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    Clinical Trial Results:
    A Phase II, Open-label, Study in Subjects with BRAF V600E-Mutated Rare Cancers with Several Histologies to Investigate the Clinical Efficacy and Safety of the Combination Therapy of Dabrafenib and Trametinib

    Summary
    EudraCT number
    		 2013-001705-87
    Trial protocol
    		 IT   SE   BE   AT   DK   NL   ES   NO  
    Global end of trial date
    10 Dec 2021

    Results information
    Results version number
    		 v2(current)
    This version publication date
    15 Sep 2023
    First version publication date
    16 Dec 2022
    Other versions
    		 v1
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    117019
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02034110
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Novartis: CDRB436X2201, GlaxoSmithKline: BRF117019
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    Novartis Campus, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.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
    10 Dec 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Dec 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Dec 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to determine Overall Response Rate (ORR) of dabrafenib + trametinib in subjects with selected rare BRAF V600E-mutated cancers.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Mar 2014
    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
    Austria: 8
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Denmark: 7
    Country: Number of subjects enrolled
    France: 26
    Country: Number of subjects enrolled
    Germany: 16
    Country: Number of subjects enrolled
    Italy: 7
    Country: Number of subjects enrolled
    Japan: 7
    Country: Number of subjects enrolled
    Korea, Republic of: 16
    Country: Number of subjects enrolled
    Netherlands: 13
    Country: Number of subjects enrolled
    Norway: 3
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    Sweden: 3
    Country: Number of subjects enrolled
    United States: 91
    Worldwide total number of subjects
    206
    EEA total number of subjects
    91
    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)
    122
    From 65 to 84 years
    81
    85 years and over
    3

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 The study was conducted in 41 centers in 14 countries worldwide.

    Pre-assignment
    Screening details
    		 Subjects were enrolled into cohorts based on the type of histology. For each histology, up to 25 patients were planned to be enrolled. A cohort could be closed or stopped early (prior to capping at 25 patients) for futility or efficacy. An uncapped expansion cohort was planned when a particular cohort was stopped early for efficacy.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Anaplastic Thyroid Cancer (ATC)
    Arm description
    		 All subjects enrolled received oral dabrafenib 150 mg bid in combination with oral trametinib 2 mg once daily. Subjects continued treatment until an unacceptable toxicity, disease progression, or death.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Trametinib
    Investigational medicinal product code
    Other name
    TMT212 GSK1120212
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    A 2 mg once daily tablet administered orally on a continuous basis.

    Investigational medicinal product name
    Dabrafenib
    Investigational medicinal product code
    Other name
    DRB436 GSK2118436
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    A 150 mg twice daily capsule administered orally on a continuous basis.

    Arm title
    		 Biliary Tract Cancer (BTC)
    Arm description
    		 All subjects enrolled received oral dabrafenib 150 mg bid in combination with oral trametinib 2 mg once daily. Subjects continued treatment until an unacceptable toxicity, disease progression, or death.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Trametinib
    Investigational medicinal product code
    Other name
    TMT212 GSK1120212
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    A 2 mg once daily tablet administered orally on a continuous basis.

    Investigational medicinal product name
    Dabrafenib
    Investigational medicinal product code
    Other name
    DRB436 GSK2118436
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    A 150 mg twice daily capsule administered orally on a continuous basis.

    Arm title
    		 Gastrointestinal Stromal Tumor (GIST)
    Arm description
    		 All subjects enrolled received oral dabrafenib 150 mg bid in combination with oral trametinib 2 mg once daily. Subjects continued treatment until an unacceptable toxicity, disease progression, or death.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Trametinib
    Investigational medicinal product code
    Other name
    TMT212 GSK1120212
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    A 2 mg once daily tablet administered orally on a continuous basis.

    Investigational medicinal product name
    Dabrafenib
    Investigational medicinal product code
    Other name
    DRB436 GSK2118436
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    A 150 mg twice daily capsule administered orally on a continuous basis.

    Arm title
    		 Low Grade (WHO G1/G2) Glioma (LGG)
    Arm description
    		 All subjects enrolled received oral dabrafenib 150 mg bid in combination with oral trametinib 2 mg once daily. Subjects continued treatment until an unacceptable toxicity, disease progression, or death.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Trametinib
    Investigational medicinal product code
    Other name
    TMT212 GSK1120212
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    A 2 mg once daily tablet administered orally on a continuous basis.

    Investigational medicinal product name
    Dabrafenib
    Investigational medicinal product code
    Other name
    DRB436 GSK2118436
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    A 150 mg twice daily capsule administered orally on a continuous basis.

    Arm title
    		 High Grade (WHO G3/G4) Glioma (HGG)
    Arm description
    		 All subjects enrolled received oral dabrafenib 150 mg bid in combination with oral trametinib 2 mg once daily. Subjects continued treatment until an unacceptable toxicity, disease progression, or death.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Trametinib
    Investigational medicinal product code
    Other name
    TMT212 GSK1120212
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    A 2 mg once daily tablet administered orally on a continuous basis.

    Investigational medicinal product name
    Dabrafenib
    Investigational medicinal product code
    Other name
    DRB436 GSK2118436
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    A 150 mg twice daily capsule administered orally on a continuous basis.

    Arm title
    		 Adenocarcinoma of the Small Intestine (ASI)
    Arm description
    		 All subjects enrolled received oral dabrafenib 150 mg bid in combination with oral trametinib 2 mg once daily. Subjects continued treatment until an unacceptable toxicity, disease progression, or death.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Trametinib
    Investigational medicinal product code
    Other name
    TMT212 GSK1120212
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    A 2 mg once daily tablet administered orally on a continuous basis.

    Investigational medicinal product name
    Dabrafenib
    Investigational medicinal product code
    Other name
    DRB436 GSK2118436
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    A 150 mg twice daily capsule administered orally on a continuous basis.

    Arm title
    		 Hairy Cell Leukemia (HCL)
    Arm description
    		 All subjects enrolled received oral dabrafenib 150 mg bid in combination with oral trametinib 2 mg once daily. Subjects continued treatment until an unacceptable toxicity, disease progression, or death.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Trametinib
    Investigational medicinal product code
    Other name
    TMT212 GSK1120212
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    A 2 mg once daily tablet administered orally on a continuous basis.

    Investigational medicinal product name
    Dabrafenib
    Investigational medicinal product code
    Other name
    DRB436 GSK2118436
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    A 150 mg twice daily capsule administered orally on a continuous basis.

    Arm title
    		 Multiple Myeloma (MM)
    Arm description
    		 All subjects enrolled received oral dabrafenib 150 mg bid in combination with oral trametinib 2 mg once daily. Subjects continued treatment until an unacceptable toxicity, disease progression, or death.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Trametinib
    Investigational medicinal product code
    Other name
    TMT212 GSK1120212
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    A 2 mg once daily tablet administered orally on a continuous basis.

    Investigational medicinal product name
    Dabrafenib
    Investigational medicinal product code
    Other name
    DRB436 GSK2118436
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    A 150 mg twice daily capsule administered orally on a continuous basis.

    Number of subjects in period 1
    		Anaplastic Thyroid Cancer (ATC) Biliary Tract Cancer (BTC) Gastrointestinal Stromal Tumor (GIST) Low Grade (WHO G1/G2) Glioma (LGG) High Grade (WHO G3/G4) Glioma (HGG) Adenocarcinoma of the Small Intestine (ASI) Hairy Cell Leukemia (HCL) Multiple Myeloma (MM)
    Started
    36
    43
    1
    13
    45
    3
    55
    10
    Primary analysis cohort
    15 [1]
    18 [2]
    1
    13
    24 [3]
    3
    24
    10
    Expansion cohort
    21 [4]
    25 [5]
    0 [6]
    0 [7]
    21 [8]
    0 [9]
    31
    0 [10]
    Completed
    24
    34
    1
    4
    28
    3
    8
    9
    Not completed
    12
    9
    0
    9
    17
    0
    47
    1
         Consent withdrawn by subject
    5
    7
    -
    3
    7
    -
    3
    1
         Physician decision
    -
    -
    -
    -
    2
    -
    1
    -
         Study closed by sponsor
    6
    2
    -
    6
    7
    -
    42
    -
         Lost to follow-up
    1
    -
    -
    -
    1
    -
    1
    -
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: For each histology, up to 25 patients were planned to be enrolled in each of the analysis cohorts. A cohort could be closed or stopped early (prior to capping at 25 patients) for futility or efficacy. An uncapped expansion cohort was planned when a particular cohort was stopped early for efficacy.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: For each histology, up to 25 patients were planned to be enrolled in each of the analysis cohorts. A cohort could be closed or stopped early (prior to capping at 25 patients) for futility or efficacy. An uncapped expansion cohort was planned when a particular cohort was stopped early for efficacy.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: For each histology, up to 25 patients were planned to be enrolled in each of the analysis cohorts. A cohort could be closed or stopped early (prior to capping at 25 patients) for futility or efficacy. An uncapped expansion cohort was planned when a particular cohort was stopped early for efficacy.
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: For each histology, up to 25 patients were planned to be enrolled in each of the analysis cohorts. A cohort could be closed or stopped early (prior to capping at 25 patients) for futility or efficacy. An uncapped expansion cohort was planned when a particular cohort was stopped early for efficacy.
    [5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: For each histology, up to 25 patients were planned to be enrolled in each of the analysis cohorts. A cohort could be closed or stopped early (prior to capping at 25 patients) for futility or efficacy. An uncapped expansion cohort was planned when a particular cohort was stopped early for efficacy.
    [6] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: For each histology, up to 25 patients were planned to be enrolled in each of the analysis cohorts. A cohort could be closed or stopped early (prior to capping at 25 patients) for futility or efficacy. An uncapped expansion cohort was planned when a particular cohort was stopped early for efficacy.
    [7] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: For each histology, up to 25 patients were planned to be enrolled in each of the analysis cohorts. A cohort could be closed or stopped early (prior to capping at 25 patients) for futility or efficacy. An uncapped expansion cohort was planned when a particular cohort was stopped early for efficacy.
    [8] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: For each histology, up to 25 patients were planned to be enrolled in each of the analysis cohorts. A cohort could be closed or stopped early (prior to capping at 25 patients) for futility or efficacy. An uncapped expansion cohort was planned when a particular cohort was stopped early for efficacy.
    [9] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: For each histology, up to 25 patients were planned to be enrolled in each of the analysis cohorts. A cohort could be closed or stopped early (prior to capping at 25 patients) for futility or efficacy. An uncapped expansion cohort was planned when a particular cohort was stopped early for efficacy.
    [10] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: For each histology, up to 25 patients were planned to be enrolled in each of the analysis cohorts. A cohort could be closed or stopped early (prior to capping at 25 patients) for futility or efficacy. An uncapped expansion cohort was planned when a particular cohort was stopped early for efficacy.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Anaplastic Thyroid Cancer (ATC)
    Reporting group description
    		 All subjects enrolled received oral dabrafenib 150 mg bid in combination with oral trametinib 2 mg once daily. Subjects continued treatment until an unacceptable toxicity, disease progression, or death.

    Reporting group title
    Biliary Tract Cancer (BTC)
    Reporting group description
    		 All subjects enrolled received oral dabrafenib 150 mg bid in combination with oral trametinib 2 mg once daily. Subjects continued treatment until an unacceptable toxicity, disease progression, or death.

    Reporting group title
    Gastrointestinal Stromal Tumor (GIST)
    Reporting group description
    		 All subjects enrolled received oral dabrafenib 150 mg bid in combination with oral trametinib 2 mg once daily. Subjects continued treatment until an unacceptable toxicity, disease progression, or death.

    Reporting group title
    Low Grade (WHO G1/G2) Glioma (LGG)
    Reporting group description
    		 All subjects enrolled received oral dabrafenib 150 mg bid in combination with oral trametinib 2 mg once daily. Subjects continued treatment until an unacceptable toxicity, disease progression, or death.

    Reporting group title
    High Grade (WHO G3/G4) Glioma (HGG)
    Reporting group description
    		 All subjects enrolled received oral dabrafenib 150 mg bid in combination with oral trametinib 2 mg once daily. Subjects continued treatment until an unacceptable toxicity, disease progression, or death.

    Reporting group title
    Adenocarcinoma of the Small Intestine (ASI)
    Reporting group description
    		 All subjects enrolled received oral dabrafenib 150 mg bid in combination with oral trametinib 2 mg once daily. Subjects continued treatment until an unacceptable toxicity, disease progression, or death.

    Reporting group title
    Hairy Cell Leukemia (HCL)
    Reporting group description
    		 All subjects enrolled received oral dabrafenib 150 mg bid in combination with oral trametinib 2 mg once daily. Subjects continued treatment until an unacceptable toxicity, disease progression, or death.

    Reporting group title
    Multiple Myeloma (MM)
    Reporting group description
    		 All subjects enrolled received oral dabrafenib 150 mg bid in combination with oral trametinib 2 mg once daily. Subjects continued treatment until an unacceptable toxicity, disease progression, or death.

    Reporting group values
    		 Anaplastic Thyroid Cancer (ATC) Biliary Tract Cancer (BTC) Gastrointestinal Stromal Tumor (GIST) Low Grade (WHO G1/G2) Glioma (LGG) High Grade (WHO G3/G4) Glioma (HGG) Adenocarcinoma of the Small Intestine (ASI) Hairy Cell Leukemia (HCL) Multiple Myeloma (MM) Total
    Number of subjects
    		 36 43 1 13 45 3 55 10 206
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0 0 0 0
        Adults (18-64 years)
    		 9 29 0 13 43 3 21 4 122
        From 65-84 years
    		 25 14 1 0 2 0 33 6 81
        85 years and over
    		 2 0 0 0 0 0 1 0 3
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 69.6 ( 9.53 ) 57.0 ( 11.88 ) 77.0 ( 999 ) 33.1 ( 11.51 ) 41.9 ( 14.70 ) 58.3 ( 3.21 ) 64.8 ( 10.77 ) 66.9 ( 6.89 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 20 24 1 9 22 1 8 5 90
        Male
    		 16 19 0 4 23 2 47 5 116
    Race/Ethnicity, Customized
    Units: Subjects
        African American/African Heritage
    		 0 0 0 0 2 1 0 1 4
        American Indian or Alaska Native
    		 0 0 0 0 1 0 0 0 1
        Asian - Central/South Asian Heritage
    		 1 0 0 0 0 0 0 0 1
        Asian - East Asian Heritage
    		 11 1 0 0 4 0 0 1 17
        Asian - Japanese Heritage
    		 2 2 0 2 1 0 0 0 7
        Asian - South East Asian Heritage
    		 2 0 0 1 1 0 0 0 4
        White - Arabic/North African Heritage
    		 1 1 0 0 2 0 1 0 5
        White - White/Caucasian/European heritage
    		 17 39 1 10 32 2 48 8 157
        Missing
    		 2 0 0 0 2 0 6 0 10
    ECOG Performance Status
    The Eastern Cooperative Oncology Group Performance Status (ECOG PS) score classifies participants according to their functional impairment, with scores ranging from 0 (fully active) to 5 (dead). ECOG PS: 0 = Fully active, able to carry on all pre-disease performance without restriction; 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work; 2 = ambulatory and capable of all self-care but unable to carry out any work activities, up and about more than 50% of waking hours
    Units: Subjects
        Grade 0
    		 4 17 1 5 14 3 25 3 72
        Grade 1
    		 30 24 0 7 24 0 27 6 118
        Grade 2
    		 2 2 0 1 7 0 3 1 16

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Anaplastic Thyroid Cancer (ATC)
    Reporting group description
    		 All subjects enrolled received oral dabrafenib 150 mg bid in combination with oral trametinib 2 mg once daily. Subjects continued treatment until an unacceptable toxicity, disease progression, or death.

