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    Clinical Trial Results:
    Long term single-arm open-label study, to assess the safety and tolerability of selexipag (ACT-293987) in patients with pulmonary arterial hypertension

    Summary
    EudraCT number
    		 2009-014992-31
    Trial protocol
    		 BE   FR   ES   SE   DK   GB   IE   PL   AT   HU   DE   SK   CZ   GR   NL   IT  
    Global end of trial date
    29 Sep 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Sep 2022
    First version publication date
    09 Sep 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    AC-065A303
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01112306
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Actelion Pharmaceuticals Ltd
    Sponsor organisation address
    Gewerbestrasse 16, Allschwil, Switzerland, 4123
    Public contact
    Clinical Registry Group, Actelion Pharmaceuticals Ltd, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Actelion Pharmaceuticals Ltd, ClinicalTrialsEU@its.jnj.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
    29 Sep 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Sep 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial was to assess long-term safety and tolerability of selexipag in subjects with pulmonary arterial hypertension (PAH).
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Jun 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 20
    Country: Number of subjects enrolled
    Australia: 37
    Country: Number of subjects enrolled
    Austria: 3
    Country: Number of subjects enrolled
    Belgium: 17
    Country: Number of subjects enrolled
    Belarus: 34
    Country: Number of subjects enrolled
    Canada: 13
    Country: Number of subjects enrolled
    Switzerland: 2
    Country: Number of subjects enrolled
    Chile: 31
    Country: Number of subjects enrolled
    China: 113
    Country: Number of subjects enrolled
    Colombia: 3
    Country: Number of subjects enrolled
    Czechia: 11
    Country: Number of subjects enrolled
    Germany: 35
    Country: Number of subjects enrolled
    Denmark: 4
    Country: Number of subjects enrolled
    Spain: 8
    Country: Number of subjects enrolled
    France: 21
    Country: Number of subjects enrolled
    United Kingdom: 9
    Country: Number of subjects enrolled
    Greece: 6
    Country: Number of subjects enrolled
    Hungary: 10
    Country: Number of subjects enrolled
    India: 15
    Country: Number of subjects enrolled
    Ireland: 4
    Country: Number of subjects enrolled
    Israel: 11
    Country: Number of subjects enrolled
    Italy: 4
    Country: Number of subjects enrolled
    Korea, Republic of: 11
    Country: Number of subjects enrolled
    Mexico: 20
    Country: Number of subjects enrolled
    Malaysia: 2
    Country: Number of subjects enrolled
    Netherlands: 4
    Country: Number of subjects enrolled
    Peru: 6
    Country: Number of subjects enrolled
    Poland: 7
    Country: Number of subjects enrolled
    Romania: 9
    Country: Number of subjects enrolled
    Russian Federation: 72
    Country: Number of subjects enrolled
    Singapore: 8
    Country: Number of subjects enrolled
    Serbia: 10
    Country: Number of subjects enrolled
    Slovakia: 1
    Country: Number of subjects enrolled
    Sweden: 10
    Country: Number of subjects enrolled
    Thailand: 4
    Country: Number of subjects enrolled
    Turkey: 8
    Country: Number of subjects enrolled
    Taiwan: 11
    Country: Number of subjects enrolled
    Ukraine: 35
    Country: Number of subjects enrolled
    United States: 80
    Worldwide total number of subjects
    709
    EEA total number of subjects
    154
    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)
    597
    From 65 to 84 years
    112
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 709 subjects were enrolled in the study. Out of the 709 subjects, 424 subjects completed the study.

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

    Arms
    Arm title
    		 Selexipag
    Arm description
    		 Subjects with pulmonary arterial hypertension (PAH) who completed the double-blind AC-065A302 GRIPHON study or experienced a morbidity/mortality event in that study, entered in this open label (OL) study. Subjects who received selexipag in GRIPHON continued to receive selexipag at the same dose (200 micrograms [mcg], twice daily [bid] up to 1600 mcg bid based on individual maximum tolerated dose) in this OL study. Subjects who were on placebo or experienced a morbidity/mortality event in GRIPHON entered the titration period of this OL-study and received lowest dose of selexipag (200 mcg, bid) and dose was titrated up to 1600 mcg bid, based on the individual maximum tolerated dose. Each subject received study drug from Day 1 until the earliest of a) selexipag became commercially available in this indication in subject’s country, b) sponsor decided to stop current study, or c) subject/investigator decided to discontinue study intervention (up to 10.5 years).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Selexipag
    Investigational medicinal product code
    Other name
    JNJ-67896049 ACT-293987
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Selexipag (up-titrated from 200 mcg bid to 1600 mcg bid based on individual maximum tolerated dose) was administered bid with food from Day 1 until the earliest of a) selexipag became commercially available in this indication in subject's country, b) sponsor decided to stop current study, or c) subject/investigator decided to discontinue study intervention (up to 10.5 years).

