number of subjects analysed
    48
    Units: Percentage of subjects
    number (not applicable)
        DAS28-4 (ESR) <2.6: Baseline (n =48)
    12.5
        DAS28-4 (ESR) <2.6: Month 3 (n =44)
    40.9
        DAS28-4 (ESR) <2.6: Month 6 (n =35)
    45.7
        DAS28-4 (ESR) <2.6: Month 9 (n =15)
    46.7
        DAS28-4 (ESR) <2.6: Month 12 (n =2)
    50.0
        DAS28-4 (ESR) <=3.2: Baseline (n =48)
    29.2
        DAS28-4 (ESR) <=3.2: Month 3 (n =44)
    68.2
        DAS28-4 (ESR) <=3.2: Month 6 (n =35)
    68.6
        DAS28-4 (ESR) <=3.2: Month 9 (n =15)
    66.7
        DAS28-4 (ESR) <=3.2: Month 12 (n =2)
    50.0
        DAS28-3 (CRP) <2.6: Baseline (n =47)
    27.7
        DAS28-3 (CRP) <2.6: Month 3 (n =42)
    61.9
        DAS28-3 (CRP) <2.6: Month 6 (n =34)
    67.6
        DAS28-3 (CRP) <2.6: Month 9 (n =15)
    80.0
        DAS28-3 (CRP) <2.6: Month 12 (n =1)
    0.0
        DAS28-3 (CRP) <=3.2: Baseline (n =47)
    53.2
        DAS28-3 (CRP) <=3.2: Month 3 (n =42)
    85.7
        DAS28-3 (CRP) <=3.2: Month 6 (n =34)
    85.3
        DAS28-3 (CRP) <=3.2: Month 9 (n =15)
    80.0
        DAS28-3 (CRP) <=3.2: Month 12 (n =1)
    0.0
    No statistical analyses for this end point

    Secondary: Initial Period: Health Assessment Questionnaire – Disability Index (HAQ-DI) Score

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    End point title
    		 Initial Period: Health Assessment Questionnaire – Disability Index (HAQ-DI) Score
    End point description
    Change from baseline by visit. The stated number of participants analyzed was the total number of participants in each group. The actual number of participants analyzed on each occasion varied, and is provided for each visit presented.
    End point type
    Secondary
    End point timeframe
    Every visit until last observation
    End point values
    		 Initial Period: Tofacitinib 5 milligram(mg) twice daily (BID) Initial Period: Tofacitinib 10 mg BID All Tofacitinib
    Number of subjects analysed
    1123
    1123
    4481
    Units: Score
    arithmetic mean (standard deviation)
        Month 1 (N=1098,3264,4362)
    -0.57 ± 0.62
    -0.61 ± 0.63
    -0.60 ± 0.63
        Month 2 (N=1067,3213,4280)
    -0.58 ± 0.62
    -0.65 ± 0.65
    -0.63 ± 0.65
        Month 3 (N=1057,3196,4253)
    -0.58 ± 0.63
    -0.66 ± 0.65
    -0.64 ± 0.65
        Month 6 (N=1029,3105,4134)
    -0.58 ± 0.65
    -0.65 ± 0.66
    -0.64 ± 0.66
        Month 9 (N=990,2992,3982)
    -0.58 ± 0.64
    -0.66 ± 0.66
    -0.64 ± 0.66
        Month 12 (N=960,2866,3826)
    -0.58 ± 0.65
    -0.66 ± 0.67
    -0.64 ± 0.67
        Month 15 (N=926,2756,3682)
    -0.61 ± 0.65
    -0.68 ± 0.68
    -0.66 ± 0.67
        Month 18 (N=898,2646,3544)
    -0.60 ± 0.65
    -0.68 ± 0.67
    -0.66 ± 0.67
        Month 21 (N=849,2542,3391)
    -0.60 ± 0.67
    -0.69 ± 0.68
    -0.67 ± 0.68
        Month 24 (N=815,2443,3258)
    -0.60 ± 0.65
    -0.69 ± 0.68
    -0.67 ± 0.67
        Month 27 (N=789,2341,3130)
    -0.62 ± 0.65
    -0.69 ± 0.68
    -0.67 ± 0.67
        Month 30 (N=757,2258,3015)
    -0.58 ± 0.66
    -0.68 ± 0.69
    -0.66 ± 0.68
        Month 33 (N=741,2194,2935)
    -0.60 ± 0.66
    -0.67 ± 0.69
    -0.66 ± 0.68
        Month 36 (N=720,2136,2856)
    -0.63 ± 0.66
    -0.67 ± 0.68
    -0.66 ± 0.67
        Month 39 (N=683,2053,2736)
    -0.59 ± 0.67
    -0.68 ± 0.69
    -0.66 ± 0.69
        Month 42 (N=649,1884,2533)
    -0.59 ± 0.67
    -0.66 ± 0.68
    -0.65 ± 0.68
        Month 45 (N=609,1636,2245)
    -0.59 ± 0.69
    -0.64 ± 0.69
    -0.63 ± 0.69
        Month 48 (N=575,1468,2043)
    -0.58 ± 0.69
    -0.64 ± 0.68
    -0.62 ± 0.68
        Month 51 (N=482,1332,1814)
    -0.59 ± 0.67
    -0.63 ± 0.66
    -0.62 ± 0.67
        Month 54 (N=463,1191,1654)
    -0.57 ± 0.68
    -0.65 ± 0.67
    -0.63 ± 0.67
        Month 57 (N=434,1011,1445)
    -0.57 ± 0.69
    -0.66 ± 0.68
    -0.63 ± 0.68
        Month 60 (N=405,916,1321)
    -0.59 ± 0.68
    -0.66 ± 0.69
    -0.64 ± 0.69
        Month 63 (N=392,828,1220)
    -0.57 ± 0.68
    -0.68 ± 0.70
    -0.64 ± 0.69
        Month 66 (N=375,702,1077)
    -0.54 ± 0.70
    -0.67 ± 0.69
    -0.63 ± 0.70
        Month 69 (N=353,484,837)
    -0.55 ± 0.70
    -0.66 ± 0.71
    -0.61 ± 0.71
        Month 72 (N=335,286,621)
    -0.57 ± 0.71
    -0.62 ± 0.73
    -0.59 ± 0.72
        Month 75 (N=303,171,474)
    -0.57 ± 0.72
    -0.58 ± 0.73
    -0.57 ± 0.72
        Month 78 (N=289,91,380)
    -0.54 ± 0.73
    -0.61 ± 0.78
    -0.56 ± 0.74
        Month 81 (N=282,54,336)
    -0.55 ± 0.73
    -0.64 ± 0.68
    -0.56 ± 0.72
        Month 84 (N=269,44,313)
    -0.53 ± 0.73
    -0.56 ± 0.68
    -0.53 ± 0.72
        Month 87 (N=262,41,303)
    -0.53 ± 0.70
    -0.53 ± 0.60
    -0.53 ± 0.69
        Month 90 (240,39,279)
    -0.52 ± 0.72
    -0.54 ± 0.61
    -0.52 ± 0.70
        Month 93 (194,28,222)
    -0.52 ± 0.75
    -0.50 ± 0.60
    -0.52 ± 0.73
        Month 96 (N=143,16,159)
    -0.54 ± 0.77
    -0.48 ± 0.58
    -0.53 ± 0.75
        Month 99 (N=64,11,75)
    -0.53 ± 0.80
    -0.44 ± 0.51
    -0.52 ± 0.76
        Month 102 (N=22,3,25)
    -0.61 ± 0.82
    -0.29 ± 0.85
    -0.58 ± 0.81
        Month 105 (N=15,3,18)
    -0.65 ± 0.91
    -0.50 ± 0.99
    -0.63 ± 0.90
        Month 108 (N=8,1,9)
    -0.89 ± 0.97
    0.13 ± 0
    -0.78 ± 0.97
        Month 111 (N=3,1,4)
    -1.29 ± 1.34
    0.25 ± 0
    -0.91 ± 1.34
        Month 114 (N=1,0,1)
    -0.13 ± 0
    0 ± 0
    -0.13 ± 0
    No statistical analyses for this end point

    Secondary: Extension Period: Change From Baseline in Health Assessment Questionnaire - Disability Index (HAQ-DI) Score at Month 3, 6, 9 and 12

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    End point title
    		 Extension Period: Change From Baseline in Health Assessment Questionnaire - Disability Index (HAQ-DI) Score at Month 3, 6, 9 and 12
    End point description
    HAQ-DI assesses the degree of difficulty a subject has experienced during the past week in 8 categories of daily living activities: dressing/grooming;arising;eating;walking;reach;grip;hygiene and other activities. Each activity category consisted of 2-3 questionnaire. Each questionnaire was scored on a 4-point scale from 0to3: 0=no difficulty;1=some difficulty;2=much difficulty;3=unable to do. Any activity that required the use of an assistive device was adjusted to a score of 2 to represent a more limited functional status. Overall score was the sum of total scores divided by the number of questionnaire answered. Total possible HAQ-DI score range: 0 and 3, where higher scores indicate more difficulty while performing daily living activities. Full analysis set included all subjects who enrolled for extension period and received at least 1 dose of open label study medication. Here, "n" signifies number of subjects who were evaluable at the specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline (Month 0 at the entry of Initial Period); Month 3, 6, 9, and 12 of Extension Period
    End point values
    		 Extension Period: Tofacitinib 5 mg
    Number of subjects analysed
    48
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n= 48)
    1.35 ± 0.63
        Change at Month 3 (n= 46)
    -0.48 ± 0.58
        Change at Month 6 (n= 35)
    -0.55 ± 0.65
        Change at Month 9 (n= 15)
    -0.58 ± 0.70
        Change at Month 12 (n= 2)
    -1.50 ± 1.94
    No statistical analyses for this end point