    Reporting group title
    Biliary Tract Cancer (BTC)
    Reporting group description
    		 All subjects enrolled received oral dabrafenib 150 mg bid in combination with oral trametinib 2 mg once daily. Subjects continued treatment until an unacceptable toxicity, disease progression, or death.

    Reporting group title
    Gastrointestinal Stromal Tumor (GIST)
    Reporting group description
    		 All subjects enrolled received oral dabrafenib 150 mg bid in combination with oral trametinib 2 mg once daily. Subjects continued treatment until an unacceptable toxicity, disease progression, or death.

    Reporting group title
    Low Grade (WHO G1/G2) Glioma (LGG)
    Reporting group description
    		 All subjects enrolled received oral dabrafenib 150 mg bid in combination with oral trametinib 2 mg once daily. Subjects continued treatment until an unacceptable toxicity, disease progression, or death.

    Reporting group title
    High Grade (WHO G3/G4) Glioma (HGG)
    Reporting group description
    		 All subjects enrolled received oral dabrafenib 150 mg bid in combination with oral trametinib 2 mg once daily. Subjects continued treatment until an unacceptable toxicity, disease progression, or death.

    Reporting group title
    Adenocarcinoma of the Small Intestine (ASI)
    Reporting group description
    		 All subjects enrolled received oral dabrafenib 150 mg bid in combination with oral trametinib 2 mg once daily. Subjects continued treatment until an unacceptable toxicity, disease progression, or death.

    Reporting group title
    Hairy Cell Leukemia (HCL)
    Reporting group description
    		 All subjects enrolled received oral dabrafenib 150 mg bid in combination with oral trametinib 2 mg once daily. Subjects continued treatment until an unacceptable toxicity, disease progression, or death.

    Reporting group title
    Multiple Myeloma (MM)
    Reporting group description
    		 All subjects enrolled received oral dabrafenib 150 mg bid in combination with oral trametinib 2 mg once daily. Subjects continued treatment until an unacceptable toxicity, disease progression, or death.

    Primary: Overall Response Rate (ORR) in the Anaplastic Thyroid Cancer (ATC) cohort

    		 Close Top of page
    End point title
    		 Overall Response Rate (ORR) in the Anaplastic Thyroid Cancer (ATC) cohort [1] [2]
    End point description
    Overall Response Rate (ORR) was defined as the percentage of participants with a tumor response (complete response [CR], partial response [PR]) by investigator assessment as defined by RECIST v1.1. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
    End point type
    Primary
    End point timeframe
    From study treatment start date until first documented complete response or partial response, assessed up to 78 months (cut-off date for FDA Submission = 14-Sep-20) and up to 92 months (cut-off date for end of study = 10-Dec-21)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis performed
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Subjects were enrolled into cohorts based on the type of histology. Each histology is presented as a distinct arm in the endpoints
    End point values
    		 Anaplastic Thyroid Cancer (ATC)
    Number of subjects analysed
    36
    Units: Percentage of Participants
    number (confidence interval 95%)
        Investigator assessment @ up to 78 months
    56 (38.1 to 72.1)
        Investigator assessment @ up to 92 months
    56 (38.1 to 72.1)
        Independent radiology review @ up to 78 months
    53 (35.5 to 69.6)
        Independent radiology review @ up to 92 months
    53 (35.5 to 69.6)
    No statistical analyses for this end point

    Primary: Overall Response Rate (ORR) in the Biliary Tract Cancer (BTC) cohort

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    End point title
    		 Overall Response Rate (ORR) in the Biliary Tract Cancer (BTC) cohort [3] [4]
    End point description
    Overall Response Rate (ORR) was defined as the percentage of participants with a tumor response (complete response [CR], partial response [PR]) by investigator assessment as defined by RECIST v1.1. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
    End point type
    Primary
    End point timeframe
    From study treatment start date until first documented complete response or partial response, assessed up to 78 months (cut-off date for FDA Submission = 14-Sep-20) and up to 92 months (cut-off date for end of study = 10-Dec-21)
    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 analysis performed
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Subjects were enrolled into cohorts based on the type of histology. Each histology is presented as a distinct arm in the endpoints
    End point values
    		 Biliary Tract Cancer (BTC)
    Number of subjects analysed
    43
    Units: Percentage of Participants
    number (confidence interval 95%)
        Investigator assessment @ up to 78 months
    53 (37.7 to 68.8)
        Investigator assessment @ up to 92 months
    53 (37.7 to 68.8)
        Independent radiology review @ up to 78 months
    47 (31.2 to 62.3)
        Independent radiology review @ up to 92 months
    47 (31.2 to 62.3)
    No statistical analyses for this end point

    Primary: Overall Response Rate (ORR) in the Low Grade (WHO G1/G2) Glioma (LGG) cohort

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    End point title
    		 Overall Response Rate (ORR) in the Low Grade (WHO G1/G2) Glioma (LGG) cohort [5] [6]
    End point description
    Overall Response Rate (ORR) was defined as the percentage of participants with a tumor response (response assessment criteria (CR, PR, and minor response [MR]) WHO Grade 1 and 2 Glioma) by investigator assessment as defined by response assessment for neuro-oncology (RANO). Specifically, ORR = number of subjects with a confirmed overall response divided by the total number of subjects in the corresponding analysis population.
    End point type
    Primary
    End point timeframe
    From study treatment start date until first documented complete response or partial response, assessed up to 78 months (cut-off date for FDA Submission = 14-Sep-20) and up to 92 months (cut-off date for end of study = 10-Dec-21)
    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 analysis performed
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Subjects were enrolled into cohorts based on the type of histology. Each histology is presented as a distinct arm in the endpoints
    End point values
    		 Low Grade (WHO G1/G2) Glioma (LGG)
    Number of subjects analysed
    13
    Units: Percentage of Participants
    number (confidence interval 95%)
        Inv. assessment/Response rate @ up to 78 months
    69 (38.6 to 90.9)
        Inv. assessment/Response rate @ up to 92 months
    69 (38.6 to 90.9)
        Indep. Rad. rev./Response rate @ up to 78 months
    69 (38.6 to 90.9)
        Indep. Rad. rev./Response rate @ up to 92 months
    62 (31.6 to 86.1)
    No statistical analyses for this end point

    Primary: Overall Response Rate (ORR) in the Gastrointestinal Stromal Tumor (GIST) cohort

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    End point title
    		 Overall Response Rate (ORR) in the Gastrointestinal Stromal Tumor (GIST) cohort [7] [8]
    End point description
    Overall Response Rate (ORR) was defined as the percentage of participants with a tumor response (complete response [CR], partial response [PR]) by investigator assessment as defined by RECIST v1.1. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
    End point type
    Primary
    End point timeframe
    From study treatment start date until first documented complete response or partial response, assessed up to 78 months (cut-off date for FDA Submission = 14-Sep-20) and up to 92 months (cut-off date for end of study = 10-Dec-21)
    Notes
    [7] - 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 analysis performed
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Subjects were enrolled into cohorts based on the type of histology. Each histology is presented as a distinct arm in the endpoints
    End point values
    		 Gastrointestinal Stromal Tumor (GIST)
    Number of subjects analysed
    0 [9]
    Units: Percentage of Participants
    number (confidence interval 95%)
        Investigator assessment @ 78 months
    ( to )
        Investigator assessment @ 92 months
    ( to )
    Notes
    [9] - insufficient number of participants with events.
    No statistical analyses for this end point

    Primary: Overall Response Rate (ORR) in the Adenocarcinoma of the Small Intestine (ASI) cohort

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    End point title
    		 Overall Response Rate (ORR) in the Adenocarcinoma of the Small Intestine (ASI) cohort [10] [11]
    End point description
    Overall Response Rate (ORR) was defined as the percentage of participants with a tumor response (complete response [CR], partial response [PR]) by investigator assessment as defined by RECIST v1.1. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
    End point type
    Primary
    End point timeframe
    From study treatment start date until first documented complete response or partial response, assessed up to 78 months (cut-off date for FDA Submission = 14-Sep-20) and up to 92 months (cut-off date for end of study = 10-Dec-21)
    Notes
    [10] - 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 analysis performed
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Subjects were enrolled into cohorts based on the type of histology. Each histology is presented as a distinct arm in the endpoints
    End point values
    		 Adenocarcinoma of the Small Intestine (ASI)
    Number of subjects analysed
    3
    Units: Percentage of Participants
    number (confidence interval 95%)
        Investigator assessment @ up to 78 months
    67 (9.4 to 99.2)
        Investigator assessment @ up to 92 months
    67 (9.4 to 99.2)
    No statistical analyses for this end point

    Primary: Overall Response Rate (ORR) in the Hairy Cell Leukemia (HCL) cohort

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    End point title
    		 Overall Response Rate (ORR) in the Hairy Cell Leukemia (HCL) cohort [12] [13]
    End point description
    Overall Response Rate (ORR) was defined as the percentage of participants with CR +/- minimal residual disease [MRD], PR by investigator assessment as defined by the Consensus Resolution Criteria adapted from the National Comprehensive Cancer Network (NCCN) guidelines. Specifically, ORR = number of subjects with a confirmed overall response divided by the total number of subjects in the corresponding analysis population.
    End point type
    Primary
    End point timeframe
    From study treatment start date until first documented complete response or partial response, assessed up to 78 months (cut-off date for FDA Submission = 14-Sep-20) and up to 92 months (cut-off date for end of study = 10-Dec-21)
    Notes
    [12] - 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 analysis performed
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Subjects were enrolled into cohorts based on the type of histology. Each histology is presented as a distinct arm in the endpoints
    End point values
    		 Hairy Cell Leukemia (HCL)
    Number of subjects analysed
    55
    Units: Percentage of Participants
    number (confidence interval 95%)
        Investigator assessment @ up to 78 months
    89 (77.8 to 95.9)
        Investigator assessment @ up to 92 months
    89 (77.8 to 95.9)
    No statistical analyses for this end point

    Primary: Overall Response Rate (ORR) in the High Grade (WHO G3/G4) Glioma (HGG) cohort

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    End point title
    		 Overall Response Rate (ORR) in the High Grade (WHO G3/G4) Glioma (HGG) cohort [14] [15]
    End point description
    Overall Response Rate (ORR) was defined as the percentage of participants with a tumor response (updated response assessment criteria (CR, PR) WHO Grade 3 and 4 Glioma) by investigator assessment as defined by modified response assessment for neuro-oncology (RANO). Specifically, ORR = number of subjects with a confirmed overall response divided by the total number of subjects in the corresponding analysis population.
    End point type
    Primary
    End point timeframe
    From study treatment start date until first documented complete response or partial response, assessed up to 78 months (cut-off date for FDA Submission = 14-Sep-20) and up to 92 months (cut-off date for end of study = 10-Dec-21)
    Notes
    [14] - 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 analysis performed
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Subjects were enrolled into cohorts based on the type of histology. Each histology is presented as a distinct arm in the endpoints
    End point values
    		 High Grade (WHO G3/G4) Glioma (HGG)
    Number of subjects analysed
    45
    Units: Percentage of Participants
    number (confidence interval 95%)
        Investigator assessment @ up to 78 months
    33 (20.0 to 49.0)
        Investigator assessment @ up to 92 months
    33 (20.0 to 49.0)
        Independent radiology review @ up to 78 months
    31 (18.2 to 46.6)
        Independent radiology review @ up to 92 months
    31 (18.2 to 46.6)
    No statistical analyses for this end point

    Primary: Overall Response Rate (ORR) in the Multiple Myeloma (MM) cohort

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    End point title
    		 Overall Response Rate (ORR) in the Multiple Myeloma (MM) cohort [16] [17]
    End point description
    Overall Response Rate (ORR) was defined as the percentage of participants with stringent complete response (sCR), CR, PR, very good partial response (VGPR) by investigator assessment as defined by the International Myeloma Working Group (IMWG) Uniform Response Criteria for Multiple Myeloma. Specifically, ORR = number of subjects with a confirmed overall response divided by the total number of subjects in the corresponding analysis population.
    End point type
    Primary
    End point timeframe
    From study treatment start date until first documented complete response or partial response, assessed up to 78 months (cut-off date for FDA Submission = 14-Sep-20) and up to 92 months (cut-off date for end of study = 10-Dec-21)
    Notes
    [16] - 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 analysis performed
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Subjects were enrolled into cohorts based on the type of histology. Each histology is presented as a distinct arm in the endpoints
    End point values
    		 Multiple Myeloma (MM)
    Number of subjects analysed
    10
    Units: Percentage of Participants
    number (confidence interval 95%)
        Investigator assessment @ up to 78 months
    50 (18.7 to 81.3)
        Investigator assessment @ up to 92 months
    50 (18.7 to 81.3)
    No statistical analyses for this end point

    Secondary: Duration of Response (DoR) in the Anaplastic Thyroid Cancer (ATC) cohort

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    End point title
    		 Duration of Response (DoR) in the Anaplastic Thyroid Cancer (ATC) cohort [18]
    End point description
    For the subset of subjects who showed a confirmed response as defined for each cohort, Duration of Response (DoR) was defined as the time (in weeks) from first documented evidence of response (the first response prior to confirmation) until time of documented disease progression or death due to any cause, whichever was first. If the subject did not have a documented date of progression or death, DoR was censored at the date of the last adequate assessment.
    End point type
    Secondary
    End point timeframe
    From first documented evidence of response (the first response prior to confirmation) until time of documented disease progression or death due to any cause, whichever comes first, assessed up to 92 months (cut-off date for end of study = 10-Dec-21)
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Subjects were enrolled into cohorts based on the type of histology. Each histology is presented as a distinct arm in the endpoints
    End point values
    		 Anaplastic Thyroid Cancer (ATC)
    Number of subjects analysed
    20
    Units: Weeks
    median (confidence interval 95%)
        Investigator assessment
    62.4 (32.1 to 999)
        Independent radiology review
    59.1 (16.6 to 171.4)
    No statistical analyses for this end point

    Secondary: Duration of Response (DoR) in the Biliary Tract Cancer (BTC) cohort

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    End point title
    		 Duration of Response (DoR) in the Biliary Tract Cancer (BTC) cohort [19]
    End point description
    For the subset of subjects who showed a confirmed response as defined for each cohort, Duration of Response (DoR) was defined as the time (in weeks) from first documented evidence of response (the first response prior to confirmation) until time of documented disease progression or death due to any cause, whichever was first. If the subject did not have a documented date of progression or death, DoR was censored at the date of the last adequate assessment.
    End point type
    Secondary
    End point timeframe
    From first documented evidence of response (the first response prior to confirmation) until time of documented disease progression or death due to any cause, whichever comes first, assessed up to 92 months (cut-off date for end of study = 10-Dec-21)
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Subjects were enrolled into cohorts based on the type of histology. Each histology is presented as a distinct arm in the endpoints
    End point values
    		 Biliary Tract Cancer (BTC)
    Number of subjects analysed
    23
    Units: Weeks
    median (confidence interval 95%)
        Investigator assessment
    38.9 (24.3 to 59.4)
        Independent radiology review
    45.4 (20.1 to 64.9)
    No statistical analyses for this end point

    Secondary: Duration of Response (DoR) in the Low Grade (WHO G1/G2) Glioma (LGG) cohort

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    End point title
    		 Duration of Response (DoR) in the Low Grade (WHO G1/G2) Glioma (LGG) cohort [20]
    End point description
    For the subset of subjects who showed a confirmed response as defined for each cohort, Duration of Response (DoR) was defined as the time (in weeks) from first documented evidence of response (the first response prior to confirmation) until time of documented disease progression or death due to any cause, whichever was first. If the subject did not have a documented date of progression or death, DoR was censored at the date of the last adequate assessment.
    End point type
    Secondary
    End point timeframe
    From first documented evidence of response (the first response prior to confirmation) until time of documented disease progression or death due to any cause, whichever comes first, assessed up to 92 months (cut-off date for end of study = 10-Dec-21)
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Subjects were enrolled into cohorts based on the type of histology. Each histology is presented as a distinct arm in the endpoints
    End point values
    		 Low Grade (WHO G1/G2) Glioma (LGG)
    Number of subjects analysed
    9
    Units: Weeks
    median (confidence interval 95%)
        Investigator assessment
    999 (24.1 to 999)
        Independent radiology review
    84.3 (16.4 to 999)
    No statistical analyses for this end point