    Number of subjects in period 1
    		Selexipag
    Started
    709
    Completed
    424
    Not completed
    285
         Adverse event, serious fatal
    175
         Consent withdrawn by subject
    31
         Unspecified
    70
         Lost to follow-up
    9

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Selexipag
    Reporting group description
    		 Subjects with pulmonary arterial hypertension (PAH) who completed the double-blind AC-065A302 GRIPHON study or experienced a morbidity/mortality event in that study, entered in this open label (OL) study. Subjects who received selexipag in GRIPHON continued to receive selexipag at the same dose (200 micrograms [mcg], twice daily [bid] up to 1600 mcg bid based on individual maximum tolerated dose) in this OL study. Subjects who were on placebo or experienced a morbidity/mortality event in GRIPHON entered the titration period of this OL-study and received lowest dose of selexipag (200 mcg, bid) and dose was titrated up to 1600 mcg bid, based on the individual maximum tolerated dose. Each subject received study drug from Day 1 until the earliest of a) selexipag became commercially available in this indication in subject’s country, b) sponsor decided to stop current study, or c) subject/investigator decided to discontinue study intervention (up to 10.5 years).

    Reporting group values
    		 Selexipag Total
    Number of subjects
    		 709 709
    Title for AgeCategorical
    Units: subjects
        Adolescents: 12-<18 yrs
    		 0 0
        Adults: >= 18 yrs
    		 709 709
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    		 47.9 ( 15.19 ) -
    Title for Gender
    Units: subjects
        Female
    		 590 590
        Male
    		 119 119

    End points

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    End points reporting groups
    Reporting group title
    Selexipag
    Reporting group description
    		 Subjects with pulmonary arterial hypertension (PAH) who completed the double-blind AC-065A302 GRIPHON study or experienced a morbidity/mortality event in that study, entered in this open label (OL) study. Subjects who received selexipag in GRIPHON continued to receive selexipag at the same dose (200 micrograms [mcg], twice daily [bid] up to 1600 mcg bid based on individual maximum tolerated dose) in this OL study. Subjects who were on placebo or experienced a morbidity/mortality event in GRIPHON entered the titration period of this OL-study and received lowest dose of selexipag (200 mcg, bid) and dose was titrated up to 1600 mcg bid, based on the individual maximum tolerated dose. Each subject received study drug from Day 1 until the earliest of a) selexipag became commercially available in this indication in subject’s country, b) sponsor decided to stop current study, or c) subject/investigator decided to discontinue study intervention (up to 10.5 years).

    Primary: Number of Subjects with Treatment-emergent Adverse Events (TEAEs) up to 3 days After Study Intervention Discontinuation

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    End point title
    		 Number of Subjects with Treatment-emergent Adverse Events (TEAEs) up to 3 days After Study Intervention Discontinuation [1]
    End point description
    An adverse event (AE) is any untoward medical event that occurs in a subject administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. A TEAE is any AE temporally associated with the use of study drug (from study drug initiation until 3 days after study drug discontinuation), whether or not considered related to the study drug. The safety set included all randomised subjects who received at least 1 dose of selexipag or placebo.
    End point type
    Primary
    End point timeframe
    Up to 3 days after drug discontinuation (Up to 10.5 years)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No inferential statistics was planned for this primary endpoint.
    End point values
    		 Selexipag
    Number of subjects analysed
    709
    Units: subjects
    684
    No statistical analyses for this end point

    Primary: Number of Subjects with TEAEs Leading to Permanent Discontinuation of Study Intervention

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    End point title
    		 Number of Subjects with TEAEs Leading to Permanent Discontinuation of Study Intervention [2]
    End point description
    An adverse event (AE) is any untoward medical event that occurs in a subject administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. A TEAE is any AE temporally associated with the use of study drug (from study drug initiation until 3 days after study drug discontinuation), whether or not considered related to the study drug. The safety set included all randomised subjects who received at least 1 dose of selexipag or placebo.
    End point type
    Primary
    End point timeframe
    Up to 10.5 years
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No inferential statistics was planned for this primary endpoint.
    End point values
    		 Selexipag
    Number of subjects analysed
    709
    Units: subjects
    129
    No statistical analyses for this end point

    Primary: Number of Subjects with Treatment-emergent Serious Adverse Events (TESAEs) up to 3 days After Study Intervention Discontinuation