    Secondary: Initial Period: Short-Form-36 Health Survey (SF-36) score

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    End point title
    		 Initial Period: Short-Form-36 Health Survey (SF-36) score
    End point description
    Change from Baseline for Physical Component and Mental Component Scores by visit. The stated number of participants analyzed was the total number of participants in each group. The actual number of participants analyzed on each occasion varied, and is provided for each visit presented.
    End point type
    Secondary
    End point timeframe
    Every visit until last observation
    End point values
    		 Initial Period: Tofacitinib 5 milligram(mg) twice daily (BID) Initial Period: Tofacitinib 10 mg BID All Tofacitinib
    Number of subjects analysed
    1123
    3358
    4481
    Units: Score
    arithmetic mean (standard deviation)
        Physical Component Month 3 (N=983,2693,3676)
    7.90 ± 8.70
    8.85 ± 8.92
    8.60 ± 8.87
        Physical Component Month 6 (N=961,2629,3590)
    8.10 ± 8.94
    9.02 ± 9.11
    8.77 ± 9.07
        Physical Component Month 9 (N=534,2499,3033)
    8.60 ± 9.07
    8.80 ± 9.20
    8.77 ± 9.18
        Physical Component Month 12 (N=903,2449,3352)
    8.44 ± 8.53
    8.78 ± 9.26
    8.69 ± 9.07
        Physical Component Month 15 (N=733,2324,3057)
    8.43 ± 8.88
    8.98 ± 9.05
    8.85 ± 9.01
        Physical Component Month 18 (N=855,2188,3043)
    8.14 ± 8.89
    8.99 ± 9.18
    8.75 ± 9.11
        Physical Component Month 21 (N=767,2005,2772)
    8.00 ± 8.70
    8.85 ± 8.96
    8.62 ± 8.90
        Physical Component Month 24(N=797,2102,2899)
    8.28 ± 8.73
    9.00 ± 9.30
    8.80 ± 9.15
        Physical Component Month 27(N=739,1663,2402)
    8.41 ± 8.84
    8.64 ± 9.16
    8.57 ± 9.06
        Physical Component Month 30 (N=708,1566,2274)
    7.78 ± 8.81
    8.56 ± 9.06
    8.32 ± 8.99
        Physical Component Month 33 (N=682,1444,2126)
    8.17 ± 8.87
    8.39 ± 9.31
    8.32 ± 9.17
        Physical Component Month 36 (N=676,1530,2206)
    8.31 ± 8.97
    8.43 ± 9.22
    8.40 ± 9.14
        Physical Component Month 39 (N=609,1176,1785)
    8.05 ± 9.26
    8.13 ± 9.14
    8.10 ± 9.18
        Physical Component Month 42 (N=573,923,1496)
    7.81 ± 9.32
    8.07 ± 9.13
    7.97 ± 9.21
        Physical Component Month 45 (N=540,652,1192)
    8.40 ± 9.87
    8.33 ± 9.40
    8.36 ± 9.61
        Physical Component Month 48 (N=537,1044,1581)
    8.12 ± 9.56
    8.27 ± 9.23
    8.22 ± 9.34
        Physical Component Month 51 (N=417,304,721)
    7.88 ± 9.69
    8.55 ± 9.70
    8.16 ± 9.69
        Physical Component Month 54 (N=396,175,571)
    7.72 ± 9.41
    8.82 ± 9.47
    8.06 ± 9.43
        Physical Component Month 57 (N=372,105,477)
    7.57 ± 9.72
    8.12 ± 9.69
    7.69 ± 9.71
        Physical Component Month 60 (N=371,259,630)
    7.94 ± 9.74
    9.29 ± 9.43
    8.49 ± 9.63
        Physical Component Month 63 (N=345,68,413)
    7.73 ± 9.76
    7.90 ± 8.98
    7.76 ± 9.63
        Physical Component Month 66 (N=327,56,383)
    7.92 ± 9.41
    7.58 ± 7.88
    7.87 ± 9.20
        Physical Component Month 69 (N=267,40,307)
    7.68 ± 9.32
    9.12 ± 7.06
    7.87 ± 9.06
        Physical Component Month 72 (N=316,54,370)
    7.90 ± 9.93
    8.70 ± 10.24
    8.02 ± 9.97
        Physical Component Month 75 (N=84,12,96)
    9.03 ± 10.96
    5.75 ± 9.05
    8.62 ± 10.75
        Physical Component Month 78 (N=55,7,62)
    10.22 ± 11.10
    7.39 ± 7.09
    9.90 ± 10.72
        Physical Component Month 81 (N=49,4,53)
    10.51 ± 10.17
    7.90 ± 13.05
    10.31 ± 10.28
        Physical Component Month 84 (N=93,11,104)
    8.93 ± 11.56
    7.14 ± 8.01
    8.74 ± 11.22
        Physical Component Month 87 (N=26,2,28)
    11.92 ± 10.49
    15.23 ± 3.64
    12.16 ± 10.15
        Physical Component Month 90 (N=12,1,13)
    13.50 ± 10.98
    16.50 ± 0
    13.73 ± 10.55
        Physical Component Month 93 (N=1,0,1)
    26.71 ± 0
    0 ± 0
    26.71 ± 0
        Physical Component Month 96 (N=5,0,5)
    4.61 ± 9.75
    0 ± 0
    4.61 ± 9.75
        Physical Component Month 99 (N=1,0,1)
    -8.26 ± 0
    0 ± 0
    -8.26 ± 0
        Mental Component Month 3 (N=983,2693,3676)
    4.37 ± 10.88
    4.91 ± 11.18
    4.77 ± 11.10
        Mental Component Month 6 (N=961,2629,3590)
    3.94 ± 10.85
    4.81 ± 11.12
    4.58 ± 11.06
        Mental Component Month 9 (N=534,2499,3033)
    4.65 ± 10.78
    5.04 ± 11.17
    4.97 ± 11.10
        Mental Component Month 12 (N=903,2449,3352)
    3.77 ± 11.03
    4.81 ± 11.43
    4.53 ± 11.33
        Mental Component Month 15 (N=733,2324,3057)
    4.14 ± 11.21
    4.79 ± 11.52
    4.63 ± 11.45
        Mental Component Month 18 (N=855,2188,3043)
    4.12 ± 11.11
    4.87 ± 11.41
    4.66 ± 11.33
        Mental Component Month 21 (N=767,2005,2772)
    4.21 ± 11.08
    4.87 ± 11.22
    4.68 ± 11.18
        Mental Component Month 24 (N=797,2102,2899)
    4.12 ± 11.06
    5.08 ± 11.32
    4.82 ± 11.26
        Mental Component Month 27 (N=739,1663,2402)
    3.67 ± 10.53
    4.91 ± 11.28
    4.53 ± 11.07
        Mental Component Month 30 (N=708,1566,2274)
    3.58 ± 11.14
    4.68 ± 11.71
    4.34 ± 11.54
        Mental Component Month 33 (N=682,1444,2126)
    3.91 ± 10.65
    4.82 ± 11.74
    4.53 ± 11.40
        Mental Component Month 36 (N=676,1530,2206)
    3.83 ± 10.94
    4.81 ± 11.60
    4.51 ± 11.40
        Mental Component Month 39 (N=609,1176,1785)
    3.60 ± 11.02
    4.59 ± 11.75
    4.25 ± 11.51
        Mental Component Month 42 (N=573,923,1496)
    3.23 ± 11.40
    4.55 ± 11.63
    4.04 ± 11.56
        Mental Component Month 45 (N=540,652,1192)
    3.16 ± 11.63
    4.40 ± 11.64
    3.83 ± 11.56
        Mental Component Month 48 (N=537,1044,1581)
    3.48 ± 11.71
    4.73 ± 11.83
    4.31 ± 11.80
        Mental Component Month 51 (N=417,304,721)
    3.61 ± 12.12
    4.83 ± 11.82
    4.13 ± 12.00
        Mental Component Month 54 (N=396,175,571)
    3.44 ± 11.77
    6.49 ± 12.67
    4.38 ± 12.12
        Mental Component Month 57 (N=372,105,477)
    3.24 ± 12.24
    5.10 ± 11.74
    3.65 ± 12.15
        Mental Component Month 60 (N=371,259,630)
    3.05 ± 12.06
    5.18 ± 12.22
    3.93 ± 12.16
        Mental Component Month 63 (N=345,68,413)
    3.04 ± 11.61
    4.22 ± 10.32
    3.23 ± 11.40
        Mental Component Month 66 (N=327,56,383)
    2.96 ± 11.32
    3.47 ± 8.33
    3.04 ± 10.93
        Mental Component Month 69 (N=267,40,307)
    3.90 ± 12.35
    4.90 ± 9.84
    4.03 ± 12.04
        Mental Component Month 72 (N=316,54,370)
    3.78 ± 11.48
    5.32 ± 12.80
    4.00 ± 11.68
        Mental Component Month 75 (N=84,12,96)
    5.04 ± 12.22
    1.52 ± 11.38
    4.60 ± 12.12
        Mental Component Month 78 (N=55,7,62)
    4.12 ± 13.37
    1.05 ± 13.28
    3.77 ± 13.29
        Mental Component Month 81 (N=49,4,53)
    6.09 ± 10.40
    2.60 ± 14.75
    5.83 ± 10.64
        Mental Component Month 84 (N=93,11,104)
    5.73 ± 13.07
    -2.36 ± 11.63
    4.87 ± 13.11
        Mental Component Month 87 (N=26,2,28)
    7.52 ± 13.03
    16.93 ± 2.66
    8.19 ± 12.79
        Mental Component Month 90 (N=12,1,13)
    4.61 ± 11.75
    18.75 ± 0
    5.65 ± 11.86
        Mental Component Month 93 (N=1,0,1)
    14.03 ± 0
    0 ± 0
    14.03 ± 0
        Mental Component Month 96 (N=5,0,5)
    7.58 ± 9.73
    0 ± 0
    7.58 ± 9.73
        Mental Component Month 99 (N=1,0,1)
    22.28 ± 0
    0 ± 0
    22.28 ± 0
    No statistical analyses for this end point

    Secondary: Initial Period: FACIT Fatigue Scale, EuroQol EQ 5D, Work Limitations Questionnaire, and RA Healthcare Resource Utilization Questionnaire (RA-HCRU)

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    End point title
    		 Initial Period: FACIT Fatigue Scale, EuroQol EQ 5D, Work Limitations Questionnaire, and RA Healthcare Resource Utilization Questionnaire (RA-HCRU)
    End point description
    Change from Baseline Scores for FACIT Fatigue Scale, EuroQol EQ 5D, Work Limitations (WL) Physical Demands, and RA Healthcare Resource Utilization Work Performance in Past 3 Months on Days Bothered by RA. The stated number of participants analyzed was the total number of participants in each group. The actual number of participants analyzed on each occasion varied, and is provided for each visit presented.
    End point type
    Secondary
    End point timeframe
    Every visit until last observation
    End point values
    		 Initial Period: Tofacitinib 5 milligram(mg) twice daily (BID) Initial Period: Tofacitinib 10 mg BID All Tofacitinib
    Number of subjects analysed
    1123
    3358
    4481
    Units: Score
    arithmetic mean (standard deviation)
        FACIT Month 6 (N=370,2544,2914)
    6.29 ± 8.98
    7.33 ± 10.57
    7.19 ± 10.39
        FACIT Month 12 (N=582,2396,2978)
    5.98 ± 9.74
    7.33 ± 10.56
    7.06 ± 10.41
        FACIT Month 18 (N=729,2168,2897)
    6.14 ± 10.06
    7.40 ± 10.65
    7.09 ± 10.51
        FACIT Month 24 (N=704,2053,2757)
    5.90 ± 9.76
    7.42 ± 10.56
    7.03 ± 10.38
        FACIT Month 30 (N=618,1525,2143)
    5.36 ± 10.08
    7.00 ± 10.91
    6.52 ± 10.70
        FACIT Month 36 (N=589,1497,2086)
    5.95 ± 9.87
    6.87 ± 10.94
    6.61 ± 10.66
        FACIT Month 42 (N=491,898,1389)
    5.35 ± 10.36
    6.83 ± 10.86
    6.31 ± 10.71
        FACIT Month 48 (N=464,1025,1489)
    6.01 ± 10.33
    6.88 ± 10.95
    6.61 ± 10.77
        FACIT Month 54 (N=330,169,499)
    6.16 ± 10.49
    8.51 ± 11.58
    6.96 ± 10.92
        FACIT Month 60 (N=318,256,574)
    5.96 ± 10.69
    8.88 ± 11.65
    7.27 ± 11.21
        FACIT Month 66 (N=277,55,332)
    5.64 ± 10.93
    6.67 ± 10.58
    5.81 ± 10.86
        FACIT Month 72 (N=272,51,323)
    5.73 ± 11.10
    8.63 ± 10.71
    6.18 ± 11.07
        FACIT Month 78 (N=32,7,39)
    12.06 ± 11.15
    0.71 ± 14.84
    10.03 ± 12.48
        FACIT Month 84 (N=74,11,85)
    9.13 ± 12.88
    2.91 ± 12.36
    8.32 ± 12.91
        FACIT Month 90 (N=6,1,7)
    18.67 ± 9.14
    10.00 ± 0
    17.43 ± 8.96
        FACIT Month 96 (N=3,0,3)
    6.00 ± 2.65
    0 ± 0
    6.00 ± 2.65
        EuroQol Month 6 (N=323,2021,2344)
    0.20 ± 0.31
    0.22 ± 0.32
    0.22 ± 0.32
        EuroQol Month 12 (N=538,1897,2435)
    0.22 ± 0.30
    0.22 ± 0.33
    0.22 ± 0.32
        EuroQol Month 18 (N=684,1748,2432)
    0.20 ± 0.32
    0.23 ± 0.33
    0.22 ± 0.33
        EuroQol Month 24 (N=664,1619,2283)
    0.20 ± 0.31
    0.23 ± 0.33
    0.22 ± 0.32
        EuroQol Month 30 (N=616,1456,2072)
    0.19 ± 0.31
    0.22 ± 0.33
    0.21 ± 0.32
        EuroQol Month 36 (N=582,1397,1979)
    0.21 ± 0.30
    0.23 ± 0.33
    0.22 ± 0.32
        EuroQol Month 42 (N=483,874,1357)
    0.18 ± 0.31
    0.24 ± 0.33
    0.22 ± 0.32
        EuroQol Month 48 (N=464,1010,1474)
    0.19 ± 0.31
    0.23 ± 0.33
    0.22 ± 0.32
        EuroQol Month 54 (N=330,167,497)
    0.22 ± 0.32
    0.32 ± 0.36
    0.22 ± 0.32
        EuroQol Month 60 (N=317,255,572)
    0.20 ± 0.33
    0.27 ± 0.35
    0.23 ± 0.34
        EuroQol Month 66 (N=276,53,329)
    0.21 ± 0.33
    0.24 ± 0.34
    0.21 ± 0.33
        EuroQol Month 72 (N=273,50,323)
    0.22 ± 0.32
    0.28 ± 0.35
    0.23 ± 0.32
        EuroQol Month 78 (N=32,7,39)
    0.36 ± 0.37
    0.10 ± 0.51
    0.31 ± 0.40
        EuroQol Month 84 (N=75,11,86)
    0.27 ± 0.35
    0.21 ± 0.43
    0.27 ± 0.36
        EuroQol Month 90 (N=6,1,7)
    0.47 ± 0.32
    0.84 ± 0
    0.52 ± 0.32
        EuroQol Month 96 (N=3,0,3)
    0.09 ± 0.04
    0 ± 0
    0.09 ± 0.04
        WL: Physical Demands Month 6 (N=109,900,1009)
    -5.34 ± 39.81
    -3.67 ± 38.17
    -3.85 ± 38.33
        WL: Physical Demands Month 12 (N=96,808,904)
    -5.31 ± 37.81
    -4.02 ± 39.25
    -4.16 ± 39.08
        WL: Physical Demands Month 18 (N=83,706,789)
    -7.97 ± 35.46
    -2.29 ± 37.48
    -2.89 ± 37.29
        WL: Physical Demands Month 24 (N=63,544,607)
    -2.62 ± 36.05
    -4.46 ± 37.54
    -4.27 ± 37.36
        WL: Physical Demands Month 30 (N=51,444,495)
    -10.12 ± 37.17
    -3.75 ± 37.67
    -4.41 ± 37.63
        WL: Physical Demands Month 36 (N=35,350,385)
    -7.31 ± 34.69
    -3.95 ± 39.58
    -4.25 ± 39.14
        WL: Physical Demands Month 42 (N=24,245,270)
    -13.51 ± 33.91
    -4.81 ± 38.98
    -5.58 ± 38.58
        WL: Physical Demands Month 48 (N=19,126,145)
    -25.86 ± 34.47
    0.73 ± 38.68
    -2.76 ± 39.09
        WL: Physical Demands Month 54 (N=2,20,22)
    -39.17 ± 62.46
    -13.27 ± 45.69
    -15.63 ± 46.18
        WL: Physical Demands Month 60 (N=0,3,3)
    0 ± 0
    -27.78 ± 34.94
    -27.78 ± 34.94
        WL: Physical Demands Month 66 (N=0,1,1)
    0 ± 0
    8.33 ± 0
    8.33 ± 0
        RA-HCRU Month 6 (N=189,1419,1608)
    -2.01 ± 6.20
    -2.08 ± 4.15
    -2.07 ± 4.44
        RA-HCRU Month 12 (N=180,1329,1509)
    -2.41 ± 6.43
    -2.26 ± 3.76
    -2.28 ± 4.17
        RA-HCRU Month 18 (N=161,1162,1323)
    -1.88 ± 2.93
    -2.24 ± 3.90
    -2.19 ± 3.80
        RA-HCRU Month 24 (N=162,1101,1263)
    -2.03 ± 3.18
    -2.22 ± 3.26
    -2.19 ± 3.25
        RA-HCRU Month 30 (N=126,785,911)
    -1.67 ± 3.02
    -2.16 ± 4.17
    -2.10 ± 4.04
        RA-HCRU Month 36 (N=106,759,865)
    -2.38 ± 2.91
    -2.32 ± 4.14
    -2.33 ± 4.01
        RA-HCRU Month 42 (N=68,455,523)
    -1.68 ± 2.84
    -2.18 ± 4.70
    -2.11 ± 4.51
        RA-HCRU Month 48 (N=66,527,593)
    -1.88 ± 3.24
    -2.15 ± 4.67
    -2.12 ± 4.53
        RA-HCRU Month 54 (N=3,39,42)
    -2.00 ± 1.00
    -2.59 ± 3.42
    -2.55 ± 3.30
        RA-HCRU Month 60 (N=4,94,98)
    -2.00 ± 3.56
    -2.88 ± 2.85
    -2.85 ± 2.87
        RA-HCRU Month 66 (N=0,0,0)
    0 ± 0
    0 ± 0
    0 ± 0
        RA-HCRU Month 72 (N=0,4,4)
    0 ± 0
    -1.25 ± 6.70
    -1.25 ± 6.70
        RA-HCRU Month 78 (0,0,0)
    0 ± 0
    0 ± 0
    0 ± 0
        RA-HCRU Month 84 (0,0,0)
    0 ± 0
    0 ± 0
    0 ± 0
        RA-HCRU Month 90 (0,0,0)
    0 ± 0
    0 ± 0
    0 ± 0
        RA-HCRU Month 96 (0,0,0)
    0 ± 0
    0 ± 0
    0 ± 0
    No statistical analyses for this end point