    Secondary: Duration of Response (DoR) in the High Grade (WHO G3/G4) Glioma (HGG) cohort

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    End point title
    		 Duration of Response (DoR) in the High Grade (WHO G3/G4) Glioma (HGG) cohort [21]
    End point description
    For the subset of subjects who showed a confirmed response as defined for each cohort, Duration of Response (DoR) was defined as the time (in weeks) from first documented evidence of response (the first response prior to confirmation) until time of documented disease progression or death due to any cause, whichever was first. If the subject did not have a documented date of progression or death, DoR was censored at the date of the last adequate assessment.
    End point type
    Secondary
    End point timeframe
    From first documented evidence of response (the first response prior to confirmation) until time of documented disease progression or death due to any cause, whichever comes first, assessed up to 92 months (cut-off date for end of study = 10-Dec-21)
    Notes
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Subjects were enrolled into cohorts based on the type of histology. Each histology is presented as a distinct arm in the endpoints
    End point values
    		 High Grade (WHO G3/G4) Glioma (HGG)
    Number of subjects analysed
    15
    Units: Weeks
    median (confidence interval 95%)
        Investigator assessment
    135.7 (32.0 to 192.0)
        Independent radiology review
    59.3 (20.1 to 116.0)
    No statistical analyses for this end point

    Secondary: Duration of Response (DoR) in the Adenocarcinoma of the Small Intestine (ASI) cohort

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    End point title
    		 Duration of Response (DoR) in the Adenocarcinoma of the Small Intestine (ASI) cohort [22]
    End point description
    For the subset of subjects who showed a confirmed response as defined for each cohort, Duration of Response (DoR) was defined as the time (in weeks) from first documented evidence of response (the first response prior to confirmation) until time of documented disease progression or death due to any cause, whichever was first. If the subject did not have a documented date of progression or death, DoR was censored at the date of the last adequate assessment.
    End point type
    Secondary
    End point timeframe
    From first documented evidence of response (the first response prior to confirmation) until time of documented disease progression or death due to any cause, whichever comes first, assessed up to 92 months (cut-off date for end of study = 10-Dec-21)
    Notes
    [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Subjects were enrolled into cohorts based on the type of histology. Each histology is presented as a distinct arm in the endpoints
    End point values
    		 Adenocarcinoma of the Small Intestine (ASI)
    Number of subjects analysed
    2
    Units: Weeks
    median (confidence interval 95%)
        Investigator assessment
    999 (999 to 999)
        Independent radiology review
    32.8 (32.1 to 999)
    No statistical analyses for this end point

    Secondary: Duration of Response (DoR) in the Hairy Cell Leukemia (HCL) cohort

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    End point title
    		 Duration of Response (DoR) in the Hairy Cell Leukemia (HCL) cohort [23]
    End point description
    For the subset of subjects who showed a confirmed response as defined for each cohort, Duration of Response (DoR) was defined as the time (in weeks) from first documented evidence of response (the first response prior to confirmation) until time of documented disease progression or death due to any cause, whichever was first. If the subject did not have a documented date of progression or death, DoR was censored at the date of the last adequate assessment.
    End point type
    Secondary
    End point timeframe
    From first documented evidence of response (the first response prior to confirmation) until time of documented disease progression or death due to any cause, whichever comes first, assessed up to 92 months (cut-off date for end of study = 10-Dec-21)
    Notes
    [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Subjects were enrolled into cohorts based on the type of histology. Each histology is presented as a distinct arm in the endpoints
    End point values
    		 Hairy Cell Leukemia (HCL)
    Number of subjects analysed
    49
    Units: Weeks
        median (confidence interval 95%)
    999 (999 to 999)
    No statistical analyses for this end point

    Secondary: Duration of Response (DoR) in the Multiple Myeloma (MM) cohort

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    End point title
    		 Duration of Response (DoR) in the Multiple Myeloma (MM) cohort [24]
    End point description
    For the subset of subjects who showed a confirmed response as defined for each cohort, Duration of Response (DoR) was defined as the time (in weeks) from first documented evidence of response (the first response prior to confirmation) until time of documented disease progression or death due to any cause, whichever was first. If the subject did not have a documented date of progression or death, DoR was censored at the date of the last adequate assessment.
    End point type
    Secondary
    End point timeframe
    From first documented evidence of response (the first response prior to confirmation) until time of documented disease progression or death due to any cause, whichever comes first, assessed up to 92 months (cut-off date for end of study = 10-Dec-21)
    Notes
    [24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Subjects were enrolled into cohorts based on the type of histology. Each histology is presented as a distinct arm in the endpoints
    End point values
    		 Multiple Myeloma (MM)
    Number of subjects analysed
    5
    Units: Weeks
        median (confidence interval 95%)
    48.1 (24.3 to 999)
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS) in the Adenocarcinoma of the Small Intestine (ASI) cohort

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    End point title
    		 Progression Free Survival (PFS) in the Adenocarcinoma of the Small Intestine (ASI) cohort [25]
    End point description
    Progression Free Survival (PFS) was defined as the interval between the first dose of study treatment and earlier date of first radiologically documented progression or death due to any cause. If the subject did not have a documented date of progression or death, PFS was censored at the date of the last adequate assessment. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started.
    End point type
    Secondary
    End point timeframe
    From study treatment start date until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 92 months (cut-off date for end of study = 10-Dec-21)
    Notes
    [25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Subjects were enrolled into cohorts based on the type of histology. Each histology is presented as a distinct arm in the endpoints
    End point values
    		 Adenocarcinoma of the Small Intestine (ASI)
    Number of subjects analysed
    3
    Units: Weeks
    median (confidence interval 95%)
        Investigator assessment
    999 (999 to 999)
        Independent radiology review
    40.1 (4.1 to 999)
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS) in the Anaplastic Thyroid Cancer (ATC) cohort

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    End point title
    		 Progression Free Survival (PFS) in the Anaplastic Thyroid Cancer (ATC) cohort [26]
    End point description
    Progression Free Survival (PFS) was defined as the interval between the first dose of study treatment and earlier date of first radiologically documented progression or death due to any cause. If the subject did not have a documented date of progression or death, PFS was censored at the date of the last adequate assessment. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started.
    End point type
    Secondary
    End point timeframe
    From study treatment start date until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 92 months (cut-off date for end of study = 10-Dec-21)
    Notes
    [26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Subjects were enrolled into cohorts based on the type of histology. Each histology is presented as a distinct arm in the endpoints
    End point values
    		 Anaplastic Thyroid Cancer (ATC)
    Number of subjects analysed
    36
    Units: Weeks
    median (confidence interval 95%)
        Investigator assessment
    29.1 (20.3 to 59.9)
        Independent radiology review
    24.1 (16.1 to 56.0)
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS) in the Biliary Tract Cancer (BTC) cohort

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    End point title
    		 Progression Free Survival (PFS) in the Biliary Tract Cancer (BTC) cohort [27]
    End point description
    Progression Free Survival (PFS) was defined as the interval between the first dose of study treatment and earlier date of first radiologically documented progression or death due to any cause. If the subject did not have a documented date of progression or death, PFS was censored at the date of the last adequate assessment. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started.
    End point type
    Secondary
    End point timeframe
    From study treatment start date until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 92 months (cut-off date for end of study = 10-Dec-21)
    Notes
    [27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Subjects were enrolled into cohorts based on the type of histology. Each histology is presented as a distinct arm in the endpoints
    End point values
    		 Biliary Tract Cancer (BTC)
    Number of subjects analysed
    43
    Units: Weeks
    median (confidence interval 95%)
        Investigator assessment
    39.0 (24.1 to 41.0)
        Independent radiology review
    32.6 (23.6 to 56.0)
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS) in the High Grade (WHO G3/G4) Glioma (HGG) cohort

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    End point title
    		 Progression Free Survival (PFS) in the High Grade (WHO G3/G4) Glioma (HGG) cohort [28]
    End point description
    Progression Free Survival (PFS) was defined as the interval between the first dose of study treatment and earlier date of first radiologically documented progression or death due to any cause. If the subject did not have a documented date of progression or death, PFS was censored at the date of the last adequate assessment.
    End point type
    Secondary
    End point timeframe
    From study treatment start date until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 92 months (cut-off date for end of study = 10-Dec-21)
    Notes
    [28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Subjects were enrolled into cohorts based on the type of histology. Each histology is presented as a distinct arm in the endpoints
    End point values
    		 High Grade (WHO G3/G4) Glioma (HGG)
    Number of subjects analysed
    45
    Units: Weeks
    median (confidence interval 95%)
        Investigator assessment
    24.0 (8.0 to 59.4)
        Independent radiology review
    19.7 (8.0 to 32.1)
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS) in the Low Grade (WHO G1/G2) Glioma (LGG) cohort

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    End point title
    		 Progression Free Survival (PFS) in the Low Grade (WHO G1/G2) Glioma (LGG) cohort [29]
    End point description
    Progression Free Survival (PFS) was defined as the interval between the first dose of study treatment and earlier date of first radiologically documented progression or death due to any cause. If the subject did not have a documented date of progression or death, PFS was censored at the date of the last adequate assessment.
    End point type
    Secondary
    End point timeframe
    From study treatment start date until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 92 months (cut-off date for end of study = 10-Dec-21)
    Notes
    [29] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Subjects were enrolled into cohorts based on the type of histology. Each histology is presented as a distinct arm in the endpoints
    End point values
    		 Low Grade (WHO G1/G2) Glioma (LGG)
    Number of subjects analysed
    13
    Units: Weeks
    median (confidence interval 95%)
        Investigator assessment
    999 (32.1 to 999)
        Independent radiology review
    40.1 (20.3 to 143.7)
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS) in the Hairy Cell Leukemia (HCL) cohort

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    End point title
    		 Progression Free Survival (PFS) in the Hairy Cell Leukemia (HCL) cohort [30]
    End point description
    Progression Free Survival (PFS) was defined as the interval between the first dose of study treatment and earlier date of first radiologically documented progression or death due to any cause. If the subject did not have a documented date of progression or death, PFS was censored at the date of the last adequate assessment.
    End point type
    Secondary
    End point timeframe
    From study treatment start date until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 92 months (cut-off date for end of study = 10-Dec-21)
    Notes
    [30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Subjects were enrolled into cohorts based on the type of histology. Each histology is presented as a distinct arm in the endpoints
    End point values
    		 Hairy Cell Leukemia (HCL)
    Number of subjects analysed
    55
    Units: Weeks
        median (confidence interval 95%)
    999 (999 to 999)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS) in the Low Grade (WHO G1/G2) Glioma (LGG) cohort

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    End point title
    		 Overall Survival (OS) in the Low Grade (WHO G1/G2) Glioma (LGG) cohort [31]
    End point description
    Overall Survival (OS) was defined as the time from first dose until death due to any cause. Censoring was performed using the date of last known contact for those who were alive at the time of analysis.
    End point type
    Secondary
    End point timeframe
    From study treatment start date until date of death from any cause, assessed up to 92 months (cut-off date for end of study = 10-Dec-21)
    Notes
    [31] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Subjects were enrolled into cohorts based on the type of histology. Each histology is presented as a distinct arm in the endpoints
    End point values
    		 Low Grade (WHO G1/G2) Glioma (LGG)
    Number of subjects analysed
    13
    Units: Weeks
        median (confidence interval 95%)
    999 (50.4 to 999)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS) in the High Grade (WHO G3/G4) Glioma (HGG) cohort

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    End point title
    		 Overall Survival (OS) in the High Grade (WHO G3/G4) Glioma (HGG) cohort [32]
    End point description
    Overall Survival (OS) was defined as the time from first dose until death due to any cause. Censoring was performed using the date of last known contact for those who were alive at the time of analysis.
    End point type
    Secondary
    End point timeframe
    From study treatment start date until date of death from any cause, assessed up to 92 months (cut-off date for end of study = 10-Dec-21)
    Notes
    [32] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Subjects were enrolled into cohorts based on the type of histology. Each histology is presented as a distinct arm in the endpoints
    End point values
    		 High Grade (WHO G3/G4) Glioma (HGG)
    Number of subjects analysed
    45
    Units: Weeks
        median (confidence interval 95%)
    76.4 (41.1 to 139.9)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS) in the Hairy Cell Leukemia (HCL) cohort

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    End point title
    		 Overall Survival (OS) in the Hairy Cell Leukemia (HCL) cohort [33]
    End point description
    Overall Survival (OS) was defined as the time from first dose until death due to any cause. Censoring was performed using the date of last known contact for those who were alive at the time of analysis.
    End point type
    Secondary
    End point timeframe
    From study treatment start date until date of death from any cause, assessed up to 92 months (cut-off date for end of study = 10-Dec-21)
    Notes
    [33] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Subjects were enrolled into cohorts based on the type of histology. Each histology is presented as a distinct arm in the endpoints
    End point values
    		 Hairy Cell Leukemia (HCL)
    Number of subjects analysed
    55
    Units: Weeks
        median (confidence interval 95%)
    999 (999 to 999)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS) in the Adenocarcinoma of the Small Intestine (ASI) cohort

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    End point title
    		 Overall Survival (OS) in the Adenocarcinoma of the Small Intestine (ASI) cohort [34]
    End point description
    Overall Survival (OS) was defined as the time from first dose until death due to any cause. Censoring was performed using the date of last known contact for those who were alive at the time of analysis.
    End point type
    Secondary
    End point timeframe
    From study treatment start date until date of death from any cause, assessed up to 92 months (cut-off date for end of study = 10-Dec-21)
    Notes
    [34] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Subjects were enrolled into cohorts based on the type of histology. Each histology is presented as a distinct arm in the endpoints
    End point values
    		 Adenocarcinoma of the Small Intestine (ASI)
    Number of subjects analysed
    3
    Units: Weeks
        median (confidence interval 95%)
    94.6 (14.9 to 999)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS) in the Multiple Myeloma (MM) cohort

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    End point title
    		 Overall Survival (OS) in the Multiple Myeloma (MM) cohort [35]
    End point description
    Overall Survival (OS) was defined as the time from first dose until death due to any cause. Censoring was performed using the date of last known contact for those who were alive at the time of analysis.
    End point type
    Secondary
    End point timeframe
    From study treatment start date until date of death from any cause, assessed up to 92 months (cut-off date for end of study = 10-Dec-21)
    Notes
    [35] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Subjects were enrolled into cohorts based on the type of histology. Each histology is presented as a distinct arm in the endpoints
    End point values
    		 Multiple Myeloma (MM)
    Number of subjects analysed
    10
    Units: Weeks
        median (confidence interval 95%)
    147.3 (12.4 to 194.0)
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS) in the Multiple Myeloma (MM) cohort

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    End point title
    		 Progression Free Survival (PFS) in the Multiple Myeloma (MM) cohort [36]
    End point description
    Progression Free Survival (PFS) was defined as the interval between the first dose of study treatment and earlier date of first radiologically documented progression or death due to any cause. If the subject did not have a documented date of progression or death, PFS was censored at the date of the last adequate assessment.
    End point type
    Secondary
    End point timeframe
    From study treatment start date until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 92 months (cut-off date for end of study = 10-Dec-21)
    Notes
    [36] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Subjects were enrolled into cohorts based on the type of histology. Each histology is presented as a distinct arm in the endpoints
    End point values
    		 Multiple Myeloma (MM)
    Number of subjects analysed
    10
    Units: Weeks
        median (confidence interval 95%)
    27.5 (10.0 to 55.9)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS) in the Anaplastic Thyroid Cancer (ATC) cohort