    Secondary: Initial Period: Preservation of joint structure in participants who had baseline radiographs obtained in their qualifying index study

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    End point title
    		 Initial Period: Preservation of joint structure in participants who had baseline radiographs obtained in their qualifying index study
    End point description
    Modified Total Sharp Score per visit. Baseline score was the last available assessment from the index study. The stated number of participants analyzed was the total number of participants in each group. The actual number of participants analyzed on each occasion varied, and is provided for each visit presented. TSS=Total Sharp Score
    End point type
    Secondary
    End point timeframe
    Every 6 months until last observation
    End point values
    		 Initial Period: Tofacitinib 5 milligram(mg) twice daily (BID) Initial Period: Tofacitinib 10 mg BID All Tofacitinib
    Number of subjects analysed
    1123
    3358
    4481
    Units: Score
    arithmetic mean (standard deviation)
        Modified TSS Baseline (N=95,1061,1156)
    20.55 ± 33.37
    24.13 ± 43.57
    23.84 ± 42.83
        Modified TSS Month 6 (N=82,937,1019)
    22.58 ± 35.10
    25.12 ± 44.42
    24.91 ± 43.74
        Modified TSS Month 12 (N=85,918,1003)
    21.26 ± 33.75
    24.73 ± 44.08
    24.44 ± 43.30
        Modified TSS Month 24 (N=77,801,878)
    22.07 ± 35.85
    24.85 ± 43.21
    24.61 ± 42.61
        Modified TSS Month 36 (N=35,379,414)
    25.88 ± 37.74
    28.22 ± 44.95
    28.02 ± 44.35
    No statistical analyses for this end point

    Secondary: Vaccine sub-study. Percent achieving a satisfactory humoral response to the pneumococcal vaccine as defined by ≥ 2-fold increase in antibody concentrations

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    End point title
    		 Vaccine sub-study. Percent achieving a satisfactory humoral response to the pneumococcal vaccine as defined by ≥ 2-fold increase in antibody concentrations
    End point description
    Number (%) of participants achieving a satisfactory humoral response to the pneumococcal vaccine as defined by ≥2-fold increase in antibody concentration from vaccine sub-study visit 2 (vaccination baseline) in ≥6 of 12 anti-pneumococcal antigens (serotypes 1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F) The number of participants was the number with a determinate antibody titer to the given vaccine antigen within the population. 95% CI is based on Clopper-Pearson exact method for response rate. Evaluable immunogenicity population.
    End point type
    Secondary
    End point timeframe
    From vaccine sub-study visit 2 (baseline) to sub-study visit 4
    End point values
    		 Tofacitinib 10 mg BID Continuous Visit 3 Tofacitinib 10 mg BID Interrupted Visit 3 Tofacitinib 10 mg BID Continuous Visit 4 Tofacitinib 10 mg BID Interrupted Visit 4
    Number of subjects analysed
    91
    91
    92
    91
    Units: Percent of participants
        number (confidence interval 95%)
    18.7 (11.3 to 28.2)
    38.5 (28.4 to 49.2)
    75.0 (64.9 to 83.4)
    84.6 (75.5 to 91.3)
    No statistical analyses for this end point

    Secondary: Vaccine sub-study. Percent achieving a satisfactory humoral response to the seasonal influenza vaccine as defined by ≥ 4-fold increase in antibody titers

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    End point title
    		 Vaccine sub-study. Percent achieving a satisfactory humoral response to the seasonal influenza vaccine as defined by ≥ 4-fold increase in antibody titers
    End point description
    Number of participants achieving a satisfactory humoral response to the seasonal influenza vaccine as defined by ≥4-fold increase in antibody titers from visit 2 (vaccination baseline) in ≥2 of 3 influenza antigens (HAI B, HAI H1N1, and HAI H3N2) The number of participants was the number with a determinate antibody titer to the given vaccine antigen within the population. 95% CI is based on Clopper-Pearson exact method for response rate. Evaluable immunogenicity population.
    End point type
    Secondary
    End point timeframe
    From vaccine sub-study visit 2 (baseline) to sub-study visit 4
    End point values
    		 Tofacitinib 10 mg BID Continuous Visit 3 Tofacitinib 10 mg BID Interrupted Visit 3 Tofacitinib 10 mg BID Continuous Visit 4 Tofacitinib 10 mg BID Interrupted Visit 4
    Number of subjects analysed
    91
    91
    92
    91
    Units: Percent of participants
        number (confidence interval 95%)
    31.9 (22.5 to 42.5)
    53.8 (43.1 to 64.4)
    66.3 (55.7 to 75.8)
    63.7 (53.0 to 73.6)
    No statistical analyses for this end point

    Secondary: Vaccine sub-study. Percentage of participants achieving protective antibody titers to the seasonal influenza vaccine as measured by a hemagglutination inhibition (HI) assay titer of ≥ 1:40 in ≥ 2 of 3 influenza antigens at vaccine sub-study visit 3 and 4

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    End point title
    		 Vaccine sub-study. Percentage of participants achieving protective antibody titers to the seasonal influenza vaccine as measured by a hemagglutination inhibition (HI) assay titer of ≥ 1:40 in ≥ 2 of 3 influenza antigens at vaccine sub-study visit 3 and 4
    End point description
    Number (%) of participants achieving protective antibody titers to the seasonal influenza vaccine as measured by an HAI assay titer of ≥1:40 in ≥2 of 3 influenza antigens measured at vaccine sub-study visits 3 and 4. The number of participants was the number with a determinate antibody titer to the given vaccine antigen within the population. 95% CI is based on Clopper-Pearson exact method for response rate. Evaluable immunogenicity population.
    End point type
    Secondary
    End point timeframe
    From vaccine sub-study visit 2 (baseline) to sub-study visit 4
    End point values
    		 Tofacitinib 10 mg BID Continuous Visit 3 Tofacitinib 10 mg BID Interrupted Visit 3 Tofacitinib 10 mg BID Continuous Visit 4 Tofacitinib 10 mg BID Interrupted Visit 4
    Number of subjects analysed
    91
    91
    92
    91
    Units: Percent of participants
        number (confidence interval 95%)
    56.0 (45.2 to 66.4)
    69.2 (58.7 to 78.5)
    75.0 (64.9 to 83.4)
    82.4 (73.0 to 89.6)
    No statistical analyses for this end point

    Secondary: Vaccine sub-study. Percentage of participants who respond to each of the 12 pneumococcal antigens as defined by ≥ 2-fold increase in antibody concentrations from vaccine sub-study visit 2 (vaccination baseline) measured at vaccine sub-study visit 4

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    End point title
    		 Vaccine sub-study. Percentage of participants who respond to each of the 12 pneumococcal antigens as defined by ≥ 2-fold increase in antibody concentrations from vaccine sub-study visit 2 (vaccination baseline) measured at vaccine sub-study visit 4
    End point description
    Number (%) of participants achieving a satisfactory humoral response to the pneumococcal vaccine as defined by ≥2-fold increase in antibody concentration from vaccine sub-study visit 2 (vaccination baseline) in ≥6 of 12 anti-pneumococcal antigens (serotypes 1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F) The number of participants was the number with a determinate antibody titer to the given vaccine antigen within the population. 95% CI is based on Clopper-Pearson exact method for response rate. Evaluable immunogenicity population.
    End point type
    Secondary
    End point timeframe
    From vaccine sub-study visit 2 (baseline) to sub-study visit 4
    End point values
    		 Tofacitinib 10 mg BID Continuous Tofacitinib 10 mg BID Interrupted
    Number of subjects analysed
    92
    91
    Units: Percent of participants
    number (confidence interval 95%)
        Serotype 1
    75 (64.9 to 83.4)
    82.4 (73.0 to 89.6)
        Serotype 3
    53.3 (42.6 to 63.7)
    71.4 (61.0 to 80.4)
        Serotype 4
    76.1 (66.1 to 84.4)
    76.9 (66.9 to 85.1)
        Serotype 5
    42.4 (32.1 to 53.1)
    49.5 (38.8 to 60.1)
        Serotype 6B
    48.9 (38.3 to 59.6)
    56 (45.2 to 66.4)
        Serotype 7F
    71.7 (61.4 to 80.6)
    78 (68.1 to 86.0)
        Serotype 9V
    64.1 (53.5 to 73.9)
    78 (68.1 to 86.0)
        Serotype 14
    71.7 (61.4 to 80.6)
    75.8 (65.7 to 84.2)
        Serotype 18C
    73.9 (63.7 to 82.5)
    83.5 (74.3 to 90.5)
        Serotype 19A
    54.3 (43.6 to 64.8)
    56.0 (45.2 to 66.4)
        Serotype 19F
    60.9 (50.1 to 70.9)
    71.4 (61.0 to 80.4)
        Serotype 23F
    53.3 (42.6 to 63.7)
    70.3 (59.8 to 79.5)
    No statistical analyses for this end point

    Secondary: Vaccine sub-study. Percentage of participants who respond to each of the 3 influenza antigens as defined by ≥ 4-fold increase in antibody titers from vaccine sub-study visit 2 (vaccination baseline) measured at vaccine sub-study visit 4

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    End point title
    		 Vaccine sub-study. Percentage of participants who respond to each of the 3 influenza antigens as defined by ≥ 4-fold increase in antibody titers from vaccine sub-study visit 2 (vaccination baseline) measured at vaccine sub-study visit 4
    End point description
    Number (%) of participants achieving a satisfactory humoral response to the seasonal influenza vaccine defined as ≥4-fold increase in antibody titers from visit 2 (vaccination baseline) in ≥2 of 3 influenza antigens (HAI B, HAI H1N1, and HAI H3N2). The number of participants was the number with a determinate antibody titer to the given vaccine antigen within the population. 95% CI is based on Clopper-Pearson exact method for response rate. Evaluable immunogenicity population.
    End point type
    Secondary
    End point timeframe
    From vaccine sub-study visit 2 (baseline) to sub-study visit 4
    End point values
    		 Tofacitinib 10 mg BID Continuous Visit 4 Tofacitinib 10 mg BID Interrupted Visit 4
    Number of subjects analysed
    92
    91
    Units: Percent of participants
    number (confidence interval 95%)
        Antigen B
    45.7 (35.2 to 56.4)
    51.6 (40.9 to 62.3)
        Antigen H1N1
    71.7 (61.4 to 80.6)
    63.7 (53.0 to 73.6)
        Antigen H3N2
    66.3 (55.7 to 75.8)
    74.7 (64.5 to 83.3)
    No statistical analyses for this end point

    Secondary: Vaccine sub-study. Fold increase of anti-pneumococcal antibody levels to each of the 12 pneumococcal antigens above vaccination baseline values (vaccine sub-study visit 2) at vaccine sub-study visit 4

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    End point title
    		 Vaccine sub-study. Fold increase of anti-pneumococcal antibody levels to each of the 12 pneumococcal antigens above vaccination baseline values (vaccine sub-study visit 2) at vaccine sub-study visit 4
    End point description
    Geometric Mean Fold Increase From Baseline of Pneumococcal Antigens Measured at Visit 4. n was the number of participants with valid and determinate assay results for the specified serotype at the given visit. The stated number of participants analyzed was the total number of participants. The actual number of participants analyzed for some serotypes varied, and is provided where it differed from the total number of participants. Confidence Intervals (CIs) were back transformations of a CI based on the Student t distribution for the mean logarithm of the concentrations. Evaluable immunogenicity population.
    End point type
    Secondary
    End point timeframe
    From vaccine sub-study visit 2 (baseline) to sub-study visit 4
    End point values
    		 Tofacitinib 10 mg BID Interrupted Tofacitinib 10 mg Continuous
    Number of subjects analysed
    91
    92
    Units: Antibody Level
    geometric mean (confidence interval 95%)
        Serotype 1 (N=89,86)
    9.26 (6.89 to 12.44)
    5.87 (4.57 to 7.55)
        Serotype 3 (N=91,89)
    4.20 (3.31 to 5.32)
    2.34 (1.97 to 2.79)
        Serotype 4 (N=91,89)
    6.29 (4.65 to 8.51)
    5.32 (4.22 to 6.71)
        Serotype 5
    2.53 (2.12 to 3.02)
    2.02 (1.75 to 2.34)
        Serotype 6B
    3.06 (2.53 to 3.69)
    2.32 (1.98 to 2.73)
        Serotype 7F (N=92,89)
    6.41 (4.97 to 8.28)
    4.69 (3.73 to 5.90)
        Serotype 9V (N=92,90)
    4.39 (3.62 to 5.34)
    3.17 (2.70 to 3.72)
        Serotype 14
    7.34 (5.50 to 9.79)
    5.23 (4.00 to 6.86)
        Serotype 18C
    7.41 (5.77 to 9.53)
    3.97 (3.28 to 4.79)
        Serotype 19A
    2.93 (2.46 to 3.50)
    2.33 (1.99 to 2.72)
        Serotype 19F (N=90,90)
    4.60 (3.64 to 5.80)
    2.97 (2.44 to 3.62)
        Serotype 23F (N=92,90)
    4.54 (3.58 to 5.75)
    2.74 (2.27 to 3.32)
    No statistical analyses for this end point

    Secondary: Vaccine sub-study. Fold increase of anti-influenza antibody levels to each of the 3 influenza antigens above vaccination baseline values (vaccine sub-study visit 2) at vaccine sub-study visit 4

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    End point title
    		 Vaccine sub-study. Fold increase of anti-influenza antibody levels to each of the 3 influenza antigens above vaccination baseline values (vaccine sub-study visit 2) at vaccine sub-study visit 4
    End point description
    Geometric Mean Fold Increase From Baseline of Influenza Antigens Measured at Visit 4. n was the number of participants with valid and determinate assay results for the specified HAI strain at the given visit. Confidence Intervals (CIs) were back transformations of a CI based on the Student t distribution for the mean logarithm of the titers. Evaluable immunogenicity population.
    End point type
    Secondary
    End point timeframe
    From vaccine sub-study visit 2 (baseline) to sub-study visit 4
    End point values
    		 Tofacitinib 10 mg BID Continuous Tofacitinib 10 mg BID Interrupted
    Number of subjects analysed
    92
    91
    Units: Antibody titer
    geometric mean (confidence interval 95%)
        Antigen B
    3.33 (2.57 to 4.32)
    4.17 (3.25 to 5.34)
        Antigen H1N1
    7.94 (5.96 to 10.58)
    6.71 (4.94 to 9.12)
        Antigen H3N2
    7.80 (5.58 to 10.91)
    8.51 (6.45 to 11.21)
    No statistical analyses for this end point

    Secondary: Vaccine sub-study. Concentrations of anti-pneumococcal antibodies at vaccine sub-study visit 3 and 4

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    End point title
    		 Vaccine sub-study. Concentrations of anti-pneumococcal antibodies at vaccine sub-study visit 3 and 4
    End point description
    Mean pneumococcal concentrations (ug/mL) at vaccine baseline (visit 2) and post-vaccination visits (visits 3 and 4) by serotype. The stated number of participants analyzed was the total number of participants in each group. The actual number of participants analyzed for each serotype varied, and is provided for each individually. ug/mL=micrograms per milliliter Evaluable immunogenicity population.
    End point type
    Secondary
    End point timeframe
    From vaccine sub-study visit 2 (baseline) to sub-study visit 4
    End point values
    		 Tofacitinib 10 mg BID Interrupted Visit 3 Tofacitinib 10 mg BID Continuous Visit 4 Tofacitinib 10 mg BID Interrupted Visit 4 Tofacitinib 10 mg BID Continuous Visit 2 Tofacitinib 10 mg BID Interrupted Visit 2 Tofacitinib 10 mg BID Continuous Visit 3
    Number of subjects analysed
    91
    92
    91
    92
    91
    92
    Units: Concentration (ug/mL)
    geometric mean (confidence interval 95%)
        Serotype 9V (N=92,90,91,91,92,91)
    2.26 (1.78 to 2.87)
    4.16 (3.29 to 5.27)
    4.80 (3.75 to 6.16)
    1.31 (1.08 to 1.60)
    1.12 (0.89 to 1.42)
    2.00 (1.64 to 2.44)
        Serotype 14 (N=92,91,91,91,92,91)
    5.03 (3.77 to 6.71)
    12.09 (8.76 to 16.69)
    15.01 (10.80 to 20.88)
    2.31 (1.79 to 2.98)
    2.05 (1.59 to 2.63)
    4.02 (3.04 to 5.32)
        Serotype 18C (N=92,91,91,91,92,91)
    2.41 (1.82 to 3.18)
    4.27 (3.34 to 5.47)
    6.61 (5.01 to 8.74)
    1.08 (0.86 to 1.36)
    0.89 (0.70 to 1.14)
    1.81 (1.43 to 2.29)
        Serotype 19F (N=90,90,90,91,92,91)
    2.17 (1.61 to 2.91)
    3.52 (2.60 to 4.76)
    5.47 (3.98 to 7.52)
    1.17 (0.92 to 1.50)
    1.18 (0.89 to 1.58)
    1.61 (1.25 to 2.08)
        Serotype 23F (92,90,90,91,92,91)
    2.24 (1.75 to 2.88)
    3.44 (2.66 to 4.44)
    5.27 (3.96 to 7.02)
    1.25 (1.01 to 1.56)
    1.16 (0.93 to 1.44)
    1.80 (1.44 to 2.25)
    No statistical analyses for this end point

    Secondary: Vaccine sub-study. Titers of anti-influenza antibodies at vaccine sub-study visit 3 and 4

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    End point title
    		 Vaccine sub-study. Titers of anti-influenza antibodies at vaccine sub-study visit 3 and 4
    End point description
    Mean influenza antibody titers at visits 3 and 4. Evaluable immunogenicity population.
    End point type
    Secondary
    End point timeframe
    From vaccine sub-study visit 2 (baseline) to sub-study visit 4
    End point values
    		 Tofacitinib 10 mg BID Continuous Visit 3 Tofacitinib 10 mg BID Interrupted Visit 3 Tofacitinib 10 mg BID Continuous Visit 4 Tofacitinib 10 mg BID Interrupted Visit 4 Tofacitinib 10 mg BID Continuous Visit 2 Tofacitinib 10 mg BID Interrupted Visit 2
    Number of subjects analysed
    91
    91
    92
    91
    92
    91
    Units: Antibody Titer
    geometric mean (confidence interval 95%)
        HAI B
    23.29 (17.92 to 30.27)
    37.45 (28.17 to 49.78)
    38.06 (28.71 to 50.47)
    45.19 (35.01 to 58.34)
    11.43 (9.38 to 13.91)
    10.85 (8.90 to 13.22)
        HAI H1N1
    52.75 (37.97 to 73.28)
    105.2 (70.76 to 156.5)
    120.2 (89.83 to 160.8)
    136.0 (97.67 to 189.4)
    15.14 (11.67 to 19.64)
    20.26 (14.86 to 27.62)
        HAI H3N2
    55.07 (38.19 to 79.43)
    83.10 (57.38 to 120.4)
    141.8 (102.9 to 195.4)
    147.2 (107.8 to 201.0)
    18.18 (13.53 to 24.44)
    17.30 (12.98 to 23.07)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    114 months for Initial Period; 13 months for Extension Period
    Adverse event reporting additional description
    The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as non serious in another subject, or one subject may have experienced both a serious and non serious event during the study.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Tofa 5mg BID; ppts with avg total daily dose across study <15
    Reporting group description
    		 Participants with non-zero average total daily dose across study <15 were assigned to 5 mg BID. avg=average; BID=twice daily; mg=milligram; ppts=participants; tofa=tofacitinib

    Reporting group title
    Tofa 10mg BID; ppts with avg total daily dose across study ≥15
    Reporting group description
    		 Participants with non-zero average total daily dose across study ≥15 were assigned to 10 mg BID. avg=average; BID=twice daily; mg=milligram; ppts=participants; tofa=tofacitinib

    Reporting group title
    All Tofacitinib
    Reporting group description
    		 All participants treated with tofacitinib from 5 mg BID and 10 mg BID groups

    Reporting group title
    Extension Period: Tofacitinib 5 mg
    Reporting group description
    		 Subjects who completed 2 years of lymphocyte assessment in Initial period and enrolled for extension period received Tofacitinib (CP-690,550) 5 mg orally, twice daily up to 12 months.