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    End point title
    		 Overall Survival (OS) in the Anaplastic Thyroid Cancer (ATC) cohort [37]
    End point description
    Overall Survival (OS) was defined as the time from first dose until death due to any cause. Censoring was performed using the date of last known contact for those who were alive at the time of analysis.
    End point type
    Secondary
    End point timeframe
    From study treatment start date until date of death from any cause, assessed up to 92 months (cut-off date for end of study = 10-Dec-21)
    Notes
    [37] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Subjects were enrolled into cohorts based on the type of histology. Each histology is presented as a distinct arm in the endpoints
    End point values
    		 Anaplastic Thyroid Cancer (ATC)
    Number of subjects analysed
    36
    Units: Weeks
        median (confidence interval 95%)
    62.9 (29.6 to 100.9)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS) in the Biliary Tract Cancer (BTC) cohort

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    End point title
    		 Overall Survival (OS) in the Biliary Tract Cancer (BTC) cohort [38]
    End point description
    Overall Survival (OS) was defined as the time from first dose until death due to any cause. Censoring was performed using the date of last known contact for those who were alive at the time of analysis.
    End point type
    Secondary
    End point timeframe
    From study treatment start date until date of death from any cause, assessed up to 92 months (cut-off date for end of study = 10-Dec-21)
    Notes
    [38] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Subjects were enrolled into cohorts based on the type of histology. Each histology is presented as a distinct arm in the endpoints
    End point values
    		 Biliary Tract Cancer (BTC)
    Number of subjects analysed
    43
    Units: Weeks
        median (confidence interval 95%)
    58.9 (45.4 to 76.6)
    No statistical analyses for this end point

    Secondary: Number of Participants with Adverse Events (AEs)

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    End point title
    		 Number of Participants with Adverse Events (AEs)
    End point description
    The distribution of adverse events (AE) was done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs) and Serious Adverse Event (TESAEs) through the monitoring of relevant clinical and laboratory safety parameters.
    End point type
    Secondary
    End point timeframe
    From study treatment start date till 30 days safety follow-up, assessed up to 92 months (cut-off date for end of study = 10-Dec-21)
    End point values
    		 Anaplastic Thyroid Cancer (ATC) Biliary Tract Cancer (BTC) Gastrointestinal Stromal Tumor (GIST) Low Grade (WHO G1/G2) Glioma (LGG) High Grade (WHO G3/G4) Glioma (HGG) Adenocarcinoma of the Small Intestine (ASI) Hairy Cell Leukemia (HCL) Multiple Myeloma (MM)
    Number of subjects analysed
    36
    43
    1
    13
    45
    3
    55
    10
    Units: Participants
        Any AE
    36
    43
    1
    12
    42
    3
    55
    9
        AEs related to study treatment
    27
    42
    1
    12
    37
    3
    52
    7
        AEs leading to permanent disc. of any study tx
    6
    1
    0
    2
    4
    1
    13
    1
        AEs leading to dose reduction
    17
    15
    1
    4
    18
    2
    29
    5
        AEs leading to dose interruption/delay
    19
    24
    1
    6
    18
    2
    40
    6
        Any SAE
    20
    17
    1
    3
    16
    0
    32
    4
        SAEs related to study treatment
    7
    9
    0
    1
    7
    0
    19
    3
        Fatal SAEs
    3
    2
    0
    0
    1
    0
    3
    0
    No statistical analyses for this end point

    Post-hoc: All collected deaths

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    End point title
    		 All collected deaths
    End point description
    On-treatment deaths were collected from first dose of study medication to 30 days after study drug discontinuation, for a maximum duration of 85 months. Post-treatment survival follow-up deaths were collected from day 31 after last dose of first dose of study medication, up to 92 months. All deaths refer to the sum of on-treatment deaths and post-treatment survival follow-up deaths.
    End point type
    Post-hoc
    End point timeframe
    On-treatment deaths: Up to 85 months. Post-treatment survival follow-up deaths: Up to 92 months.
    End point values
    		 Anaplastic Thyroid Cancer (ATC) Biliary Tract Cancer (BTC) Gastrointestinal Stromal Tumor (GIST) Low Grade (WHO G1/G2) Glioma (LGG) High Grade (WHO G3/G4) Glioma (HGG) Adenocarcinoma of the Small Intestine (ASI) Hairy Cell Leukemia (HCL) Multiple Myeloma (MM)
    Number of subjects analysed
    36
    43
    1
    13
    45
    3
    55
    10
    Units: Participants
        On-treatment deaths
    6
    6
    0
    1
    2
    0
    4
    1
        Post-treatment survival follow-up deaths
    18
    28
    1
    3
    26
    3
    4
    8
        All deaths
    24
    34
    1
    4
    28
    3
    8
    9
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported from first dose of study treatment until end of study treatment plus 30 days, up to approximately 85 months (study treatment with dabrafenib and trametinib ranged from 1 to 84 months).
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    Anaplastic Thyroid Cancer (ATC)
    Reporting group description
    		 All subjects enrolled received oral dabrafenib 150 mg bid in combination with oral trametinib 2 mg once daily. Subjects continued treatment until an unacceptable toxicity, disease progression, or death.

    Reporting group title
    Biliary Tract Cancer (BTC)
    Reporting group description
    		 All subjects enrolled received oral dabrafenib 150 mg bid in combination with oral trametinib 2 mg once daily. Subjects continued treatment until an unacceptable toxicity, disease progression, or death.

    Reporting group title
    Gastrointestinal Stromal Tumor (GIST)
    Reporting group description
    		 All subjects enrolled received oral dabrafenib 150 mg bid in combination with oral trametinib 2 mg once daily. Subjects continued treatment until an unacceptable toxicity, disease progression, or death.

    Reporting group title
    Low Grade (WHO G1/G2) Glioma (LGG)
    Reporting group description
    		 All subjects enrolled received oral dabrafenib 150 mg bid in combination with oral trametinib 2 mg once daily. Subjects continued treatment until an unacceptable toxicity, disease progression, or death.

    Reporting group title
    Total
    Reporting group description
    		 All subjects enrolled in the study received oral dabrafenib 150 mg bid in combination with oral trametinib 2 mg once daily. Subjects continued treatment until an unacceptable toxicity, disease progression, or death.

    Reporting group title
    Adenocarcinoma of the Small Intestine (ASI)
    Reporting group description
    		 All subjects enrolled received oral dabrafenib 150 mg bid in combination with oral trametinib 2 mg once daily. Subjects continued treatment until an unacceptable toxicity, disease progression, or death.

    Reporting group title
    Hairy Cell Leukemia (HCL)
    Reporting group description
    		 All subjects enrolled received oral dabrafenib 150 mg bid in combination with oral trametinib 2 mg once daily. Subjects continued treatment until an unacceptable toxicity, disease progression, or death.

    Reporting group title
    Multiple Myeloma (MM)
    Reporting group description
    		 All subjects enrolled received oral dabrafenib 150 mg bid in combination with oral trametinib 2 mg once daily. Subjects continued treatment until an unacceptable toxicity, disease progression, or death.

    Reporting group title
    High Grade (WHO G3/G4) Glioma (HGG)
    Reporting group description
    		 All subjects enrolled received oral dabrafenib 150 mg bid in combination with oral trametinib 2 mg once daily. Subjects continued treatment until an unacceptable toxicity, disease progression, or death.