    Serious adverse events
    		 Tofa 5mg BID; ppts with avg total daily dose across study <15 Tofa 10mg BID; ppts with avg total daily dose across study ≥15 All Tofacitinib Extension Period: Tofacitinib 5 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    346 / 1123 (30.81%)
    997 / 3358 (29.69%)
    1343 / 4481 (29.97%)
    5 / 48 (10.42%)
         number of deaths (all causes)
    39
    46
    85
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    5q minus syndrome
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute promyelocytic leukaemia
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma of appendix
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma of the cervix
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adrenal adenoma
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    B-cell lymphoma
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    B-cell small lymphocytic lymphoma
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    3 / 1123 (0.27%)
    12 / 3358 (0.36%)
    15 / 4481 (0.33%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    6 / 12
    7 / 15
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Benign salivary gland neoplasm
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Benign tracheal neoplasm
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder neoplasm
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder transitional cell carcinoma
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    4 / 1123 (0.36%)
    12 / 3358 (0.36%)
    16 / 4481 (0.36%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    6 / 12
    7 / 16
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer metastatic
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Bronchial carcinoma
         subjects affected / exposed
    1 / 1123 (0.09%)
    3 / 3358 (0.09%)
    4 / 4481 (0.09%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 3
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervix carcinoma
         subjects affected / exposed
    1 / 1123 (0.09%)
    1 / 3358 (0.03%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervix carcinoma stage 0
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholesteatoma
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Choroid plexus papilloma
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colon adenoma
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    2 / 1123 (0.18%)
    1 / 3358 (0.03%)
    3 / 4481 (0.07%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Colon cancer metastatic
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colorectal adenocarcinoma
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diffuse large B-cell lymphoma
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endometrial adenocarcinoma
         subjects affected / exposed
    1 / 1123 (0.09%)
    2 / 3358 (0.06%)
    3 / 4481 (0.07%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endometrial cancer
         subjects affected / exposed
    1 / 1123 (0.09%)
    1 / 3358 (0.03%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endometrial cancer stage I
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Extranodal marginal zone B-cell lymphoma (MALT type)
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fibroadenoma of breast
         subjects affected / exposed
    2 / 1123 (0.18%)
    1 / 3358 (0.03%)
    3 / 4481 (0.07%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fibroma
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gallbladder cancer
         subjects affected / exposed
    1 / 1123 (0.09%)
    1 / 3358 (0.03%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Gastric cancer
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Glioblastoma multiforme
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    Hepatic cancer
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    Hodgkin’s disease
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intraductal proliferative breast lesion
         subjects affected / exposed
    0 / 1123 (0.00%)
    3 / 3358 (0.09%)
    3 / 4481 (0.07%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    1 / 1123 (0.09%)
    2 / 3358 (0.06%)
    3 / 4481 (0.07%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Kaposi’s sarcoma
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laryngeal cancer
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laryngeal squamous cell carcinoma
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leiomyosarcoma
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lipoma
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liposarcoma
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 1123 (0.00%)
    4 / 3358 (0.12%)
    4 / 4481 (0.09%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 4
    3 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    Lung adenocarcinoma metastatic
         subjects affected / exposed
    0 / 1123 (0.00%)
    3 / 3358 (0.09%)
    3 / 4481 (0.07%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    2 / 2
    2 / 2
    0 / 0
    Lung cancer metastatic
         subjects affected / exposed
    0 / 1123 (0.00%)
    3 / 3358 (0.09%)
    3 / 4481 (0.07%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    2 / 3
    2 / 3
    0 / 0
    Lung neoplasm
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    2 / 1123 (0.18%)
    3 / 3358 (0.09%)
    5 / 4481 (0.11%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    1 / 3
    1 / 5
    0 / 0
    Lymphoma
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    3 / 1123 (0.27%)
    8 / 3358 (0.24%)
    11 / 4481 (0.25%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    7 / 8
    9 / 11
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma in situ
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant peritoneal neoplasm
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mantle cell lymphoma
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Marginal zone lymphoma stage II
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Medullary thyroid cancer
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningioma
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    0 / 0
    Metastases to liver
         subjects affected / exposed
    1 / 1123 (0.09%)
    1 / 3358 (0.03%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Metastases to lung
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    Metastases to lymph nodes
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    Metastasis
         subjects affected / exposed
    1 / 1123 (0.09%)
    1 / 3358 (0.03%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastatic malignant melanoma
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mucoepidermoid carcinoma
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasm
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasm malignant
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nodular melanoma
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-Hodgkin’s lymphoma
         subjects affected / exposed
    2 / 1123 (0.18%)
    2 / 3358 (0.06%)
    4 / 4481 (0.09%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-small cell lung cancer
         subjects affected / exposed
    1 / 1123 (0.09%)
    1 / 3358 (0.03%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    Non-small cell lung cancer metastatic
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    Oesophageal carcinoma
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian adenoma
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian cancer
         subjects affected / exposed
    1 / 1123 (0.09%)
    1 / 3358 (0.03%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian cancer metastatic
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian germ cell teratoma
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Papillary thyroid cancer
         subjects affected / exposed
    1 / 1123 (0.09%)
    2 / 3358 (0.06%)
    3 / 4481 (0.07%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Parathyroid tumour
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 1123 (0.00%)
    7 / 3358 (0.21%)
    7 / 4481 (0.16%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 7
    2 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostatic adenoma
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal cancer
         subjects affected / exposed
    2 / 1123 (0.18%)
    0 / 3358 (0.00%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    2 / 1123 (0.18%)
    1 / 3358 (0.03%)
    3 / 4481 (0.07%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sebaceous carcinoma
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin cancer
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small cell lung cancer
         subjects affected / exposed
    2 / 1123 (0.18%)
    0 / 3358 (0.00%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    Small cell lung cancer metastatic
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    Small intestine carcinoma
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spindle cell sarcoma
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    2 / 1123 (0.18%)
    10 / 3358 (0.30%)
    12 / 4481 (0.27%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    6 / 10
    7 / 12
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    2 / 1123 (0.18%)
    2 / 3358 (0.06%)
    4 / 4481 (0.09%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 2
    3 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    3 / 1123 (0.27%)
    4 / 3358 (0.12%)
    7 / 4481 (0.16%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 5
    3 / 8
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of the cervix
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of the tongue
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of the vulva
         subjects affected / exposed
    1 / 1123 (0.09%)
    1 / 3358 (0.03%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Synovial sarcoma
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    T-cell lymphoma
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thyroid adenoma
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thyroid cancer
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thyroid neoplasm
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour necrosis
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ureteral neoplasm
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    7 / 1123 (0.62%)
    14 / 3358 (0.42%)
    21 / 4481 (0.47%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 7
    1 / 14
    1 / 21
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vulval cancer stage 0
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma 1
    Additional description: MedDRA v20.1
         subjects affected / exposed
    0 / 1123 (0.00%)
    0 / 3358 (0.00%)
    0 / 4481 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Accelerated hypertension
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic aneurysm
         subjects affected / exposed
    2 / 1123 (0.18%)
    3 / 3358 (0.09%)
    5 / 4481 (0.11%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic dissection
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic stenosis
         subjects affected / exposed
    1 / 1123 (0.09%)
    1 / 3358 (0.03%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arteriosclerosis
         subjects affected / exposed
    1 / 1123 (0.09%)
    1 / 3358 (0.03%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    6 / 1123 (0.53%)
    9 / 3358 (0.27%)
    15 / 4481 (0.33%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    3 / 7
    3 / 10
    6 / 17
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Extremity necrosis
         subjects affected / exposed
    1 / 1123 (0.09%)
    1 / 3358 (0.03%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    3 / 1123 (0.27%)
    7 / 3358 (0.21%)
    10 / 4481 (0.22%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    2 / 8
    2 / 12
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    3 / 1123 (0.27%)
    8 / 3358 (0.24%)
    11 / 4481 (0.25%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    3 / 5
    4 / 10
    7 / 15
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery occlusion
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral venous disease
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Thromboangiitis obliterans
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    2 / 1123 (0.18%)
    1 / 3358 (0.03%)
    3 / 4481 (0.07%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Varicose vein
         subjects affected / exposed
    0 / 1123 (0.00%)
    5 / 3358 (0.15%)
    5 / 4481 (0.11%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Arthrodesis
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip arthroplasty
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Knee arthroplasty
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    1 / 1123 (0.09%)
    2 / 3358 (0.06%)
    3 / 4481 (0.07%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foetal death
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Unintended pregnancy
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Abscess sterile
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    2 / 1123 (0.18%)
    1 / 3358 (0.03%)
    3 / 4481 (0.07%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    2 / 1123 (0.18%)
    1 / 3358 (0.03%)
    3 / 4481 (0.07%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    5 / 1123 (0.45%)
    12 / 3358 (0.36%)
    17 / 4481 (0.38%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 12
    0 / 17
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    3 / 1123 (0.27%)
    1 / 3358 (0.03%)
    4 / 4481 (0.09%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    3 / 3
    1 / 1
    4 / 4
    0 / 0
    Drug ineffective
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fibrosis
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hernia
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    2 / 1123 (0.18%)
    2 / 3358 (0.06%)
    4 / 4481 (0.09%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    1 / 2
    2 / 2
    3 / 4
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 1123 (0.18%)
    1 / 3358 (0.03%)
    3 / 4481 (0.07%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral swelling
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    5 / 1123 (0.45%)
    5 / 3358 (0.15%)
    10 / 4481 (0.22%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    3 / 5
    2 / 5
    5 / 10
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Allergy to arthropod bite
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Allergy to arthropod sting
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaphylactic reaction
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaphylactic shock
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Social circumstances
    Activities of daily living impaired
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Physical abuse
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Adenomyosis
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 1123 (0.00%)
    4 / 3358 (0.12%)
    4 / 4481 (0.09%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast enlargement
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast hyperplasia
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast mass
         subjects affected / exposed
    1 / 1123 (0.09%)
    1 / 3358 (0.03%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervical dysplasia
         subjects affected / exposed
    0 / 1123 (0.00%)
    3 / 3358 (0.09%)
    3 / 4481 (0.07%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystocele
         subjects affected / exposed
    1 / 1123 (0.09%)
    1 / 3358 (0.03%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysfunctional uterine bleeding
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endometrial dysplasia
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fallopian tube cyst
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic ovarian cyst
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Menometrorrhagia
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metrorrhagia
         subjects affected / exposed
    1 / 1123 (0.09%)
    2 / 3358 (0.06%)
    3 / 4481 (0.07%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    1 / 1123 (0.09%)
    8 / 3358 (0.24%)
    9 / 4481 (0.20%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 8
    1 / 9
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postmenopausal haemorrhage
         subjects affected / exposed
    1 / 1123 (0.09%)
    2 / 3358 (0.06%)
    3 / 4481 (0.07%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostatomegaly
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectocele
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine polyp
         subjects affected / exposed
    1 / 1123 (0.09%)
    1 / 3358 (0.03%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine prolapse
         subjects affected / exposed
    3 / 1123 (0.27%)
    1 / 3358 (0.03%)
    4 / 4481 (0.09%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterovaginal prolapse
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vaginal prolapse
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute interstitial pneumonitis
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 1123 (0.09%)
    1 / 3358 (0.03%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 1123 (0.09%)
    3 / 3358 (0.09%)
    4 / 4481 (0.09%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    2 / 2
    2 / 2
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    2 / 1123 (0.18%)
    2 / 3358 (0.06%)
    4 / 4481 (0.09%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Adenoidal hypertrophy
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Alveolitis allergic
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchiectasis
         subjects affected / exposed
    0 / 1123 (0.00%)
    3 / 3358 (0.09%)
    3 / 4481 (0.07%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    5 / 1123 (0.45%)
    6 / 3358 (0.18%)
    11 / 4481 (0.25%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    2 / 6
    2 / 11
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
    Cough
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 1123 (0.18%)
    4 / 3358 (0.12%)
    6 / 4481 (0.13%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 4
    2 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 1123 (0.09%)
    1 / 3358 (0.03%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydrothorax
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 1123 (0.09%)
    3 / 3358 (0.09%)
    4 / 4481 (0.09%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laryngeal oedema
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract inflammation
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung infiltration
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Organising pneumonia
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 1123 (0.00%)
    3 / 3358 (0.09%)
    3 / 4481 (0.07%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 1123 (0.00%)
    3 / 3358 (0.09%)
    3 / 4481 (0.07%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    3 / 1123 (0.27%)
    16 / 3358 (0.48%)
    19 / 4481 (0.42%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    4 / 16
    4 / 20
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    1 / 1123 (0.09%)
    1 / 3358 (0.03%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary mass
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiration abnormal
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory acidosis
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    5 / 1123 (0.45%)
    3 / 3358 (0.09%)