    Serious adverse events
    		 Anaplastic Thyroid Cancer (ATC) Biliary Tract Cancer (BTC) Gastrointestinal Stromal Tumor (GIST) Low Grade (WHO G1/G2) Glioma (LGG) Total Adenocarcinoma of the Small Intestine (ASI) Hairy Cell Leukemia (HCL) Multiple Myeloma (MM) High Grade (WHO G3/G4) Glioma (HGG)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    20 / 36 (55.56%)
    17 / 43 (39.53%)
    1 / 1 (100.00%)
    3 / 13 (23.08%)
    93 / 206 (45.15%)
    0 / 3 (0.00%)
    32 / 55 (58.18%)
    4 / 10 (40.00%)
    16 / 45 (35.56%)
         number of deaths (all causes)
    6
    6
    0
    1
    20
    0
    4
    1
    2
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of the cervix
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bowen's disease
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder transitional cell carcinoma
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder neoplasm
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    2 / 206 (0.97%)
    0 / 3 (0.00%)
    2 / 55 (3.64%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    4 / 206 (1.94%)
    0 / 3 (0.00%)
    4 / 55 (7.27%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    5 / 7
    0 / 0
    5 / 7
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma pancreas
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic lymphocytic leukaemia
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastatic squamous cell carcinoma
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Invasive breast carcinoma
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hodgkin's disease
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal stromal tumour
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    4 / 206 (1.94%)
    0 / 3 (0.00%)
    4 / 55 (7.27%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    3 / 14
    0 / 0
    3 / 14
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    4 / 206 (1.94%)
    0 / 3 (0.00%)
    4 / 55 (7.27%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    4 / 5
    0 / 0
    4 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    2 / 206 (0.97%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic thrombosis
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    3 / 206 (1.46%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    1 / 10 (10.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fat necrosis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    4 / 206 (1.94%)
    0 / 3 (0.00%)
    4 / 55 (7.27%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 5
    0 / 0
    2 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Pyrexia
         subjects affected / exposed
    1 / 36 (2.78%)
    9 / 43 (20.93%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    23 / 206 (11.17%)
    0 / 3 (0.00%)
    10 / 55 (18.18%)
    1 / 10 (10.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    2 / 4
    10 / 13
    0 / 0
    1 / 1
    26 / 38
    0 / 0
    10 / 17
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Haemophagocytic lymphohistiocytosis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Aspiration
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary granuloma
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    3 / 206 (1.46%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 3
    0 / 0
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    3 / 36 (8.33%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    3 / 206 (1.46%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary haematoma
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Hallucination
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device failure
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    3 / 206 (1.46%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    3 / 3
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    2 / 206 (0.97%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Clavicle fracture
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    2 / 206 (0.97%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural discomfort
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    2 / 206 (0.97%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 4
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Conduction disorder
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac ventricular thrombosis
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stress cardiomyopathy
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Amnesia
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ataxia
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    2 / 206 (0.97%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral thrombosis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral cyst
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Central nervous system lesion
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    2 / 206 (0.97%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    2 / 45 (4.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Guillain-Barre syndrome
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Facial nerve disorder
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    4 / 206 (1.94%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    4 / 45 (8.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 4
    0 / 0
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paralysis recurrent laryngeal nerve
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    2 / 206 (0.97%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    1 / 1
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemolytic uraemic syndrome
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    2 / 206 (0.97%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Autoimmune haemolytic anaemia
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    2 / 206 (0.97%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    2 / 206 (0.97%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    3 / 206 (1.46%)
    0 / 3 (0.00%)
    2 / 55 (3.64%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Amaurosis fugax
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    1 / 10 (10.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diplopia
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    2 / 206 (0.97%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    1 / 10 (10.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    4 / 206 (1.94%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    1 / 10 (10.00%)
    3 / 45 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 4
    0 / 0
    0 / 0
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal stenosis
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestinal haemorrhage
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    1 / 1 (100.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    2 / 206 (0.97%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    1 / 10 (10.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    7 / 206 (3.40%)
    0 / 3 (0.00%)
    2 / 55 (3.64%)
    0 / 10 (0.00%)
    3 / 45 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    1 / 1
    2 / 7
    0 / 0
    0 / 2
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic cytolysis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    0 / 36 (0.00%)
    3 / 43 (6.98%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    3 / 206 (1.46%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
    0 / 0
    0 / 4
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erythema nodosum
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    2 / 206 (0.97%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Calculus urinary
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    2 / 36 (5.56%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    3 / 206 (1.46%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 0
    0 / 0
    1 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenocortical insufficiency acute
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cervicitis human papilloma virus
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    2 / 206 (0.97%)
    0 / 3 (0.00%)
    2 / 55 (3.64%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacterial diarrhoea
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    2 / 206 (0.97%)
    0 / 3 (0.00%)
    2 / 55 (3.64%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 4
    0 / 0
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis pseudomonas
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterobacter infection
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    1 / 10 (10.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic infection
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Parotitis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Otitis media acute
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymph node tuberculosis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    1 / 10 (10.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    8 / 36 (22.22%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    13 / 206 (6.31%)
    0 / 3 (0.00%)
    4 / 55 (7.27%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 2
    0 / 0
    0 / 0
    0 / 18
    0 / 0
    0 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia necrotising
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    1 / 10 (10.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 36 (5.56%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    8 / 206 (3.88%)
    0 / 3 (0.00%)
    2 / 55 (3.64%)
    1 / 10 (10.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 1
    2 / 9
    0 / 0
    2 / 3
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 36 (2.78%)
    3 / 43 (6.98%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    5 / 206 (2.43%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
    0 / 0
    0 / 5
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 4
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    2 / 206 (0.97%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    3 / 206 (1.46%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemic hyperosmolar nonketotic syndrome
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Anaplastic Thyroid Cancer (ATC) Biliary Tract Cancer (BTC) Gastrointestinal Stromal Tumor (GIST) Low Grade (WHO G1/G2) Glioma (LGG) Total Adenocarcinoma of the Small Intestine (ASI) Hairy Cell Leukemia (HCL) Multiple Myeloma (MM) High Grade (WHO G3/G4) Glioma (HGG)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    36 / 36 (100.00%)
    43 / 43 (100.00%)
    1 / 1 (100.00%)
    12 / 13 (92.31%)
    201 / 206 (97.57%)
    3 / 3 (100.00%)
    55 / 55 (100.00%)
    9 / 10 (90.00%)
    42 / 45 (93.33%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    4 / 206 (1.94%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    2 / 45 (4.44%)
         occurrences all number
    0
    0
    0
    1
    5
    0
    1
    0
    3
    Seborrhoeic keratosis
         subjects affected / exposed
    2 / 36 (5.56%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    7 / 206 (3.40%)
    0 / 3 (0.00%)
    2 / 55 (3.64%)
    0 / 10 (0.00%)
    2 / 45 (4.44%)
         occurrences all number
    2
    1
    0
    0
    7
    0
    2
    0
    2
    Melanocytic naevus
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    2 / 13 (15.38%)
    4 / 206 (1.94%)
    0 / 3 (0.00%)
    2 / 55 (3.64%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    2
    4
    0
    2
    0
    0
    Lipoma
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Fibroma
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Basal cell carcinoma
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    15 / 206 (7.28%)
    0 / 3 (0.00%)
    13 / 55 (23.64%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    3
    0
    0
    25
    0
    21
    0
    1
    Vascular disorders
    Lymphoedema
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    2 / 206 (0.97%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    1
    2
    0
    1
    0
    0
    Hypotension
         subjects affected / exposed
    5 / 36 (13.89%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    2 / 13 (15.38%)
    15 / 206 (7.28%)
    0 / 3 (0.00%)
    8 / 55 (14.55%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    6
    0
    0
    3
    18
    0
    9
    0
    0
    Hypertension
         subjects affected / exposed
    1 / 36 (2.78%)
    6 / 43 (13.95%)
    0 / 1 (0.00%)
    2 / 13 (15.38%)
    21 / 206 (10.19%)
    1 / 3 (33.33%)
    8 / 55 (14.55%)
    1 / 10 (10.00%)
    2 / 45 (4.44%)
         occurrences all number
    1
    6
    0
    3
    26
    1
    11
    1
    3
    Hot flush
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    5 / 206 (2.43%)
    0 / 3 (0.00%)
    3 / 55 (5.45%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    1
    0
    0
    5
    0
    3
    0
    1
    Flushing
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    6 / 206 (2.91%)
    1 / 3 (33.33%)
    3 / 55 (5.45%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    0
    1
    10
    1
    7
    0
    0
    Varicose vein
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    13 / 36 (36.11%)
    14 / 43 (32.56%)
    0 / 1 (0.00%)
    8 / 13 (61.54%)
    86 / 206 (41.75%)
    0 / 3 (0.00%)
    29 / 55 (52.73%)
    3 / 10 (30.00%)
    19 / 45 (42.22%)
         occurrences all number
    20
    17
    0
    9
    148
    0
    76
    3
    23
    Asthenia
         subjects affected / exposed
    3 / 36 (8.33%)
    7 / 43 (16.28%)
    1 / 1 (100.00%)
    0 / 13 (0.00%)
    19 / 206 (9.22%)
    0 / 3 (0.00%)
    3 / 55 (5.45%)
    1 / 10 (10.00%)
    4 / 45 (8.89%)
         occurrences all number
    4
    9
    1
    0
    27
    0
    5
    1
    7
    Chills
         subjects affected / exposed
    8 / 36 (22.22%)
    12 / 43 (27.91%)
    0 / 1 (0.00%)
    3 / 13 (23.08%)
    61 / 206 (29.61%)
    1 / 3 (33.33%)
    30 / 55 (54.55%)
    2 / 10 (20.00%)
    5 / 45 (11.11%)
         occurrences all number
    14
    21
    0
    5
    195
    1
    147
    2
    5
    Feeling cold
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    3 / 206 (1.46%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    2
    0
    0
    1
    3
    0
    0
    0
    0
    Gait disturbance
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    7 / 206 (3.40%)
    0 / 3 (0.00%)
    2 / 55 (3.64%)
    1 / 10 (10.00%)
    2 / 45 (4.44%)
         occurrences all number
    1
    1
    0
    0
    7
    0
    2
    1
    2
    Influenza like illness
         subjects affected / exposed
    0 / 36 (0.00%)
    3 / 43 (6.98%)
    0 / 1 (0.00%)
    2 / 13 (15.38%)
    13 / 206 (6.31%)
    0 / 3 (0.00%)
    7 / 55 (12.73%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    5
    0
    2
    18
    0
    10
    0
    1
    Injection site reaction
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    3 / 206 (1.46%)
    0 / 3 (0.00%)
    3 / 55 (5.45%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    0
    4
    0
    4
    0
    0
    Oedema peripheral
         subjects affected / exposed
    5 / 36 (13.89%)
    4 / 43 (9.30%)
    0 / 1 (0.00%)
    2 / 13 (15.38%)
    44 / 206 (21.36%)
    1 / 3 (33.33%)
    27 / 55 (49.09%)
    2 / 10 (20.00%)
    3 / 45 (6.67%)
         occurrences all number
    6
    4
    0
    3
    63
    1
    44
    2
    3
    Mucosal inflammation
         subjects affected / exposed
    3 / 36 (8.33%)
    3 / 43 (6.98%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    12 / 206 (5.83%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    2 / 10 (20.00%)
    2 / 45 (4.44%)
         occurrences all number
    3
    4
    0
    2
    14
    0
    1
    2
    2
    Nodule
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    2 / 206 (0.97%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    2
    0
    0
    2
    4
    0
    0
    0
    0
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 36 (5.56%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    3 / 13 (23.08%)
    11 / 206 (5.34%)
    1 / 3 (33.33%)
    3 / 55 (5.45%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    2
    1
    0
    3
    11
    1
    3
    0
    1
    Oedema
         subjects affected / exposed
    1 / 36 (2.78%)
    3 / 43 (6.98%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    6 / 206 (2.91%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    2 / 45 (4.44%)
         occurrences all number
    1
    3
    0
    0
    6
    0
    0
    0
    2
    Malaise
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    2 / 13 (15.38%)
    9 / 206 (4.37%)
    0 / 3 (0.00%)
    6 / 55 (10.91%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    2
    0
    0
    2
    23
    0
    19
    0
    0
    Pain
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    5 / 206 (2.43%)
    1 / 3 (33.33%)
    1 / 55 (1.82%)
    1 / 10 (10.00%)
    0 / 45 (0.00%)
         occurrences all number
    2
    0
    0
    0
    5
    1
    1
    1
    0
    Peripheral swelling
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    3 / 206 (1.46%)
    0 / 3 (0.00%)
    2 / 55 (3.64%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    1
    3
    0
    2
    0
    0
    Pyrexia
         subjects affected / exposed
    17 / 36 (47.22%)
    25 / 43 (58.14%)
    1 / 1 (100.00%)
    8 / 13 (61.54%)
    108 / 206 (52.43%)
    2 / 3 (66.67%)
    41 / 55 (74.55%)
    3 / 10 (30.00%)
    11 / 45 (24.44%)
         occurrences all number
    35
    56
    7
    18
    337
    3
    183
    5
    30
    Thirst
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    2 / 206 (0.97%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    1
    2
    0
    1
    0
    0
    Xerosis
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    3 / 206 (1.46%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    1
    1
    0
    1
    3
    0
    0
    0
    0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    4 / 206 (1.94%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    1
    0
    1
    4
    0
    1
    0
    1
    Sarcoidosis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    4 / 206 (1.94%)
    0 / 3 (0.00%)
    3 / 55 (5.45%)
    1 / 10 (10.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    0
    4
    0
    3
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    8 / 36 (22.22%)
    7 / 43 (16.28%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    31 / 206 (15.05%)
    0 / 3 (0.00%)
    13 / 55 (23.64%)
    1 / 10 (10.00%)
    2 / 45 (4.44%)
         occurrences all number
    9
    7
    0
    0
    38
    0
    18
    1
    3
    Dysphonia
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    4 / 206 (1.94%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    1
    0
    0
    1
    4
    0
    1
    0
    1
    Hiccups
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    2 / 206 (0.97%)
    1 / 3 (33.33%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    1
    1
    0
    0
    Haemoptysis
         subjects affected / exposed
    4 / 36 (11.11%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    4 / 206 (1.94%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    4
    0
    0
    0
    4
    0
    0
    0
    0
    Epistaxis
         subjects affected / exposed
    1 / 36 (2.78%)
    2 / 43 (4.65%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    13 / 206 (6.31%)
    0 / 3 (0.00%)
    7 / 55 (12.73%)
    0 / 10 (0.00%)
    2 / 45 (4.44%)
         occurrences all number
    1
    3
    0
    7
    22
    0
    9
    0
    2
    Cough
         subjects affected / exposed
    4 / 36 (11.11%)
    10 / 43 (23.26%)
    0 / 1 (0.00%)
    3 / 13 (23.08%)
    56 / 206 (27.18%)
    0 / 3 (0.00%)
    30 / 55 (54.55%)
    1 / 10 (10.00%)
    8 / 45 (17.78%)
         occurrences all number
    4
    11
    0
    5
    88
    0
    57
    1
    10
    Lung disorder
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    2 / 206 (0.97%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    1 / 10 (10.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    1
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    3 / 206 (1.46%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    2
    0
    0
    0
    3
    0
    1
    0
    0
    Rhinitis allergic
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    5 / 206 (2.43%)
    0 / 3 (0.00%)
    3 / 55 (5.45%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    2
    0
    0
    0
    7
    0
    5
    0
    0
    Pulmonary embolism
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    3 / 206 (1.46%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    2
    0
    0
    0
    3
    0
    1
    0
    0
    Upper-airway cough syndrome
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    8 / 206 (3.88%)
    0 / 3 (0.00%)
    7 / 55 (12.73%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    0
    0
    10
    0
    9
    0
    0
    Pneumonitis
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    4 / 206 (1.94%)
    0 / 3 (0.00%)
    2 / 55 (3.64%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    2