    8 / 4481 (0.18%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    2 / 5
    1 / 3
    3 / 8
    0 / 0
         deaths causally related to treatment / all
    1 / 3
    0 / 1
    1 / 4
    0 / 0
    Rhinitis allergic
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sleep apnoea syndrome
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Affective disorder
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Alcoholism
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anxiety disorder
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    1 / 1123 (0.09%)
    1 / 3358 (0.03%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 1123 (0.09%)
    1 / 3358 (0.03%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 1123 (0.00%)
    3 / 3358 (0.09%)
    3 / 4481 (0.07%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug abuse
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post-traumatic stress disorder
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychotic disorder due to a general medical condition
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Restlessness
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stress
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depression 1
    Additional description: MedDRA v20.1
         subjects affected / exposed
    0 / 1123 (0.00%)
    0 / 3358 (0.00%)
    0 / 4481 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device electrical impedance issue
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device loosening
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    2 / 1123 (0.18%)
    2 / 3358 (0.06%)
    4 / 4481 (0.09%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Biliary colic
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholangitis acute
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Cholangitis chronic
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    2 / 1123 (0.18%)
    1 / 3358 (0.03%)
    3 / 4481 (0.07%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 1123 (0.09%)
    4 / 3358 (0.12%)
    5 / 4481 (0.11%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    1 / 1123 (0.09%)
    3 / 3358 (0.09%)
    4 / 4481 (0.09%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    10 / 1123 (0.89%)
    13 / 3358 (0.39%)
    23 / 4481 (0.51%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 10
    1 / 14
    2 / 24
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gallbladder disorder
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gallbladder non-functioning
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic cirrhosis
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic congestion
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    2 / 1123 (0.18%)
    0 / 3358 (0.00%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Hepatic steatosis
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    1 / 1123 (0.09%)
    1 / 3358 (0.03%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertransaminasaemia
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sphincter of Oddi dysfunction
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Airway peak pressure increased
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    B-lymphocyte count increased
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac murmur
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Electrocardiogram T wave abnormal
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Electrocardiogram T wave inversion
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Electrocardiogram abnormal
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematocrit decreased
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 1123 (0.00%)
    4 / 3358 (0.12%)
    4 / 4481 (0.09%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Human papilloma virus test positive
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver function test increased
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metamyelocyte count increased
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myelocyte count increased
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Red blood cell sedimentation rate increased
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Troponin I increased
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Weight increased
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acetabulum fracture
         subjects affected / exposed
    0 / 1123 (0.00%)
    3 / 3358 (0.09%)
    3 / 4481 (0.07%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anastomotic ulcer
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    2 / 1123 (0.18%)
    7 / 3358 (0.21%)
    9 / 4481 (0.20%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 7
    0 / 9
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Burns second degree
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervical vertebral fracture
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dislocation of vertebra
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Exposure via father
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    7 / 1123 (0.62%)
    9 / 3358 (0.27%)
    16 / 4481 (0.36%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 9
    0 / 16
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    4 / 1123 (0.36%)
    3 / 3358 (0.09%)
    7 / 4481 (0.16%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
    0 / 9
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    2 / 1123 (0.18%)
    12 / 3358 (0.36%)
    14 / 4481 (0.31%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 12
    0 / 14
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foetal exposure during pregnancy
         subjects affected / exposed
    1 / 1123 (0.09%)
    2 / 3358 (0.06%)
    3 / 4481 (0.07%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    1 / 1123 (0.09%)
    4 / 3358 (0.12%)
    5 / 4481 (0.11%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Forearm fracture
         subjects affected / exposed
    1 / 1123 (0.09%)
    2 / 3358 (0.06%)
    3 / 4481 (0.07%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fractured ischium
         subjects affected / exposed
    1 / 1123 (0.09%)
    1 / 3358 (0.03%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gun shot wound
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    6 / 1123 (0.53%)
    2 / 3358 (0.06%)
    8 / 4481 (0.18%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
    0 / 8
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    2 / 1123 (0.18%)
    11 / 3358 (0.33%)
    13 / 4481 (0.29%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 12
    0 / 14
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Incorrect dose administered
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    1 / 1123 (0.09%)
    4 / 3358 (0.12%)
    5 / 4481 (0.11%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation postoperative
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint injury
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    1 / 1123 (0.09%)
    3 / 3358 (0.09%)
    4 / 4481 (0.09%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ligament rupture
         subjects affected / exposed
    1 / 1123 (0.09%)
    1 / 3358 (0.03%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 1123 (0.09%)
    3 / 3358 (0.09%)
    4 / 4481 (0.09%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    2 / 1123 (0.18%)
    1 / 3358 (0.03%)
    3 / 4481 (0.07%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Maternal exposure timing unspecified
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    1 / 1123 (0.09%)
    3 / 3358 (0.09%)
    4 / 4481 (0.09%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscle injury
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Patella fracture
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Periprosthetic fracture
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Perirenal haematoma
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 1123 (0.00%)
    3 / 3358 (0.09%)
    3 / 4481 (0.07%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural oedema
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative hernia
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative ileus
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    4 / 1123 (0.36%)
    3 / 3358 (0.09%)
    7 / 4481 (0.16%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
    0 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 1123 (0.00%)
    5 / 3358 (0.15%)
    5 / 4481 (0.11%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 1123 (0.00%)
    5 / 3358 (0.15%)
    5 / 4481 (0.11%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    Scapula fracture
         subjects affected / exposed
    1 / 1123 (0.09%)
    1 / 3358 (0.03%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skull fracture
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Soft tissue injury
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal column injury
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 1123 (0.00%)
    4 / 3358 (0.12%)
    4 / 4481 (0.09%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sternal fracture
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    2 / 1123 (0.18%)
    10 / 3358 (0.30%)
    12 / 4481 (0.27%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 10
    0 / 12
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thermal burn
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 1123 (0.00%)
    7 / 3358 (0.21%)
    7 / 4481 (0.16%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 8
    0 / 8
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Traumatic liver injury
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Twiddler’s syndrome
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    1 / 1123 (0.09%)
    3 / 3358 (0.09%)
    4 / 4481 (0.09%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 1123 (0.09%)
    4 / 3358 (0.12%)
    5 / 4481 (0.11%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture 1
    Additional description: MedDRA v20.1
         subjects affected / exposed
    0 / 1123 (0.00%)
    0 / 3358 (0.00%)
    0 / 4481 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Atrial septal defect
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Developmental hip dysplasia
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydrocele
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tourette’s disorder
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    4 / 1123 (0.36%)
    4 / 3358 (0.12%)
    8 / 4481 (0.18%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 4
    1 / 8
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    3 / 1123 (0.27%)
    5 / 3358 (0.15%)
    8 / 4481 (0.18%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 5
    2 / 8
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic valve incompetence
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic valve stenosis
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    2 / 1123 (0.18%)
    1 / 3358 (0.03%)
    3 / 4481 (0.07%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    6 / 1123 (0.53%)
    14 / 3358 (0.42%)
    20 / 4481 (0.45%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    4 / 15
    4 / 21
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    2 / 1123 (0.18%)
    1 / 3358 (0.03%)
    3 / 4481 (0.07%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    1 / 1123 (0.09%)
    1 / 3358 (0.03%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 1123 (0.09%)
    1 / 3358 (0.03%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bundle branch block right
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 1123 (0.09%)
    1 / 3358 (0.03%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
    Cardiac failure
         subjects affected / exposed
    3 / 1123 (0.27%)
    5 / 3358 (0.15%)
    8 / 4481 (0.18%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 5
    1 / 9
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    4 / 1123 (0.36%)
    3 / 3358 (0.09%)
    7 / 4481 (0.16%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
    0 / 9
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    3 / 1123 (0.27%)
    1 / 3358 (0.03%)
    4 / 4481 (0.09%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Cardiovascular insufficiency
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    4 / 1123 (0.36%)
    11 / 3358 (0.33%)
    15 / 4481 (0.33%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 11
    1 / 15
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    2 / 1123 (0.18%)
    0 / 3358 (0.00%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery thrombosis
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive heart disease
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    Long QT syndrome
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mitral valve stenosis
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    8 / 1123 (0.71%)
    13 / 3358 (0.39%)
    21 / 4481 (0.47%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 8
    3 / 13
    4 / 21
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    4 / 1123 (0.36%)
    3 / 3358 (0.09%)
    7 / 4481 (0.16%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 3
    2 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    2 / 1123 (0.18%)
    1 / 3358 (0.03%)
    3 / 4481 (0.07%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 1123 (0.09%)
    1 / 3358 (0.03%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stress cardiomyopathy
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 1123 (0.09%)
    2 / 3358 (0.06%)
    3 / 4481 (0.07%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tricuspid valve incompetence
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular arrhythmia
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wolff-Parkinson-White syndrome
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain injury
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Brain stem infarction
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    Carotid artery aneurysm
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Central nervous system lesion
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebellar ataxia
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral arteriosclerosis
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral haematoma
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 1123 (0.09%)
    4 / 3358 (0.12%)
    5 / 4481 (0.11%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 1123 (0.18%)
    6 / 3358 (0.18%)
    8 / 4481 (0.18%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 6
    1 / 8
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Cervical cord compression
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervical myelopathy
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervical radiculopathy
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 1123 (0.09%)
    2 / 3358 (0.06%)
    3 / 4481 (0.07%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Facial nerve disorder
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Facial paralysis
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    1 / 1123 (0.09%)
    2 / 3358 (0.06%)
    3 / 4481 (0.07%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    Headache
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemianopia
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intensive care unit acquired weakness
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intracranial aneurysm
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intraventricular haemorrhage
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 1123 (0.00%)
    3 / 3358 (0.09%)
    3 / 4481 (0.07%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar radiculopathy
         subjects affected / exposed
    1 / 1123 (0.09%)
    1 / 3358 (0.03%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbosacral radiculopathy
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolic encephalopathy
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Monoplegia
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple sclerosis
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myasthenia gravis
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myelopathy
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nerve root compression
         subjects affected / exposed
    1 / 1123 (0.09%)
    2 / 3358 (0.06%)
    3 / 4481 (0.07%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuritis
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pachymeningitis
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Parkinson’s disease
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post herpetic neuralgia
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Posterior reversible encephalopathy syndrome
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 1123 (0.09%)
    1 / 3358 (0.03%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Quadriparesis
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radicular syndrome
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radiculopathy
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ruptured cerebral aneurysm
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 1123 (0.09%)
    9 / 3358 (0.27%)
    10 / 4481 (0.22%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 9
    0 / 10
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sensory loss
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Serotonin syndrome
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small fibre neuropathy
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal claudication
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal subdural haematoma
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spondylitic myelopathy
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 1123 (0.09%)
    5 / 3358 (0.15%)
    6 / 4481 (0.13%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tension headache
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    2 / 1123 (0.18%)
    11 / 3358 (0.33%)
    13 / 4481 (0.29%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    3 / 12
    3 / 14
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vasculitis cerebral
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 1123 (0.36%)
    10 / 3358 (0.30%)
    14 / 4481 (0.31%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    4 / 10
    5 / 14
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic anaemia
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 1123 (0.09%)
    3 / 3358 (0.09%)
    4 / 4481 (0.09%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 3
    3 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mastocytosis
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    2 / 1123 (0.18%)
    0 / 3358 (0.00%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paratracheal lymphadenopathy
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Splenic infarction
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Acute vestibular syndrome
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vertigo
         subjects affected / exposed
    1 / 1123 (0.09%)
    1 / 3358 (0.03%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vertigo positional
         subjects affected / exposed
    1 / 1123 (0.09%)
    3 / 3358 (0.09%)
    4 / 4481 (0.09%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vestibular disorder
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    2 / 1123 (0.18%)
    8 / 3358 (0.24%)
    10 / 4481 (0.22%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 8
    1 / 11
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Glaucoma
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Keratitis interstitial
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Necrotising retinitis