    0
    0
    0
    4
    0
    2
    0
    0
    Pleural effusion
         subjects affected / exposed
    2 / 36 (5.56%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    3 / 206 (1.46%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    3
    1
    0
    0
    4
    0
    0
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 43 (4.65%)
    0 / 1 (0.00%)
    2 / 13 (15.38%)
    16 / 206 (7.77%)
    0 / 3 (0.00%)
    11 / 55 (20.00%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    2
    0
    2
    20
    0
    15
    0
    1
    Nasal congestion
         subjects affected / exposed
    2 / 36 (5.56%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    23 / 206 (11.17%)
    0 / 3 (0.00%)
    20 / 55 (36.36%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    2
    1
    0
    0
    35
    0
    32
    0
    0
    Productive cough
         subjects affected / exposed
    3 / 36 (8.33%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    13 / 206 (6.31%)
    0 / 3 (0.00%)
    9 / 55 (16.36%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    3
    1
    0
    0
    16
    0
    12
    0
    0
    Wheezing
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    4 / 206 (1.94%)
    0 / 3 (0.00%)
    3 / 55 (5.45%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    0
    0
    4
    0
    3
    0
    0
    Psychiatric disorders
    Depressed mood
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    2 / 206 (0.97%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    1 / 10 (10.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    1
    1
    Confusional state
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    2 / 13 (15.38%)
    8 / 206 (3.88%)
    0 / 3 (0.00%)
    3 / 55 (5.45%)
    1 / 10 (10.00%)
    2 / 45 (4.44%)
         occurrences all number
    0
    0
    0
    2
    14
    0
    6
    2
    4
    Anxiety
         subjects affected / exposed
    1 / 36 (2.78%)
    3 / 43 (6.98%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    9 / 206 (4.37%)
    0 / 3 (0.00%)
    4 / 55 (7.27%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    1
    3
    0
    1
    10
    0
    5
    0
    0
    Agitation
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    2 / 13 (15.38%)
    3 / 206 (1.46%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    0
    0
    2
    3
    0
    0
    0
    1
    Sleep disorder
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    3 / 206 (1.46%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    1
    0
    0
    1
    3
    0
    0
    0
    1
    Depression
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    2 / 13 (15.38%)
    10 / 206 (4.85%)
    0 / 3 (0.00%)
    5 / 55 (9.09%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    1
    1
    0
    2
    10
    0
    5
    0
    1
    Emotional disorder
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Insomnia
         subjects affected / exposed
    5 / 36 (13.89%)
    6 / 43 (13.95%)
    0 / 1 (0.00%)
    2 / 13 (15.38%)
    26 / 206 (12.62%)
    1 / 3 (33.33%)
    9 / 55 (16.36%)
    1 / 10 (10.00%)
    2 / 45 (4.44%)
         occurrences all number
    5
    6
    0
    2
    26
    1
    9
    1
    2
    Libido decreased
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    4 / 206 (1.94%)
    0 / 3 (0.00%)
    4 / 55 (7.27%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    0
    4
    0
    4
    0
    0
    Mood swings
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 36 (2.78%)
    2 / 43 (4.65%)
    0 / 1 (0.00%)
    2 / 13 (15.38%)
    7 / 206 (3.40%)
    0 / 3 (0.00%)
    2 / 55 (3.64%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    2
    2
    0
    2
    8
    0
    2
    0
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 36 (11.11%)
    7 / 43 (16.28%)
    0 / 1 (0.00%)
    3 / 13 (23.08%)
    41 / 206 (19.90%)
    0 / 3 (0.00%)
    18 / 55 (32.73%)
    0 / 10 (0.00%)
    9 / 45 (20.00%)
         occurrences all number
    6
    12
    0
    3
    69
    0
    39
    0
    9
    Aspartate aminotransferase increased
         subjects affected / exposed
    5 / 36 (13.89%)
    11 / 43 (25.58%)
    0 / 1 (0.00%)
    4 / 13 (30.77%)
    50 / 206 (24.27%)
    0 / 3 (0.00%)
    21 / 55 (38.18%)
    0 / 10 (0.00%)
    9 / 45 (20.00%)
         occurrences all number
    8
    18
    0
    4
    96
    0
    53
    0
    13
    Blood alkaline phosphatase increased
         subjects affected / exposed
    6 / 36 (16.67%)
    9 / 43 (20.93%)
    0 / 1 (0.00%)
    3 / 13 (23.08%)
    36 / 206 (17.48%)
    0 / 3 (0.00%)
    16 / 55 (29.09%)
    2 / 10 (20.00%)
    0 / 45 (0.00%)
         occurrences all number
    8
    12
    0
    7
    58
    0
    29
    2
    0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 36 (0.00%)
    3 / 43 (6.98%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    5 / 206 (2.43%)
    0 / 3 (0.00%)
    2 / 55 (3.64%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    3
    0
    0
    5
    0
    2
    0
    0
    Blood creatinine increased
         subjects affected / exposed
    2 / 36 (5.56%)
    5 / 43 (11.63%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    22 / 206 (10.68%)
    0 / 3 (0.00%)
    13 / 55 (23.64%)
    1 / 10 (10.00%)
    1 / 45 (2.22%)
         occurrences all number
    3
    6
    0
    0
    32
    0
    21
    1
    1
    Blood glucose increased
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    9 / 206 (4.37%)
    0 / 3 (0.00%)
    4 / 55 (7.27%)
    1 / 10 (10.00%)
    2 / 45 (4.44%)
         occurrences all number
    0
    2
    0
    1
    11
    0
    5
    1
    2
    Blood oestrogen decreased
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Ejection fraction decreased
         subjects affected / exposed
    3 / 36 (8.33%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    17 / 206 (8.25%)
    0 / 3 (0.00%)
    7 / 55 (12.73%)
    1 / 10 (10.00%)
    5 / 45 (11.11%)
         occurrences all number
    6
    0
    0
    1
    24
    0
    11
    1
    5
    Blood urea increased
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    2 / 206 (0.97%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    2
    0
    0
    0
    2
    0
    0
    0
    0
    Blood uric acid increased
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    2 / 206 (0.97%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    1
    0
    1
    2
    0
    0
    0
    0
    C-reactive protein increased
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    6 / 206 (2.91%)
    0 / 3 (0.00%)
    2 / 55 (3.64%)
    1 / 10 (10.00%)
    2 / 45 (4.44%)
         occurrences all number
    0
    1
    0
    0
    7
    0
    3
    1
    2
    Blood testosterone decreased
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    3 / 206 (1.46%)
    0 / 3 (0.00%)
    3 / 55 (5.45%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    3
    0
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    3 / 36 (8.33%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    11 / 206 (5.34%)
    0 / 3 (0.00%)
    5 / 55 (9.09%)
    1 / 10 (10.00%)
    1 / 45 (2.22%)
         occurrences all number
    3
    0
    0
    1
    14
    0
    6
    1
    3
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    3 / 36 (8.33%)
    12 / 43 (27.91%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    19 / 206 (9.22%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    2 / 45 (4.44%)
         occurrences all number
    5
    13
    0
    1
    22
    0
    1
    0
    2
    Glycosylated haemoglobin increased
         subjects affected / exposed
    0 / 36 (0.00%)
    3 / 43 (6.98%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    3 / 206 (1.46%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    3
    0
    0
    3
    0
    0
    0
    0
    Lipase increased
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    2 / 13 (15.38%)
    3 / 206 (1.46%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    2
    3
    0
    1
    0
    0
    Platelet count decreased
         subjects affected / exposed
    1 / 36 (2.78%)
    5 / 43 (11.63%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    11 / 206 (5.34%)
    0 / 3 (0.00%)
    3 / 55 (5.45%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    4
    9
    0
    1
    18
    0
    3
    0
    1
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 43 (4.65%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    6 / 206 (2.91%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    2 / 45 (4.44%)
         occurrences all number
    0
    2
    0
    2
    11
    0
    5
    0
    2
    Neutrophil count decreased
         subjects affected / exposed
    3 / 36 (8.33%)
    4 / 43 (9.30%)
    0 / 1 (0.00%)
    3 / 13 (23.08%)
    20 / 206 (9.71%)
    0 / 3 (0.00%)
    2 / 55 (3.64%)
    0 / 10 (0.00%)
    8 / 45 (17.78%)
         occurrences all number
    4
    4
    0
    5
    43
    0
    5
    0
    25
    Neutrophil count increased
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    5 / 206 (2.43%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    2 / 45 (4.44%)
         occurrences all number
    3
    0
    0
    0
    7
    0
    1
    0
    3
    Liver function test increased
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    2 / 206 (0.97%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    1 / 10 (10.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    1
    1
    0
    Urine output decreased
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Weight decreased
         subjects affected / exposed
    4 / 36 (11.11%)
    3 / 43 (6.98%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    13 / 206 (6.31%)
    1 / 3 (33.33%)
    3 / 55 (5.45%)
    1 / 10 (10.00%)
    0 / 45 (0.00%)
         occurrences all number
    4
    3
    0
    1
    13
    1
    3
    1
    0
    Weight increased
         subjects affected / exposed
    1 / 36 (2.78%)
    4 / 43 (9.30%)
    0 / 1 (0.00%)
    3 / 13 (23.08%)
    12 / 206 (5.83%)
    1 / 3 (33.33%)
    2 / 55 (3.64%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    1
    4
    0
    3
    12
    1
    2
    0
    1
    White blood cell count decreased
         subjects affected / exposed
    5 / 36 (13.89%)
    10 / 43 (23.26%)
    0 / 1 (0.00%)
    3 / 13 (23.08%)
    27 / 206 (13.11%)
    0 / 3 (0.00%)
    3 / 55 (5.45%)
    0 / 10 (0.00%)
    6 / 45 (13.33%)
         occurrences all number
    15
    16
    0
    9
    66
    0
    7
    0
    19
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    10 / 206 (4.85%)
    0 / 3 (0.00%)
    10 / 55 (18.18%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    0
    11
    0
    11
    0
    0
    Fall
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 43 (4.65%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    13 / 206 (6.31%)
    0 / 3 (0.00%)
    9 / 55 (16.36%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    5
    0
    1
    18
    0
    11
    0
    1
    Procedural pain
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    4 / 206 (1.94%)
    1 / 3 (33.33%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    1
    1
    0
    0
    4
    1
    1
    0
    0
    Radiation associated pain
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    1 / 10 (10.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    1
    0
    Skin laceration
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    3 / 206 (1.46%)
    0 / 3 (0.00%)
    3 / 55 (5.45%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    0
    4
    0
    4
    0
    0
    Thermal burn
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Cardiac disorders
    Atrioventricular block first degree
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    5 / 206 (2.43%)
    0 / 3 (0.00%)
    4 / 55 (7.27%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    0
    0
    5
    0
    4
    0
    0
    Bradycardia
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Sinus bradycardia
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    16 / 206 (7.77%)
    0 / 3 (0.00%)
    13 / 55 (23.64%)
    0 / 10 (0.00%)
    2 / 45 (4.44%)
         occurrences all number
    1
    0
    0
    0
    18
    0
    15
    0
    2
    Tachycardia
         subjects affected / exposed
    2 / 36 (5.56%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    5 / 206 (2.43%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    2
    1
    0
    1
    5
    0
    1
    0
    0
    Atrial fibrillation
         subjects affected / exposed
    2 / 36 (5.56%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    10 / 206 (4.85%)
    0 / 3 (0.00%)
    7 / 55 (12.73%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    3
    1
    0
    0
    15
    0
    11
    0
    0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    5 / 206 (2.43%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    4 / 45 (8.89%)
         occurrences all number
    0
    0
    0
    1
    5
    0
    0
    0
    4
    Balance disorder
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    4 / 206 (1.94%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    2 / 45 (4.44%)
         occurrences all number
    0
    0
    0
    1
    4
    0
    1
    0
    2
    Facial paralysis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Epilepsy
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    4 / 206 (1.94%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    3 / 45 (6.67%)
         occurrences all number
    0
    1
    0
    0
    8
    0
    0
    0
    7
    Dysgeusia
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    6 / 206 (2.91%)
    0 / 3 (0.00%)
    5 / 55 (9.09%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    2
    0
    0
    9
    0
    7
    0
    0
    Dizziness
         subjects affected / exposed
    7 / 36 (19.44%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    2 / 13 (15.38%)
    36 / 206 (17.48%)
    0 / 3 (0.00%)
    20 / 55 (36.36%)
    1 / 10 (10.00%)
    5 / 45 (11.11%)
         occurrences all number
    7
    1
    0
    2
    52
    0
    35
    1
    6
    Hypoaesthesia
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    6 / 206 (2.91%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    1 / 10 (10.00%)
    3 / 45 (6.67%)
         occurrences all number
    2
    0
    0
    0
    7
    0
    1
    1
    3
    Head discomfort
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Headache
         subjects affected / exposed
    8 / 36 (22.22%)
    10 / 43 (23.26%)
    0 / 1 (0.00%)
    8 / 13 (61.54%)
    65 / 206 (31.55%)
    0 / 3 (0.00%)
    21 / 55 (38.18%)
    0 / 10 (0.00%)
    18 / 45 (40.00%)
         occurrences all number
    10
    12
    0
    18
    107
    0
    45
    0
    22
    Hemiparesis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    4 / 206 (1.94%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    3 / 45 (6.67%)
         occurrences all number
    0
    0
    0
    1
    4
    0
    0
    0
    3
    Hydrocephalus
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Facial paresis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Neuralgia
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    4 / 206 (1.94%)
    0 / 3 (0.00%)
    4 / 55 (7.27%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    0
    5
    0
    5
    0
    0
    Memory impairment
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    3 / 13 (23.08%)
    6 / 206 (2.91%)
    0 / 3 (0.00%)
    2 / 55 (3.64%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    0
    0
    3
    6
    0
    2
    0
    1
    Intercostal neuralgia
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    IIIrd nerve disorder
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Neuropathy peripheral
         subjects affected / exposed
    2 / 36 (5.56%)
    2 / 43 (4.65%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    6 / 206 (2.91%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    2
    2
    0
    0
    6
    0
    1
    0
    1
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    3 / 206 (1.46%)
    0 / 3 (0.00%)
    3 / 55 (5.45%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    3
    0
    0
    Paraesthesia
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    17 / 206 (8.25%)
    0 / 3 (0.00%)
    9 / 55 (16.36%)
    1 / 10 (10.00%)
    4 / 45 (8.89%)
         occurrences all number
    1
    1
    0
    1
    17
    0
    9
    1
    4
    Palatal palsy
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Nystagmus
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    5 / 206 (2.43%)
    0 / 3 (0.00%)
    3 / 55 (5.45%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    1
    0
    0
    6
    0
    4
    0
    1
    Polyneuropathy
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    4 / 206 (1.94%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    2
    0
    0
    1
    4
    0
    1
    0
    0
    Pyramidal tract syndrome
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Sciatica
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    4 / 206 (1.94%)
    0 / 3 (0.00%)
    3 / 55 (5.45%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    1
    0
    0
    4
    0
    3
    0
    0
    VIth nerve disorder
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Tremor
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    4 / 206 (1.94%)
    0 / 3 (0.00%)
    4 / 55 (7.27%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    0
    5
    0
    5
    0
    0
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    2 / 36 (5.56%)
    2 / 43 (4.65%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    10 / 206 (4.85%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    4 / 45 (8.89%)
         occurrences all number
    2
    2
    0
    1
    13
    0
    1
    0
    7
    Anaemia
         subjects affected / exposed
    12 / 36 (33.33%)
    10 / 43 (23.26%)
    0 / 1 (0.00%)
    4 / 13 (30.77%)
    48 / 206 (23.30%)
    0 / 3 (0.00%)
    10 / 55 (18.18%)
    3 / 10 (30.00%)
    9 / 45 (20.00%)
         occurrences all number
    14
    11
    0
    5
    54
    0
    11
    3
    10
    Lymphopenia
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    2 / 206 (0.97%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    4
    5
    0
    1
    0
    0
    Microcytic anaemia
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    1 / 10 (10.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    1
    0
    Neutropenia
         subjects affected / exposed
    2 / 36 (5.56%)
    3 / 43 (6.98%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    24 / 206 (11.65%)
    1 / 3 (33.33%)
    6 / 55 (10.91%)
    4 / 10 (40.00%)
    7 / 45 (15.56%)
         occurrences all number
    2
    3
    0
    1
    27
    1
    8
    4
    8
    Thrombocytopenia
         subjects affected / exposed
    2 / 36 (5.56%)
    7 / 43 (16.28%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    20 / 206 (9.71%)
    0 / 3 (0.00%)
    3 / 55 (5.45%)
    3 / 10 (30.00%)
    4 / 45 (8.89%)
         occurrences all number
    4
    12
    0
    1
    28
    0
    4
    3
    4
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    10 / 206 (4.85%)
    0 / 3 (0.00%)
    7 / 55 (12.73%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    2
    0
    0
    1
    10
    0
    7
    0
    0
    Hypoacusis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    3 / 206 (1.46%)
    0 / 3 (0.00%)
    2 / 55 (3.64%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    1
    3
    0
    2
    0
    0
    Tinnitus
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    4 / 206 (1.94%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    1
    0
    0
    1
    4
    0
    1
    0
    1
    Vertigo
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    3 / 13 (23.08%)
    11 / 206 (5.34%)
    0 / 3 (0.00%)
    6 / 55 (10.91%)
    0 / 10 (0.00%)
    2 / 45 (4.44%)
         occurrences all number
    0
    0
    0
    4
    15
    0
    9
    0
    2
    Eye disorders
    Dry eye
         subjects affected / exposed
    1 / 36 (2.78%)
    2 / 43 (4.65%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    10 / 206 (4.85%)
    0 / 3 (0.00%)
    5 / 55 (9.09%)
    1 / 10 (10.00%)
    0 / 45 (0.00%)
         occurrences all number
    1
    2
    0
    1
    10
    0
    5
    1
    0
    Cataract
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    6 / 206 (2.91%)
    0 / 3 (0.00%)
    4 / 55 (7.27%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    1
    1
    0
    0
    6
    0
    4
    0
    0
    Diplopia
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    2 / 13 (15.38%)
    2 / 206 (0.97%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    2
    2
    0
    0
    0
    0
    Eye pain
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    5 / 206 (2.43%)
    0 / 3 (0.00%)
    2 / 55 (3.64%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    1
    0
    1
    5
    0
    2
    0
    1
    Eyelid oedema
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    3 / 206 (1.46%)
    0 / 3 (0.00%)
    2 / 55 (3.64%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    1
    3
    0
    2
    0
    0
    Iritis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Lacrimation increased
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    3 / 206 (1.46%)
    0 / 3 (0.00%)
    3 / 55 (5.45%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    3
    0
    0
    Vision blurred
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    2 / 13 (15.38%)
    23 / 206 (11.17%)
    0 / 3 (0.00%)
    14 / 55 (25.45%)
    0 / 10 (0.00%)
    5 / 45 (11.11%)
         occurrences all number
    1
    1
    0
    2
    33
    0
    24
    0
    5
    Papilloedema
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    2 / 206 (0.97%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    0
    0
    1
    2
    0
    0
    0
    1
    Photophobia
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    6 / 206 (2.91%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    3 / 45 (6.67%)
         occurrences all number
    1
    0
    0
    1
    6
    0
    1
    0
    3
    Saccadic eye movement
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Uveitis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    4 / 206 (1.94%)
    0 / 3 (0.00%)
    3 / 55 (5.45%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    3
    6
    0
    3
    0
    0
    Macular oedema
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    2
    2
    0
    0
    0
    0
    Visual impairment
         subjects affected / exposed
    4 / 36 (11.11%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    10 / 206 (4.85%)
    0 / 3 (0.00%)
    3 / 55 (5.45%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    4
    1
    0
    1
    14
    0
    7
    0
    1
    Vitreous floaters
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    7 / 206 (3.40%)
    0 / 3 (0.00%)
    7 / 55 (12.73%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    0
    7
    0
    7
    0
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    2 / 206 (0.97%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    1
    0
    1
    2
    0
    0
    0
    0
    Abdominal distension
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    2 / 13 (15.38%)
    7 / 206 (3.40%)
    0 / 3 (0.00%)
    2 / 55 (3.64%)
    1 / 10 (10.00%)
    0 / 45 (0.00%)
         occurrences all number
    1
    1
    0
    2
    7
    0
    2
    1
    0
    Diarrhoea
         subjects affected / exposed
    7 / 36 (19.44%)
    14 / 43 (32.56%)
    0 / 1 (0.00%)
    4 / 13 (30.77%)
    53 / 206 (25.73%)
    1 / 3 (33.33%)
    19 / 55 (34.55%)
    3 / 10 (30.00%)
    5 / 45 (11.11%)
         occurrences all number
    12
    19
    0
    11
    89
    1
    36
    3
    7
    Abdominal pain lower
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    2 / 36 (5.56%)
    7 / 43 (16.28%)
    0 / 1 (0.00%)
    2 / 13 (15.38%)
    15 / 206 (7.28%)
    0 / 3 (0.00%)
    3 / 55 (5.45%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    2
    9
    0
    3
    18
    0
    3
    0
    1
    Constipation
         subjects affected / exposed
    8 / 36 (22.22%)
    9 / 43 (20.93%)
    1 / 1 (100.00%)
    4 / 13 (30.77%)
    56 / 206 (27.18%)
    1 / 3 (33.33%)
    22 / 55 (40.00%)
    3 / 10 (30.00%)
    8 / 45 (17.78%)
         occurrences all number
    8
    10
    1
    4
    64
    1
    28
    3
    9
    Abdominal pain
         subjects affected / exposed
    2 / 36 (5.56%)
    5 / 43 (11.63%)
    0 / 1 (0.00%)
    2 / 13 (15.38%)
    26 / 206 (12.62%)
    2 / 3 (66.67%)
    12 / 55 (21.82%)
    1 / 10 (10.00%)
    2 / 45 (4.44%)
         occurrences all number
    2
    5
    0
    3
    31
    3
    14
    2
    2
    Dry mouth
         subjects affected / exposed
    5 / 36 (13.89%)
    8 / 43 (18.60%)
    0 / 1 (0.00%)
    2 / 13 (15.38%)
    27 / 206 (13.11%)
    0 / 3 (0.00%)
    8 / 55 (14.55%)
    1 / 10 (10.00%)
    3 / 45 (6.67%)
         occurrences all number
    7
    8
    0
    2
    33
    0
    12
    1
    3
    Dyspepsia
         subjects affected / exposed
    1 / 36 (2.78%)
    3 / 43 (6.98%)
    1 / 1 (100.00%)
    3 / 13 (23.08%)
    14 / 206 (6.80%)
    0 / 3 (0.00%)
    5 / 55 (9.09%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    5
    3
    1
    4
    20
    0
    6
    0
    1
    Dysphagia
         subjects affected / exposed
    6 / 36 (16.67%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    8 / 206 (3.88%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    6
    0
    0
    1
    8
    0
    0
    0
    1
    Flatulence
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    2 / 206 (0.97%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    0
    0
    1
    2
    0
    0
    0
    1
    Noninfective gingivitis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Gingival bleeding
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Haemorrhoids
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    4 / 206 (1.94%)
    0 / 3 (0.00%)
    3 / 55 (5.45%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    1
    0
    0
    4
    0
    3
    0
    0
    Hyperaesthesia teeth
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Nausea
         subjects affected / exposed
    12 / 36 (33.33%)
    18 / 43 (41.86%)
    1 / 1 (100.00%)
    7 / 13 (53.85%)
    84 / 206 (40.78%)
    0 / 3 (0.00%)
    27 / 55 (49.09%)
    5 / 10 (50.00%)
    14 / 45 (31.11%)
         occurrences all number
    17
    27
    1
    18
    130
    0
    45
    6
    16
    Gastrooesophageal reflux disease
         subjects affected / exposed
    3 / 36 (8.33%)
    2 / 43 (4.65%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    16 / 206 (7.77%)
    1 / 3 (33.33%)
    6 / 55 (10.91%)
    1 / 10 (10.00%)
    2 / 45 (4.44%)
         occurrences all number
    3
    3
    0
    4
    20
    1
    6
    1
    2
    Oral pain
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    4 / 206 (1.94%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    1
    1
    0
    1
    4
    0
    1
    0
    0
    Retching
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Salivary gland mass
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Stomatitis
         subjects affected / exposed
    2 / 36 (5.56%)
    3 / 43 (6.98%)
    1 / 1 (100.00%)
    2 / 13 (15.38%)
    12 / 206 (5.83%)
    0 / 3 (0.00%)
    3 / 55 (5.45%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    3
    3
    5
    2
    17
    0
    3
    0
    1
    Vomiting
         subjects affected / exposed
    7 / 36 (19.44%)
    15 / 43 (34.88%)
    1 / 1 (100.00%)
    4 / 13 (30.77%)
    55 / 206 (26.70%)
    1 / 3 (33.33%)
    13 / 55 (23.64%)
    3 / 10 (30.00%)
    11 / 45 (24.44%)
         occurrences all number
    8
    31
    5
    6
    89
    1
    18
    7
    13
    Toothache
         subjects affected / exposed
    1 / 36 (2.78%)
    2 / 43 (4.65%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    6 / 206 (2.91%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    1
    2
    0
    1
    6
    0
    1
    0
    1
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    0 / 36 (0.00%)
    5 / 43 (11.63%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    10 / 206 (4.85%)
    0 / 3 (0.00%)
    3 / 55 (5.45%)
    0 / 10 (0.00%)
    2 / 45 (4.44%)
         occurrences all number
    0
    5
    0
    0
    12
    0
    4
    0
    3
    Dry skin
         subjects affected / exposed
    4 / 36 (11.11%)
    4 / 43 (9.30%)
    0 / 1 (0.00%)
    5 / 13 (38.46%)
    33 / 206 (16.02%)
    1 / 3 (33.33%)
    17 / 55 (30.91%)
    0 / 10 (0.00%)
    2 / 45 (4.44%)
         occurrences all number
    4
    4
    0
    6
    38
    1
    17
    0
    6
    Dermatitis acneiform
         subjects affected / exposed
    1 / 36 (2.78%)
    4 / 43 (9.30%)
    0 / 1 (0.00%)
    2 / 13 (15.38%)
    34 / 206 (16.50%)
    0 / 3 (0.00%)
    22 / 55 (40.00%)
    0 / 10 (0.00%)
    5 / 45 (11.11%)
         occurrences all number
    2
    7
    0
    2
    53
    0
    35
    0
    7
    Alopecia
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    10 / 206 (4.85%)
    0 / 3 (0.00%)
    2 / 55 (3.64%)
    2 / 10 (20.00%)
    4 / 45 (8.89%)
         occurrences all number
    3
    0
    0
    1
    12
    0
    2
    2
    4
    Actinic keratosis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    6 / 206 (2.91%)
    0 / 3 (0.00%)
    6 / 55 (10.91%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    0
    8
    0
    8
    0
    0
    Acne
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 43 (4.65%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    5 / 206 (2.43%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    2 / 45 (4.44%)
         occurrences all number
    0
    2
    0
    1
    7
    0
    0
    0
    4
    Erythema
         subjects affected / exposed
    1 / 36 (2.78%)
    5 / 43 (11.63%)
    0 / 1 (0.00%)
    3 / 13 (23.08%)
    15 / 206 (7.28%)
    0 / 3 (0.00%)
    5 / 55 (9.09%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    1
    5
    0
    12
    27
    0
    8
    0
    1
    Erythema nodosum
         subjects affected / exposed
    1 / 36 (2.78%)
    2 / 43 (4.65%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    6 / 206 (2.91%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    1
    2
    0
    2
    7
    0
    1
    0
    1
    Hyperkeratosis
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 43 (4.65%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    7 / 206 (3.40%)
    0 / 3 (0.00%)
    4 / 55 (7.27%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    2
    0
    0
    8
    0
    5
    0
    1
    Hyperhidrosis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    9 / 206 (4.37%)
    0 / 3 (0.00%)
    8 / 55 (14.55%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    0
    0
    0
    12
    0
    11
    0
    1
    Hidradenitis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    4
    4
    0
    0
    0
    0
    Ingrowing nail
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Piloerection
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Night sweats
         subjects affected / exposed
    3 / 36 (8.33%)
    3 / 43 (6.98%)
    0 / 1 (0.00%)
    3 / 13 (23.08%)
    13 / 206 (6.31%)
    2 / 3 (66.67%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    4
    3
    0
    3
    16
    2
    3
    0
    1
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    2 / 36 (5.56%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    6 / 206 (2.91%)
    0 / 3 (0.00%)
    3 / 55 (5.45%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    2
    1
    0
    0
    6
    0
    3
    0
    0
    Papule
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    3 / 206 (1.46%)
    1 / 3 (33.33%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    0
    0
    0
    3
    1
    1
    0
    1
    Photosensitivity reaction
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    6 / 206 (2.91%)
    0 / 3 (0.00%)
    4 / 55 (7.27%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    1
    0
    0
    6
    0
    4
    0
    1
    Nail discolouration
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    2 / 206 (0.97%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    1
    0
    1
    2
    0
    0
    0
    0
    Rash maculo-papular
         subjects affected / exposed
    3 / 36 (8.33%)
    4 / 43 (9.30%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    28 / 206 (13.59%)
    1 / 3 (33.33%)
    19 / 55 (34.55%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    3
    5
    0
    2
    69
    1
    58
    0
    0
    Rash
         subjects affected / exposed
    10 / 36 (27.78%)
    12 / 43 (27.91%)
    0 / 1 (0.00%)
    4 / 13 (30.77%)
    52 / 206 (25.24%)
    0 / 3 (0.00%)
    11 / 55 (20.00%)
    3 / 10 (30.00%)
    12 / 45 (26.67%)
         occurrences all number
    13
    14
    0
    11
    80
    0
    17
    3
    22
    Pruritus
         subjects affected / exposed
    4 / 36 (11.11%)
    5 / 43 (11.63%)
    0 / 1 (0.00%)
    6 / 13 (46.15%)
    25 / 206 (12.14%)
    0 / 3 (0.00%)
    10 / 55 (18.18%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    6
    5
    0
    6
    31
    0
    14
    0
    0
    Seborrhoeic dermatitis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    2 / 206 (0.97%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    0
    0
    1
    2
    0
    0
    0
    1
    Skin striae
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    2 / 13 (15.38%)
    2 / 206 (0.97%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    2
    2
    0
    0
    0
    0
    Skin plaque
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Skin mass
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    6 / 206 (2.91%)
    0 / 3 (0.00%)
    2 / 55 (3.64%)
    1 / 10 (10.00%)
    0 / 45 (0.00%)
         occurrences all number
    1
    1
    0
    3
    8
    0
    2
    1
    0
    Skin lesion
         subjects affected / exposed
    2 / 36 (5.56%)
    2 / 43 (4.65%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    5 / 206 (2.43%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    2
    2
    0
    0
    5
    0
    1
    0
    0
    Skin hyperpigmentation
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    2 / 206 (0.97%)
    1 / 3 (33.33%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    1
    1
    0
    0
    Skin atrophy
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    3 / 206 (1.46%)
    0 / 3 (0.00%)
    3 / 55 (5.45%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    3
    0
    0
    Xeroderma
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    1 / 10 (10.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    1
    0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 36 (0.00%)
    3 / 43 (6.98%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    4 / 206 (1.94%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    3
    0
    0
    4
    0
    1
    0
    0
    Chromaturia
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Haematuria
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    15 / 206 (7.28%)
    0 / 3 (0.00%)
    10 / 55 (18.18%)
    0 / 10 (0.00%)
    2 / 45 (4.44%)
         occurrences all number
    4
    0
    0
    1
    21
    0
    14
    0
    2
    Pollakiuria
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    10 / 206 (4.85%)
    0 / 3 (0.00%)
    9 / 55 (16.36%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    0
    0
    10
    0
    9
    0
    0
    Proteinuria
         subjects affected / exposed
    2 / 36 (5.56%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    3 / 13 (23.08%)
    9 / 206 (4.37%)
    0 / 3 (0.00%)
    2 / 55 (3.64%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    2
    1
    0
    6
    12
    0
    2
    0
    1
    Renal failure
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    2 / 206 (0.97%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    1 / 10 (10.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    1
    0
    0
    2
    0
    0
    1
    0
    Urinary retention
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    2 / 13 (15.38%)
    4 / 206 (1.94%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    2
    0
    0
    2
    5
    0
    1
    0
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    4 / 36 (11.11%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    6 / 206 (2.91%)
    0 / 3 (0.00%)
    2 / 55 (3.64%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    4
    0
    0
    0
    6
    0
    2
    0
    0
    Musculoskeletal and connective tissue disorders
    Joint swelling
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 43 (4.65%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    5 / 206 (2.43%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    2
    0
    1
    5
    0
    1
    0
    1
    Joint stiffness
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Muscle spasms
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 43 (4.65%)
    0 / 1 (0.00%)
    2 / 13 (15.38%)
    15 / 206 (7.28%)
    0 / 3 (0.00%)
    6 / 55 (10.91%)
    0 / 10 (0.00%)
    5 / 45 (11.11%)
         occurrences all number
    0
    2
    0
    4
    20
    0
    7
    0
    7
    Arthralgia
         subjects affected / exposed
    5 / 36 (13.89%)
    6 / 43 (13.95%)
    0 / 1 (0.00%)
    7 / 13 (53.85%)
    48 / 206 (23.30%)
    0 / 3 (0.00%)
    21 / 55 (38.18%)
    2 / 10 (20.00%)
    7 / 45 (15.56%)
         occurrences all number
    8
    8
    0
    11
    76
    0
    40
    2
    7
    Arthritis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    5 / 206 (2.43%)
    0 / 3 (0.00%)
    5 / 55 (9.09%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    0
    6
    0
    6
    0
    0
    Back pain
         subjects affected / exposed
    6 / 36 (16.67%)
    4 / 43 (9.30%)
    0 / 1 (0.00%)
    3 / 13 (23.08%)
    30 / 206 (14.56%)
    0 / 3 (0.00%)
    13 / 55 (23.64%)
    1 / 10 (10.00%)
    3 / 45 (6.67%)
         occurrences all number
    6
    5
    0
    4
    35
    0
    15
    1
    4
    Bone pain
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    1 / 10 (10.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    1
    0
    Flank pain
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    4 / 206 (1.94%)
    0 / 3 (0.00%)
    2 / 55 (3.64%)
    1 / 10 (10.00%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    0
    0
    5
    0
    3
    1
    0
    Foot deformity
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Joint range of motion decreased
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    3 / 206 (1.46%)
    0 / 3 (0.00%)
    2 / 55 (3.64%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    1
    3
    0
    2
    0
    0
    Muscle twitching
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    2 / 206 (0.97%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    0
    0
    1
    2
    0
    0
    0
    1
    Pain in extremity
         subjects affected / exposed
    1 / 36 (2.78%)
    3 / 43 (6.98%)
    0 / 1 (0.00%)
    2 / 13 (15.38%)
    30 / 206 (14.56%)
    0 / 3 (0.00%)
    19 / 55 (34.55%)
    1 / 10 (10.00%)
    4 / 45 (8.89%)
         occurrences all number
    1
    5
    0
    2
    41
    0
    27
    1
    5
    Neck pain
         subjects affected / exposed
    3 / 36 (8.33%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    7 / 206 (3.40%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    2 / 45 (4.44%)
         occurrences all number
    3
    1
    0
    0
    13
    0
    7
    0
    2
    Neck mass
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    2
    2
    0
    0
    0
    0
    Pain in jaw
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    2 / 206 (0.97%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    1
    0
    1
    2
    0
    0
    0
    0
    Myalgia
         subjects affected / exposed
    2 / 36 (5.56%)
    8 / 43 (18.60%)
    0 / 1 (0.00%)
    2 / 13 (15.38%)
    45 / 206 (21.84%)
    0 / 3 (0.00%)
    25 / 55 (45.45%)
    1 / 10 (10.00%)
    7 / 45 (15.56%)
         occurrences all number
    2
    9
    0
    2
    96
    0
    71
    1
    11
    Musculoskeletal pain
         subjects affected / exposed
    0 / 36 (0.00%)
    3 / 43 (6.98%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    4 / 206 (1.94%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    3
    0
    0
    4
    0
    0
    0
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    5 / 206 (2.43%)
    0 / 3 (0.00%)
    3 / 55 (5.45%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    1
    1
    0
    0
    5
    0
    3
    0
    0
    Muscular weakness
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    10 / 206 (4.85%)
    0 / 3 (0.00%)
    2 / 55 (3.64%)
    1 / 10 (10.00%)
    4 / 45 (8.89%)
         occurrences all number
    1
    1
    0
    2
    11
    0
    2
    1
    4
    Myopathy
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Synovial cyst
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    2 / 206 (0.97%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    1 / 10 (10.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    1
    1
    Spinal pain
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    2 / 206 (0.97%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    2 / 10 (20.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    2
    0
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    2 / 206 (0.97%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    1
    2
    0
    1
    0
    0
    Abdominal abscess
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    3
    3
    0
    0
    0
    0
    Bronchitis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    6 / 206 (2.91%)
    0 / 3 (0.00%)
    5 / 55 (9.09%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    1
    8
    0
    7
    0
    0
    COVID-19
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    3 / 206 (1.46%)
    0 / 3 (0.00%)
    2 / 55 (3.64%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    1