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Optic disc drusen
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retinal artery occlusion
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ulcerative keratitis
         subjects affected / exposed
    1 / 1123 (0.09%)
    1 / 3358 (0.03%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uveitis
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Visual acuity reduced
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal incarcerated hernia
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 1123 (0.00%)
    3 / 3358 (0.09%)
    3 / 4481 (0.07%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    2 / 1123 (0.18%)
    0 / 3358 (0.00%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 1123 (0.09%)
    1 / 3358 (0.03%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic gastritis
         subjects affected / exposed
    1 / 1123 (0.09%)
    1 / 3358 (0.03%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 1123 (0.09%)
    5 / 3358 (0.15%)
    6 / 4481 (0.13%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 5
    3 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    1 / 1123 (0.09%)
    1 / 3358 (0.03%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Crohn’s disease
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 1123 (0.18%)
    8 / 3358 (0.24%)
    10 / 4481 (0.22%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 8
    3 / 10
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    3 / 1123 (0.27%)
    5 / 3358 (0.15%)
    8 / 4481 (0.18%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    3 / 5
    4 / 8
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulum
         subjects affected / exposed
    2 / 1123 (0.18%)
    0 / 3358 (0.00%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal polyp
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterocele
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fistula of small intestine
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Food poisoning
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric disorder
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric perforation
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric polyps
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 1123 (0.09%)
    1 / 3358 (0.03%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    3 / 1123 (0.27%)
    4 / 3358 (0.12%)
    7 / 4481 (0.16%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
    0 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorder
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 1123 (0.18%)
    0 / 3358 (0.00%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal inflammation
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal perforation
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 1123 (0.18%)
    0 / 3358 (0.00%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Haematochezia
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic erosive gastritis
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hiatus hernia
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 1123 (0.09%)
    2 / 3358 (0.06%)
    3 / 4481 (0.07%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestinal stenosis
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mesenteric vein thrombosis
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal spasm
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 1123 (0.09%)
    4 / 3358 (0.12%)
    5 / 4481 (0.11%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 5
    2 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    4 / 1123 (0.36%)
    4 / 3358 (0.12%)
    8 / 4481 (0.18%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 4
    2 / 8
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
    Peptic ulcer haemorrhage
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 1123 (0.09%)
    1 / 3358 (0.03%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal prolapse
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retroperitoneal haematoma
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 1123 (0.00%)
    3 / 3358 (0.09%)
    3 / 4481 (0.07%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tooth disorder
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tooth impacted
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    1 / 1123 (0.09%)
    3 / 3358 (0.09%)
    4 / 4481 (0.09%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 1123 (0.09%)
    1 / 3358 (0.03%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Actinic keratosis
         subjects affected / exposed
    1 / 1123 (0.09%)
    1 / 3358 (0.03%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Decubitus ulcer
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug reaction with eosinophilia and systemic symptoms
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Panniculitis
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Scar pain
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin lesion
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    6 / 1123 (0.53%)
    6 / 3358 (0.18%)
    12 / 4481 (0.27%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 6
    1 / 12
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Anuria
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Calculus bladder
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Calculus urinary
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mixed incontinence
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    2 / 1123 (0.18%)
    5 / 3358 (0.15%)
    7 / 4481 (0.16%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
    0 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Obstructive uropathy
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Proteinuria
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelocaliectasis
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    1 / 1123 (0.09%)
    3 / 3358 (0.09%)
    4 / 4481 (0.09%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    3 / 1123 (0.27%)
    1 / 3358 (0.03%)
    4 / 4481 (0.09%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ureteral necrosis
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ureteric stenosis
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    0 / 1123 (0.00%)
    4 / 3358 (0.12%)
    4 / 4481 (0.09%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urethral meatus stenosis
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary incontinence
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Goitre
         subjects affected / exposed
    3 / 1123 (0.27%)
    7 / 3358 (0.21%)
    10 / 4481 (0.22%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 7
    1 / 10
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    Hyperparathyroidism primary
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperthyroidism
         subjects affected / exposed
    0 / 1123 (0.00%)
    4 / 3358 (0.12%)
    4 / 4481 (0.09%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Acquired claw toe
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    1 / 1123 (0.09%)
    8 / 3358 (0.24%)
    9 / 4481 (0.20%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 8
    1 / 9
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    1 / 1123 (0.09%)
    4 / 3358 (0.12%)
    5 / 4481 (0.11%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthropathy
         subjects affected / exposed
    0 / 1123 (0.00%)
    4 / 3358 (0.12%)
    4 / 4481 (0.09%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atlantoaxial instability
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    4 / 1123 (0.36%)
    13 / 3358 (0.39%)
    17 / 4481 (0.38%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 14
    0 / 20
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone disorder
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    1 / 1123 (0.09%)
    1 / 3358 (0.03%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervical spinal stenosis
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dupuytren’s contracture
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Exostosis
         subjects affected / exposed
    1 / 1123 (0.09%)
    1 / 3358 (0.03%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Extraskeletal ossification
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Finger deformity
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foot deformity
         subjects affected / exposed
    5 / 1123 (0.45%)
    12 / 3358 (0.36%)
    17 / 4481 (0.38%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 12
    0 / 18
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gouty arthritis
         subjects affected / exposed
    2 / 1123 (0.18%)
    0 / 3358 (0.00%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Groin pain
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemarthrosis
         subjects affected / exposed
    1 / 1123 (0.09%)
    1 / 3358 (0.03%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hand deformity
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc disorder
         subjects affected / exposed
    0 / 1123 (0.00%)
    4 / 3358 (0.12%)
    4 / 4481 (0.09%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    3 / 1123 (0.27%)
    11 / 3358 (0.33%)
    14 / 4481 (0.31%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 11
    0 / 15
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint contracture
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint destruction
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint range of motion decreased
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint swelling
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Kyphosis
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ligament disorder
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    5 / 1123 (0.45%)
    4 / 3358 (0.12%)
    9 / 4481 (0.20%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
    0 / 9
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meniscal degeneration
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metatarsalgia
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 1123 (0.00%)
    3 / 3358 (0.09%)
    3 / 4481 (0.07%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myopathy
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    21 / 1123 (1.87%)
    63 / 3358 (1.88%)
    84 / 4481 (1.87%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 25
    2 / 67
    2 / 92
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    2 / 1123 (0.18%)
    5 / 3358 (0.15%)
    7 / 4481 (0.16%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 5
    1 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    2 / 1123 (0.18%)
    1 / 3358 (0.03%)
    3 / 4481 (0.07%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Polyarthritis
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rheumatic disorder
         subjects affected / exposed
    2 / 1123 (0.18%)
    1 / 3358 (0.03%)
    3 / 4481 (0.07%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    11 / 1123 (0.98%)
    23 / 3358 (0.68%)
    34 / 4481 (0.76%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 12
    2 / 24
    2 / 36
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rheumatoid nodule
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 1123 (0.00%)
    7 / 3358 (0.21%)
    7 / 4481 (0.16%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 7
    0 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal column stenosis
         subjects affected / exposed
    1 / 1123 (0.09%)
    8 / 3358 (0.24%)
    9 / 4481 (0.20%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 9
    0 / 10
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spondylitis
         subjects affected / exposed
    1 / 1123 (0.09%)
    1 / 3358 (0.03%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spondylolisthesis
         subjects affected / exposed
    2 / 1123 (0.18%)
    8 / 3358 (0.24%)
    10 / 4481 (0.22%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 8
    0 / 10
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Synovial disorder
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Synovitis
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tendon calcification
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tenosynovitis
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal wall abscess
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abscess
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    1 / 1123 (0.09%)
    3 / 3358 (0.09%)
    4 / 4481 (0.09%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 3
    3 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abscess neck
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    6 / 1123 (0.53%)
    11 / 3358 (0.33%)
    17 / 4481 (0.38%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    2 / 6
    2 / 11
    4 / 17
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    0 / 1123 (0.00%)
    3 / 3358 (0.09%)
    3 / 4481 (0.07%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    1 / 1123 (0.09%)
    4 / 3358 (0.12%)
    5 / 4481 (0.11%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    3 / 4
    3 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Arthritis infective
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    0 / 1123 (0.00%)
    3 / 3358 (0.09%)
    3 / 4481 (0.07%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 1123 (0.09%)
    2 / 3358 (0.06%)
    3 / 4481 (0.07%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacterial pyelonephritis
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bartholin’s abscess
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone tuberculosis
         subjects affected / exposed
    1 / 1123 (0.09%)
    1 / 3358 (0.03%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    1 / 1123 (0.09%)
    1 / 3358 (0.03%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    3 / 1123 (0.27%)
    5 / 3358 (0.15%)
    8 / 4481 (0.18%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    3 / 5
    5 / 8
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    Bursitis infective
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Campylobacter gastroenteritis
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 1123 (0.18%)
    14 / 3358 (0.42%)
    16 / 4481 (0.36%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    7 / 14
    7 / 16
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis gangrenous
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic sinusitis
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic tonsillitis
         subjects affected / exposed
    1 / 1123 (0.09%)
    1 / 3358 (0.03%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridial infection
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colonic abscess
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus chorioretinitis
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus hepatitis
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dengue fever
         subjects affected / exposed
    0 / 1123 (0.00%)
    3 / 3358 (0.09%)
    3 / 4481 (0.07%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 1123 (0.09%)
    3 / 3358 (0.09%)
    4 / 4481 (0.09%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 3
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    Diabetic gangrene
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disseminated tuberculosis
         subjects affected / exposed
    3 / 1123 (0.27%)
    4 / 3358 (0.12%)
    7 / 4481 (0.16%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    4 / 4
    7 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    5 / 1123 (0.45%)
    12 / 3358 (0.36%)
    17 / 4481 (0.38%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    4 / 5
    8 / 12
    12 / 17
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    1 / 1123 (0.09%)
    1 / 3358 (0.03%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    Epstein-Barr virus infection
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    2 / 1123 (0.18%)
    2 / 3358 (0.06%)
    4 / 4481 (0.09%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 2
    3 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Extradural abscess
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye infection fungal
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 1123 (0.18%)
    13 / 3358 (0.39%)
    15 / 4481 (0.33%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    4 / 13
    4 / 15
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 1123 (0.00%)
    4 / 3358 (0.12%)
    4 / 4481 (0.09%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal viral infection
         subjects affected / exposed
    2 / 1123 (0.18%)
    0 / 3358 (0.00%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Groin abscess
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    H1N1 influenza
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    HIV infection
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis A
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis B
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis C
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis E
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes dermatitis
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes simplex
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes virus infection
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    2 / 1123 (0.18%)
    16 / 3358 (0.48%)
    18 / 4481 (0.40%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    16 / 16
    18 / 18
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster cutaneous disseminated
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster disseminated
         subjects affected / exposed
    0 / 1123 (0.00%)
    5 / 3358 (0.15%)
    5 / 4481 (0.11%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 5
    5 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster oticus
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Incision site infection
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infected seroma
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infectious colitis
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infectious mononucleosis
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infective exacerbation of bronchiectasis
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infective spondylitis
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    3 / 1123 (0.27%)
    0 / 3358 (0.00%)
    3 / 4481 (0.07%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint abscess
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint tuberculosis
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 1123 (0.09%)
    1 / 3358 (0.03%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection bacterial
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lyme disease
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymph node tuberculosis
         subjects affected / exposed
    0 / 1123 (0.00%)
    3 / 3358 (0.09%)
    3 / 4481 (0.07%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningitis bacterial
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningitis cryptococcal
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningococcal bacteraemia
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningoencephalitis bacterial
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Necrotising fasciitis
         subjects affected / exposed
    1 / 1123 (0.09%)
    1 / 3358 (0.03%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal candidiasis
         subjects affected / exposed
    1 / 1123 (0.09%)
    1 / 3358 (0.03%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ophthalmic herpes simplex
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ophthalmic herpes zoster