    3
    0
    2
    0
    0
    Conjunctivitis
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    10 / 206 (4.85%)
    0 / 3 (0.00%)
    8 / 55 (14.55%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    1
    1
    0
    0
    11
    0
    9
    0
    0
    Folliculitis
         subjects affected / exposed
    1 / 36 (2.78%)
    2 / 43 (4.65%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    10 / 206 (4.85%)
    0 / 3 (0.00%)
    2 / 55 (3.64%)
    1 / 10 (10.00%)
    3 / 45 (6.67%)
         occurrences all number
    1
    2
    0
    4
    16
    0
    3
    1
    5
    Nasopharyngitis
         subjects affected / exposed
    2 / 36 (5.56%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    5 / 13 (38.46%)
    20 / 206 (9.71%)
    0 / 3 (0.00%)
    4 / 55 (7.27%)
    1 / 10 (10.00%)
    7 / 45 (15.56%)
         occurrences all number
    2
    1
    0
    15
    37
    0
    7
    1
    11
    Gastroenteritis
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    4 / 206 (1.94%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    1 / 10 (10.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    2
    0
    2
    6
    0
    0
    1
    1
    Gingivitis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    2 / 13 (15.38%)
    3 / 206 (1.46%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    2
    3
    0
    1
    0
    0
    Herpes zoster
         subjects affected / exposed
    0 / 36 (0.00%)
    3 / 43 (6.98%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    5 / 206 (2.43%)
    0 / 3 (0.00%)
    2 / 55 (3.64%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    3
    0
    0
    5
    0
    2
    0
    0
    Infection
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    5 / 206 (2.43%)
    0 / 3 (0.00%)
    2 / 55 (3.64%)
    2 / 10 (20.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    0
    0
    0
    7
    0
    2
    2
    3
    Fungal infection
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    7 / 206 (3.40%)
    0 / 3 (0.00%)
    4 / 55 (7.27%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    3
    0
    0
    0
    9
    0
    4
    0
    2
    Onychomycosis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    3 / 206 (1.46%)
    0 / 3 (0.00%)
    2 / 55 (3.64%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    1
    3
    0
    2
    0
    0
    Oral candidiasis
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    3 / 206 (1.46%)
    1 / 3 (33.33%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    1
    0
    0
    0
    3
    1
    0
    0
    1
    Oral herpes
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    4 / 206 (1.94%)
    0 / 3 (0.00%)
    3 / 55 (5.45%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    0
    0
    0
    6
    0
    5
    0
    1
    Oropharyngeal candidiasis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    1 / 10 (10.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    1
    0
    Sinusitis
         subjects affected / exposed
    2 / 36 (5.56%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    10 / 206 (4.85%)
    0 / 3 (0.00%)
    4 / 55 (7.27%)
    1 / 10 (10.00%)
    1 / 45 (2.22%)
         occurrences all number
    2
    1
    0
    1
    11
    0
    5
    1
    1
    Pharyngitis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    2 / 13 (15.38%)
    4 / 206 (1.94%)
    0 / 3 (0.00%)
    2 / 55 (3.64%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    2
    4
    0
    2
    0
    0
    Pneumonia
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    9 / 206 (4.37%)
    0 / 3 (0.00%)
    6 / 55 (10.91%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    1
    0
    0
    1
    10
    0
    7
    0
    1
    Rash pustular
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    4 / 206 (1.94%)
    0 / 3 (0.00%)
    3 / 55 (5.45%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    2
    0
    0
    5
    0
    3
    0
    0
    Rhinitis
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    7 / 206 (3.40%)
    0 / 3 (0.00%)
    5 / 55 (9.09%)
    1 / 10 (10.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    1
    0
    0
    8
    0
    6
    1
    0
    Paronychia
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    5 / 206 (2.43%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    3 / 45 (6.67%)
         occurrences all number
    0
    1
    0
    1
    8
    0
    0
    0
    6
    Skin candida
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    2 / 206 (0.97%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    1
    2
    0
    1
    0
    0
    Skin infection
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    4 / 206 (1.94%)
    0 / 3 (0.00%)
    4 / 55 (7.27%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    0
    5
    0
    5
    0
    0
    Streptococcal infection
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    1 / 10 (10.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    1
    0
    Subcutaneous abscess
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    1 / 206 (0.49%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    3
    3
    0
    0
    0
    0
    Tooth infection
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    10 / 206 (4.85%)
    0 / 3 (0.00%)
    8 / 55 (14.55%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    1
    1
    0
    0
    13
    0
    11
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 36 (8.33%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    21 / 206 (10.19%)
    0 / 3 (0.00%)
    15 / 55 (27.27%)
    0 / 10 (0.00%)
    2 / 45 (4.44%)
         occurrences all number
    4
    1
    0
    0
    28
    0
    20
    0
    3
    Urinary tract infection
         subjects affected / exposed
    2 / 36 (5.56%)
    2 / 43 (4.65%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    22 / 206 (10.68%)
    1 / 3 (33.33%)
    8 / 55 (14.55%)
    2 / 10 (20.00%)
    6 / 45 (13.33%)
         occurrences all number
    2
    2
    0
    1
    31
    1
    14
    2
    9
    Tooth abscess
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    2 / 206 (0.97%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    1
    0
    1
    2
    0
    0
    0
    0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    2 / 206 (0.97%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    1 / 10 (10.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    1
    1
    Decreased appetite
         subjects affected / exposed
    12 / 36 (33.33%)
    10 / 43 (23.26%)
    0 / 1 (0.00%)
    2 / 13 (15.38%)
    40 / 206 (19.42%)
    0 / 3 (0.00%)
    7 / 55 (12.73%)
    3 / 10 (30.00%)
    6 / 45 (13.33%)
         occurrences all number
    15
    12
    0
    2
    49
    0
    10
    4
    6
    Dehydration
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    4 / 206 (1.94%)
    0 / 3 (0.00%)
    2 / 55 (3.64%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    0
    2
    5
    0
    2
    0
    0
    Diabetes mellitus
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    3 / 206 (1.46%)
    0 / 3 (0.00%)
    3 / 55 (5.45%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    3
    0
    0
    Hypercalcaemia
         subjects affected / exposed
    3 / 36 (8.33%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    6 / 206 (2.91%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    4
    1
    0
    0
    7
    0
    1
    0
    1
    Hyperglycaemia
         subjects affected / exposed
    5 / 36 (13.89%)
    8 / 43 (18.60%)
    0 / 1 (0.00%)
    2 / 13 (15.38%)
    44 / 206 (21.36%)
    0 / 3 (0.00%)
    25 / 55 (45.45%)
    0 / 10 (0.00%)
    4 / 45 (8.89%)
         occurrences all number
    5
    9
    0
    2
    74
    0
    53
    0
    5
    Hyperkalaemia
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 43 (2.33%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    8 / 206 (3.88%)
    0 / 3 (0.00%)
    4 / 55 (7.27%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    1
    1
    0
    1
    11
    0
    5
    0
    3
    Hyperuricaemia
         subjects affected / exposed
    2 / 36 (5.56%)
    2 / 43 (4.65%)
    0 / 1 (0.00%)
    1 / 13 (7.69%)
    8 / 206 (3.88%)
    0 / 3 (0.00%)
    3 / 55 (5.45%)
    0 / 10 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    2
    2
    0
    5
    12
    0
    3
    0
    0
    Hypoalbuminaemia
         subjects affected / exposed
    7 / 36 (19.44%)
    3 / 43 (6.98%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    20 / 206 (9.71%)
    0 / 3 (0.00%)
    6 / 55 (10.91%)
    0 / 10 (0.00%)
    4 / 45 (8.89%)
         occurrences all number
    7
    6
    0
    0
    23
    0
    6
    0
    4
    Hypocalcaemia
         subjects affected / exposed
    5 / 36 (13.89%)
    0 / 43 (0.00%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    8 / 206 (3.88%)
    0 / 3 (0.00%)
    0 / 55 (0.00%)
    1 / 10 (10.00%)
    2 / 45 (4.44%)
         occurrences all number
    6
    0
    0
    0
    9
    0
    0
    1
    2
    Hypophosphataemia
         subjects affected / exposed
    1 / 36 (2.78%)
    2 / 43 (4.65%)
    0 / 1 (0.00%)
    2 / 13 (15.38%)
    20 / 206 (9.71%)
    0 / 3 (0.00%)
    11 / 55 (20.00%)
    0 / 10 (0.00%)
    4 / 45 (8.89%)
         occurrences all number
    1
    2
    0
    9
    31
    0
    14
    0
    5
    Hypokalaemia
         subjects affected / exposed
    4 / 36 (11.11%)
    4 / 43 (9.30%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    15 / 206 (7.28%)
    0 / 3 (0.00%)
    3 / 55 (5.45%)
    2 / 10 (20.00%)
    2 / 45 (4.44%)
         occurrences all number
    4
    8
    0
    0
    23
    0
    6
    3
    2
    Hypomagnesaemia
         subjects affected / exposed
    2 / 36 (5.56%)
    5 / 43 (11.63%)
    0 / 1 (0.00%)
    2 / 13 (15.38%)
    15 / 206 (7.28%)
    0 / 3 (0.00%)
    2 / 55 (3.64%)
    0 / 10 (0.00%)
    4 / 45 (8.89%)
         occurrences all number
    2
    10
    0
    3
    24
    0
    2
    0
    7
    Hyponatraemia
         subjects affected / exposed
    7 / 36 (19.44%)
    5 / 43 (11.63%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    15 / 206 (7.28%)
    0 / 3 (0.00%)
    2 / 55 (3.64%)
    0 / 10 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    11
    8
    0
    0
    24
    0
    3
    0
    2
    Hypoglycaemia
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 43 (4.65%)
    0 / 1 (0.00%)
    0 / 13 (0.00%)
    6 / 206 (2.91%)
    0 / 3 (0.00%)
    1 / 55 (1.82%)
    0 / 10 (0.00%)
    3 / 45 (6.67%)
         occurrences all number
    0
    2
    0
    0
    13
    0
    5
    0
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Jul 2013
    Amendment 1: • Added EudraCT Number. • Removed cardiac enzyme (troponin) from list of clinical laboratory assessments to be completed. • Clarified inclusion criteria. Mandatory tumor sample and BM aspirate sample are required at Screening. • Added text to the exclusion criteria to confirm that no histology-specific exclusion criteria were included. • Corrected reference to CT scan (i.e., changed to MRI scan) as CT is not permitted in these cohorts. • Removed statement that progressive disease sample collection was mandatory for ATC, HCL and MM cohorts as it was inconsistent with the time and events tables.
    18 Dec 2013
    Amendment 2: •Primary endpoint: added use of Modified RANO and RANO response criteria in gliomas •Inclusion criteria: deleted reference to CLIA approved laboratory; revised prior treatment for subjects with MM; added: GIST subjects require progression on imatinib and sunitinib; Added subjects with specified histology and no available treatment options per local or regional SOC; Added for WHO Grade 2 glioma: only subjects not suitable for chemotherapy eligible •Safety: Added estimation of blood volume collected during study; Removed reference to QTcF as stopping criteria for QTc prolongation is limited to use of Bazett formula for correction; Removed use of MUGA scan to assess cardiac ejection fraction; added procedure to be performed by same operator throughout the study; removed requirement of reporting symptomatic events as SAE, and in case of asymptomatic absolute decrease of >10% in LVEF compared to baseline and ejection fraction below institutional LLN, study treatment must be discontinued; Added “Monitoring of Non-Cutaneous Secondary/Recurrent Malignancy” for use of dabrafenib; Revised: CV events may occur also with dabrafenib or in combination and revised QTc prolongation; Clarified management of hypertension with persistent increase in systolic and/or diastolic BP to be managed by recommendations and study treatment to discontinue in asymptomatic or symptomatic hypertension; Revised cutaneous SCC to remove reference to keratoacanthomas; added requirement of dermatological examinations monthly for 6 months after treatment discontinuation; “Medications to be Used with Caution”: updated reference for drugs known to induce QTc prolongation; inclusion of guidelines for management and dose reduction for renal insufficiency when considered treatment related; Added new section: Formation of data monitoring committee to review safety and efficacy data during interim analyses and to indicate that independent hematologist and oncologist will serve on this committee.
    21 Jul 2014
    Amendment 3: • Revised dabrafenib and trametinib sections in the protocol to delete redundant information, updated with revised protocol language and standard asset language. • Revised the “Concomitant medication and non-drug therapies section” to clarify the use of anticoagulants, palliative radiation and use of dabrafenib during radiotherapy. • Added language pertaining to retrospective confirmation of histology type for ATC cohort. • Revised the vision changes and ophthalmic exam language with standard asset language. • Revised the disease assessment sections to clarify type of assessment, timing and evaluation criteria. • Revised the stopping criteria, management, and dose modification for special events to reflect changes in standard asset language. Added Ex Vivo sub study for HCL cohort.
    24 Oct 2014
    Amendment 4: • Revised the protocol in response to the recent decision for the substantial amendment of a Voluntary Harmonization Procedure (VHP-SA) submission of Amendment 3 of the protocol. • Revised to update regulatory approval status of trametinib monotherapy and trametinib in combination with dabrafenib. • Revised Inclusion criteria #5 and #4, respectively, to clarify that the criterion applies to subjects who are already receiving corticosteroid therapy. • Revised to criterion #1 to clarify that the status of delayed toxicity applies to all types of therapy and not solely chemotherapy. • Revised text to align with the Summary of Product Characteristics language as requested by the VHP.
    28 Apr 2015
    Amendment 5: • Revised LVEF stopping criteria to indicate when to report as SAE. • Removed BRAT diet from diarrhea management guidelines. • Removed oral contraceptives from the prohibited medications list and provided supporting information regarding interaction with dabrafenib. • Specified oral formulation for selected prohibited medications and medications to be used with caution. • Clarified which samples to be submitted for confirmation of BRAF mutation status; definition of SAEs revised for protocol specific SAEs based on updated list of AE of special interest. • Removed ATC sample collection for possible independent histology confirmation. • Added new section for malignancies to include section on cutaneous squamous cell carcinoma, new primary melanoma and non-cutaneous malignancies based on updated asset language for dabrafenib and trametinib. • Clarified use of NSAIDs in subjects with MM for pyrexia and action to be taken with dabrafenib with pneumonitis. • Revised disease assessments for solid tumors to clarify imaging modality to be used for specific cohorts. • Revised the statistical section to reflect change in study sample size and trial simulation output.
    05 Jan 2016
    Amendment 6: • Updated the risk assessment for dabrafenib and trametinib combination therapy. • Clarified the dose modification wording for dabrafenib and trametinib with respect to drug reductions and re-escalation. • Re-implemented ATC pathology sample collection for a potential independent histology confirmation. It also implemented samples collection for a potential independent histology confirmation for WHO Grade 1-4 Glioma cohorts. • Clarified the disease assessment method for WHO Grade 1-4 Glioma cohort. • Updated the baseline and on-treatment assessments for the HCL cohort. • Added additional analysis populations that are planned for the interim analyses. • Added expansion cohorts for all cohorts that meet the criteria for early stopping for efficacy at an interim analysis. • Clarified the definition for DOR for all response categories.
    19 Jul 2016
    Amendment 7: • Deleted/replaced references to GlaxoSmithKline or its staff with that of Novartis and its authorized agents to align with the change of sponsorship. • Made administrative changes to align with Novartis processes and procedures.
    14 Dec 2017
    Amendment 8: • Updated Time and Event table for pregnancy, blood sample for CBC, peripheral blood sample staining for hairy cell count, flow cytometry for peripheral blood sample, and extended follow-ups to align with the footnotes. Added TSH, free T4 for ATC cohort only. Modified the instruction for HCL subjects who were tolerating study drug treatment beyond week 48. These subjects could reduce the frequency of response assessment evaluation from every 4 weeks (+/-3 days) to every 8 weeks (+/-3 days) if appropriate in the judgement of the treating investigator. • Evaluations at extended follow up were updated. • Updated post-baseline Laboratory and Disease Assessments for HCL subjects. • Clarified HbA1c testing is included in “Clinical Chemistry. • Updated the contraception requirements for male subjects. • Updated medications to be used with Caution: removed statement regarding Dabrafenib solubility at higher pH. Consequently, proton pump inhibitors removed from Medications to be used with Caution. • Reinstated a sentence outlining the time period for detecting adverse events and serious adverse events inadvertently removed at amendment 7. • Corrected the number of samples and amount of peripheral blood to be collected. • Updated RANO Response Criteria under ‘Disease progression (PD) for WHO Grade 1 or 2 Glioma.
    12 Feb 2019
    Amendment 9: • Updated change to contraception requirements for female subjects. • Updated definition for study completion and updated language clarifying the possible options for alternative supply of study treatment for those subjects who continue to derive clinical benefit at study completion. • Clarified the analysis population for supportive final efficacy analysis. • Updated date of final analyses as the date representing a minimum follow up of approximately 2 years for all subjects enrolled. • Removed reference to pooled ORR calculations across histologies.
    09 Jan 2020
    Amendment 10: • The primary purpose of amendment 10 is to align the dose modification section of the protocol related to severe cutaneous adverse reactions, as updated in the dabrafenib and trametinib investigator’s brochures edition 11. • In addition, baseline results of IDH mutation status and MGMT methylation status were to be collected as part of disease characteristics for subjects in the LGG or HGG cohorts only. Data collected only where available as part of medical records; retrospective testing is not requested or required. • References to the use of oral (hormonal) contraceptives being “permitted” or “used with caution” were removed from the relevant sections in alignment with changes made at protocol amendment #9 to update female contraception requirements. These sections were inadvertently not updated at the previous amendment.
    04 Jun 2020
    Amendment 11: • The main purposes of this amendment were to extend the study by one additional year for more mature estimates of duration of response, progression free survival and overall survival; and to change the primary analysis population of the final efficacy analysis from the BRAF V600E population to the ITT population. • To reduce burden on subjects, collections for blood and tissue samples for predictive and pharmacodynamic biomarker research as well as PK sampling at follow up were discontinued as the majority of the planned biomarker analyses have been completed and the PK profile of the regimen is now well characterized. • Disease assessment intervals after the first 48 weeks of study treatment for subjects in the HCL cohort was extended from “at least every 8 weeks” to “at least every 12 weeks”.

    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.
    Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com for complete trial results.
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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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