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 1123 (0.00%)
    4 / 3358 (0.12%)
    4 / 4481 (0.09%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 5
    5 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic inflammatory disease
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Periorbital cellulitis
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Perirectal abscess
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritoneal tuberculosis
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 1123 (0.09%)
    3 / 3358 (0.09%)
    4 / 4481 (0.09%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonsillar abscess
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pertussis
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngeal abscess
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    21 / 1123 (1.87%)
    70 / 3358 (2.08%)
    91 / 4481 (2.03%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    10 / 21
    53 / 71
    63 / 92
    0 / 0
         deaths causally related to treatment / all
    2 / 4
    3 / 4
    5 / 8
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    Pneumonia cryptococcal
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia cytomegaloviral
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia legionella
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia necrotising
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    1 / 1123 (0.09%)
    1 / 3358 (0.03%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia streptococcal
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative abscess
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 1123 (0.00%)
    5 / 3358 (0.15%)
    5 / 4481 (0.11%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 5
    4 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Primary syphilis
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psoas abscess
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    1 / 1123 (0.09%)
    7 / 3358 (0.21%)
    8 / 4481 (0.18%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    7 / 7
    8 / 8
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulpitis dental
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    3 / 1123 (0.27%)
    2 / 3358 (0.06%)
    5 / 4481 (0.11%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 2
    5 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 1123 (0.09%)
    5 / 3358 (0.15%)
    6 / 4481 (0.13%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 5
    2 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyoderma streptococcal
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyometra
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal abscess
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal abscess
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal cyst infection
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 1123 (0.00%)
    5 / 3358 (0.15%)
    5 / 4481 (0.11%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 5
    4 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retinitis
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Salpingo-oophoritis
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Secondary syphilis
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    5 / 1123 (0.45%)
    8 / 3358 (0.24%)
    13 / 4481 (0.29%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 5
    5 / 8
    6 / 13
    0 / 0
         deaths causally related to treatment / all
    1 / 3
    2 / 2
    3 / 5
    0 / 0
    Sepsis syndrome
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    3 / 1123 (0.27%)
    4 / 3358 (0.12%)
    7 / 4481 (0.16%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 4
    5 / 7
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    1 / 2
    2 / 3
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 1123 (0.00%)
    4 / 3358 (0.12%)
    4 / 4481 (0.09%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinusitis aspergillus
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinusitis fungal
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Splenic abscess
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 1123 (0.00%)
    3 / 3358 (0.09%)
    3 / 4481 (0.07%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 1123 (0.09%)
    1 / 3358 (0.03%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Streptococcal infection
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Superinfection
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    1 / 1123 (0.09%)
    2 / 3358 (0.06%)
    3 / 4481 (0.07%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxic shock syndrome
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    Tuberculosis
         subjects affected / exposed
    1 / 1123 (0.09%)
    1 / 3358 (0.03%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tuberculosis of central nervous system
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tubo-ovarian abscess
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 1123 (0.00%)
    2 / 3358 (0.06%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection bacterial
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    8 / 1123 (0.71%)
    14 / 3358 (0.42%)
    22 / 4481 (0.49%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    6 / 10
    9 / 14
    15 / 24
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    2 / 1123 (0.18%)
    0 / 3358 (0.00%)
    2 / 4481 (0.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Varicella zoster virus infection
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vestibular neuronitis
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound infection bacterial
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound infection staphylococcal
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster 1
    Additional description: MedDRA v20.1
         subjects affected / exposed
    0 / 1123 (0.00%)
    0 / 3358 (0.00%)
    0 / 4481 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia 1
    Additional description: MedDRA v20.1
         subjects affected / exposed
    0 / 1123 (0.00%)
    0 / 3358 (0.00%)
    0 / 4481 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    3 / 1123 (0.27%)
    6 / 3358 (0.18%)
    9 / 4481 (0.20%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
    0 / 9
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 1123 (0.09%)
    3 / 3358 (0.09%)
    4 / 4481 (0.09%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia unawareness
         subjects affected / exposed
    0 / 1123 (0.00%)
    1 / 3358 (0.03%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    3 / 1123 (0.27%)
    1 / 3358 (0.03%)
    4 / 4481 (0.09%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolic syndrome
         subjects affected / exposed
    1 / 1123 (0.09%)
    0 / 3358 (0.00%)
    1 / 4481 (0.02%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Obesity
         subjects affected / exposed
    0 / 1123 (0.00%)
    3 / 3358 (0.09%)
    3 / 4481 (0.07%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Tofa 5mg BID; ppts with avg total daily dose across study <15 Tofa 10mg BID; ppts with avg total daily dose across study ≥15 All Tofacitinib Extension Period: Tofacitinib 5 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    807 / 1123 (71.86%)
    2422 / 3358 (72.13%)
    3229 / 4481 (72.06%)
    3 / 48 (6.25%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    63 / 1123 (5.61%)
    122 / 3358 (3.63%)
    185 / 4481 (4.13%)
    0 / 48 (0.00%)
         occurrences all number
    79
    155
    234
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    91 / 1123 (8.10%)
    247 / 3358 (7.36%)
    338 / 4481 (7.54%)
    0 / 48 (0.00%)
         occurrences all number
    127
    316
    443
    0
    Blood creatinine increased
         subjects affected / exposed
    60 / 1123 (5.34%)
    116 / 3358 (3.45%)
    176 / 4481 (3.93%)
    0 / 48 (0.00%)
         occurrences all number
    66
    123
    189
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    64 / 1123 (5.70%)
    209 / 3358 (6.22%)
    273 / 4481 (6.09%)
    0 / 48 (0.00%)
         occurrences all number
    74
    247
    321
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    139 / 1123 (12.38%)
    311 / 3358 (9.26%)
    450 / 4481 (10.04%)
    0 / 48 (0.00%)
         occurrences all number
    160
    352
    512
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    67 / 1123 (5.97%)
    201 / 3358 (5.99%)
    268 / 4481 (5.98%)
    0 / 48 (0.00%)
         occurrences all number
    79
    239
    318
    0
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    64 / 1123 (5.70%)
    176 / 3358 (5.24%)
    240 / 4481 (5.36%)
    0 / 48 (0.00%)
         occurrences all number
    75
    202
    277
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    72 / 1123 (6.41%)
    213 / 3358 (6.34%)
    285 / 4481 (6.36%)
    0 / 48 (0.00%)
         occurrences all number
    86
    252
    338
    0
    Nausea
         subjects affected / exposed
    56 / 1123 (4.99%)
    175 / 3358 (5.21%)
    231 / 4481 (5.16%)
    0 / 48 (0.00%)
         occurrences all number
    60
    196
    256
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    65 / 1123 (5.79%)
    202 / 3358 (6.02%)
    267 / 4481 (5.96%)
    0 / 48 (0.00%)
         occurrences all number
    75
    229
    304
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    87 / 1123 (7.75%)
    265 / 3358 (7.89%)
    352 / 4481 (7.86%)
    0 / 48 (0.00%)
         occurrences all number
    119
    341
    460
    0
    Back pain
         subjects affected / exposed
    106 / 1123 (9.44%)
    291 / 3358 (8.67%)
    397 / 4481 (8.86%)
    0 / 48 (0.00%)
         occurrences all number
    141
    330
    471
    0
    Rheumatoid arthritis
         subjects affected / exposed
    103 / 1123 (9.17%)
    293 / 3358 (8.73%)
    396 / 4481 (8.84%)
    0 / 48 (0.00%)
         occurrences all number
    141
    386
    527
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    141 / 1123 (12.56%)
    430 / 3358 (12.81%)
    571 / 4481 (12.74%)
    0 / 48 (0.00%)
         occurrences all number
    226
    625
    851
    0
    Herpes zoster
         subjects affected / exposed
    117 / 1123 (10.42%)
    373 / 3358 (11.11%)
    490 / 4481 (10.94%)
    0 / 48 (0.00%)
         occurrences all number
    123
    402
    525
    0
    Influenza
         subjects affected / exposed
    78 / 1123 (6.95%)
    199 / 3358 (5.93%)
    277 / 4481 (6.18%)
    0 / 48 (0.00%)
         occurrences all number
    96
    249
    345
    0
    Nasopharyngitis
         subjects affected / exposed
    138 / 1123 (12.29%)
    517 / 3358 (15.40%)
    655 / 4481 (14.62%)
    0 / 48 (0.00%)
         occurrences all number
    220
    812
    1032
    0
    Pharyngitis
         subjects affected / exposed
    58 / 1123 (5.16%)
    148 / 3358 (4.41%)
    206 / 4481 (4.60%)
    0 / 48 (0.00%)
         occurrences all number
    61
    180
    241
    0
    Sinusitis
         subjects affected / exposed
    70 / 1123 (6.23%)
    239 / 3358 (7.12%)
    309 / 4481 (6.90%)
    0 / 48 (0.00%)
         occurrences all number
    117
    358
    475
    0
    Upper respiratory tract infection
         subjects affected / exposed
    228 / 1123 (20.30%)
    613 / 3358 (18.25%)
    841 / 4481 (18.77%)
    0 / 48 (0.00%)
         occurrences all number
    439
    1083
    1522
    0
    Urinary tract infection
         subjects affected / exposed
    161 / 1123 (14.34%)
    447 / 3358 (13.31%)
    608 / 4481 (13.57%)
    0 / 48 (0.00%)
         occurrences all number
    283
    739
    1022
    0
    Bronchitis 1
    Additional description: MedDRA 20.1
         subjects affected / exposed
    0 / 1123 (0.00%)
    0 / 3358 (0.00%)
    0 / 4481 (0.00%)
    3 / 48 (6.25%)
         occurrences all number
    0
    0
    0
    3
    Metabolism and nutrition disorders
    Hypercholesterolaemia
         subjects affected / exposed
    62 / 1123 (5.52%)
    153 / 3358 (4.56%)
    215 / 4481 (4.80%)
    0 / 48 (0.00%)
         occurrences all number
    67
    170
    237
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Feb 2007
    The amendment was based on recommendations from the USA Food and Drug Administration about safety monitoring parameters for this protocol including some recommendations on specific cut-off values for certain parameters e.g., requiring some to be stricter than suggested by the Sponsor. For example, the (confirmed) hemoglobin level requiring discontinuation was raised from 7.5 to 8.0 g/dL. In addition, monitoring guidelines were added for subjects with serum creatinine levels >10% from baseline at the time of discontinuation.
    25 Jul 2007
    Updated exclusion criteria with the following modification for exclusion criteria number 11, 15 and 16, respectively: Included history of recurrent or disseminated herpes zoster or as otherwise judged by the Investigator; if an intra-articular injection was performed in the course of a qualifying study <4 weeks before the baseline visit of this study, the injected joint was to be considered to have its pre-injection status from the index study for the full length of this protocol; bariatric procedures, such as gastric banding, that simply divide the stomach into separate chambers were not exclusionary. Updated with rescue therapy for subjects who were not on stable, background opioid therapy. Measurement of the ESR was added to several visits, in order to facilitate determination of the DAS 28-4 (ESR) response. In addition, ACR responses were determined at every 3 months throughout the study instead of only during the first year of participation. Updated with intake of dietary supplements allowed during the study. Updated with prohibition of vaccination with live components during the study and for 8 weeks after last dose of study drug.
    21 Jan 2009
    The primary justification for this amendment was to provide for dosing of subjects at 10 mg BID and provide for long-term follow-up testing (e.g., radiographs of hands and feet, lipid profiles) consistent with tofacitinib Phase 3 protocols.
    18 Feb 2009
    Updated assessment of cardiovascular (CV) risk as every 6 months through Month 24 and then yearly after Month 24 throughout the document. Updated dose of tofacitinib as 5 mg BID and 10 mg BID in secondary objectives. Specified ESR and CRP for laboratory testing and SF-36 Health Survey in Section 6.1.3. Added DAS 2/8 assessment in Section 6.2.3 and height in Section 6.2.5.
    30 Jun 2009
    The purpose of this amendment was to align with Phase 3 protocols, to decrease the withdrawal period required for adalimumab (Humira®), and extend the supply of tofacitinib to at least 2 years after first global marketing approval.
    26 Feb 2010
    Removed the option for subjects to enroll in non-drug extension Study A3921029 after 26 February 2010. Removed text in inclusion criteria regarding subjects who discontinued their qualifying index study due to lack of efficacy. The criteria required 24 weeks of participation in the index study in order to be eligible to enroll in Study A3921024. This text was removed to accommodate differing timeframe requirements in the index study protocols. Updated monitoring and discontinuation guidelines surrounding serum creatinine elevations to allow for adjustments in concomitant medications and study drug dosing.
    24 Dec 2010
    Schedule of Activities: plasma samples for the analysis of tofacitinib concentrations were to be collected to explore relationships with long-term efficacy and safety outcomes. Included exploratory objective of establishing the PK of tofacitinib. Moved HAQ-DI to the second secondary objective. Clarified monitoring guideline for serum creatinine. Removed wording to allow intra-articular hyaluronate sodium injections prior to the Month 6 visit if appropriate and clarified frequency. Added guideline on use of opioid agent hydrocodone.
    30 Aug 2012
    Added an exclusion criterion for lymphocytopenia, monitoring and discontinuation criteria with regard to lymphocyte counts <500/mm3. Removed active tuberculosis (TB) infection to clarify that any subject with active TB infection was not allowed to receive the study drug. Added description of the relationship between treated and serious infections and lymphocyte counts <500/mm3 in the RA tofacitinib program. Added to the list of contraceptive methods that were considered highly effective. Added the requirement for written dosing instructions. Added language for drug storage temperature monitoring. Added language: “Topical administration, eg, cutaneous, ophthalmic, or intravaginal, of medications that are prohibited if administered systemically, are allowed in the study”. Modified CV risk factor assessment requirements after screening. Decreased frequency for radiographs of hands and feet after Month 12. Added language allowing for additional safety endpoint adjudication. Clarified requirement for the average weekly alcohol consumption to be updated at visits every 6 months through Month 24 and then annually thereafter for all subjects.
    11 Mar 2013
    Additional hepatitis B tests added. Medical history and vaccination of zoster added. Washout period for CYP3A inhibitors and/or CYP3A inducers added. Clarified the allowed non-steroidal anti-inflammatory drugs/cyclooxygenase-2 inhibitors/oral corticosteroids during the study.
    05 Feb 2014
    Added a follow-up visit (at least 28 days after the last dose of study drug). Removed the tests of apoliprotein A and B. Decreased the frequency of ECG testing during the study. Removed work limitation questionnaire. Reduced the frequency of questionnaires (SF-36 Health Survey, FACIT Fatigue, EuroQol EQ-5D, RA-HCRU) to be performed annually. Specified the collections of radiographs of hands/feet procedures up to Month 36 only and at EOT visit. Added lymphocyte substudy. Extended the study duration to November 2019 or up to the marketing approval of tofacitinib in certain countries. Allowed subjects to reduce the study dose to 5 mg BID from 10 mg BID at the discretion of the Investigators. Allowed subjects who were enrolled to receive either 5 or 10 mg BID dose at the discretion of the Investigators. Added the discussions of potential reproductive risk and contraceptive use. Added and removed some prohibited concomitant drugs and clarified that study drug was to be interrupted if a CYP3A inhibitor was administered concomitantly. Applied the existing discontinuation criterion of opportunistic infection to all subjects.
    15 Jan 2015
    Added TB screening annually for subjects in the high-risk countries. Removed height measurements during the study and weight measurements at some timepoints during the study. Removed temperature, rheumatoid factor, anti-cyclic citrullinated peptide, ECG, urinalysis, and radiographs of hands and feet. Removed SF-36, FACIT Fatigue, EQ-5D, RA Healthcare questionnaires. Reduced the study duration to April 2016 for subjects who were not participating in the lymphocyte substudy and clarified the study durations for subjects who were participating in the lymphocyte substudy. Added more definitions/clarifications of medication errors. Clarified wording to continue a subject with latent TB infection during the study. Added Cohort 3 to enroll subjects from Study A3921237 in the lymphocyte substudy.

    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.
    All information is based on protocol Amendment 25 with a database release date of 02 March 2017. One serious adverse event in the Tofacitinib 5mg BID group could not be coded ("septic shock and pneumonia") and has not been included.
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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