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    End point title
    		 Number of Subjects with Treatment-emergent Serious Adverse Events (TESAEs) up to 3 days After Study Intervention Discontinuation [3]
    End point description
    An adverse event is any untoward medical event that occurs in a subject administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. SAE is any AE that results in: death, persistent or significant disability/incapacity, requires inpatient hospitalisation or prolongation of existing hospitalisation, is life-threatening experience, is a congenital anomaly/birth defect and may jeopardise subject and/or may require medical or surgical intervention to prevent one of the outcomes listed above. Those SAEs occurring during study drug administration, that is, between study drug initiation and three days after study drug discontinuation, are defined as treatment-emergent SAEs. The safety set included all randomised subjects who received at least 1 dose of selexipag or placebo.
    End point type
    Primary
    End point timeframe
    Up to 3 days after drug discontinuation (Up to 10.5 years)
    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: No inferential statistics was planned for this primary endpoint.
    End point values
    		 Selexipag
    Number of subjects analysed
    709
    Units: subjects
    420
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 10.5 years for serious and other (non-serious) adverse events and up to 11.2 years for all-cause mortality
    Adverse event reporting additional description
    The safety set included all randomised subjects who received at least 1 dose of selexipag or placebo.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Selexipag
    Reporting group description
    		 Subjects with pulmonary arterial hypertension (PAH) who completed the double-blind AC-065A302 GRIPHON study or experienced a morbidity/mortality event in that study, entered in this open label (OL) study. Subjects who received selexipag in GRIPHON continued to receive selexipag at the same dose (200 micrograms [mcg], twice daily [bid] up to 1600 mcg bid based on individual maximum tolerated dose) in this OL study. Subjects who were on placebo or experienced a morbidity/mortality event in GRIPHON entered the titration period of this OL-study and received lowest dose of selexipag (200 mcg, bid) and dose was titrated up to 1600 mcg bid, based on the individual maximum tolerated dose. Each subject received study drug from Day 1 until the earliest of a) selexipag became commercially available in this indication in subject’s country, b) sponsor decided to stop current study, or c) subject/investigator decided to discontinue study intervention (up to 10.5 years).

    Serious adverse events
    		 Selexipag
    Total subjects affected by serious adverse events
         subjects affected / exposed
    420 / 709 (59.24%)
         number of deaths (all causes)
    186
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of Colon
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Benign Salivary Gland Neoplasm
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Breast Cancer Metastatic
         subjects affected / exposed
    2 / 709 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Breast Cancer Recurrent
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Carcinoid Tumour of the Stomach
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Endometrial Cancer Stage I
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Endometrial Adenocarcinoma
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Extranodal Marginal Zone B-Cell Lymphoma (Malt Type)
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infected Neoplasm
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatocellular Carcinoma
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Lung Adenocarcinoma
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung Neoplasm Malignant
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metastases to the Mediastinum
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nodal Marginal Zone B-Cell Lymphoma
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Ovarian Germ Cell Teratoma Benign
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Papillary Thyroid Cancer
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Uterine Leiomyoma
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Circulatory Collapse
         subjects affected / exposed
    2 / 709 (0.28%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Deep Vein Thrombosis
         subjects affected / exposed
    3 / 709 (0.42%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Hypotension
         subjects affected / exposed
    6 / 709 (0.85%)
         occurrences causally related to treatment / all
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    Hypovolaemic Shock
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Orthostatic Hypotension
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Peripheral Ischaemia
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Peripheral Arterial Occlusive Disease
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vasculitis
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Superior Vena Cava Perforation
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Venous Thrombosis Limb
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Benign Breast Lump Removal
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Balloon Atrial Septostomy
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Breast Conserving Surgery
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Coronary Arterial Stent Insertion
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Drug Therapy
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac Pacemaker Insertion
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Coronary Angioplasty
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastric Bypass
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fasciotomy
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Heart and Lung Transplant
         subjects affected / exposed
    2 / 709 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Hip Arthroplasty
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Knee Operation
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung Transplant
         subjects affected / exposed
    5 / 709 (0.71%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Nephrectomy
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ovarian Cystectomy
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Packed Red Blood Cell Transfusion
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rehabilitation Therapy
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Percutaneous Coronary Intervention
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Transfusion
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Varicose Vein Operation
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular Operation
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion Missed
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pregnancy
         subjects affected / exposed
    5 / 709 (0.71%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Abortion Spontaneous
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Catheter Site Erythema
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Catheter Site Thrombosis
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Chest Discomfort
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Chest Pain
         subjects affected / exposed
    7 / 709 (0.99%)
         occurrences causally related to treatment / all
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    Death
         subjects affected / exposed
    3 / 709 (0.42%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 3
    Drowning
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Drug Interaction
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Drug Ineffective
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Euthanasia
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Gait Disturbance
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Generalised Oedema
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Multiple Organ Dysfunction Syndrome
         subjects affected / exposed
    8 / 709 (1.13%)
         occurrences causally related to treatment / all
    0 / 8
         deaths causally related to treatment / all
    0 / 7
    Oedema Peripheral
         subjects affected / exposed
    4 / 709 (0.56%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Peripheral Swelling
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Organ Failure
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyrexia
         subjects affected / exposed
    5 / 709 (0.71%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Sudden Cardiac Death
         subjects affected / exposed
    3 / 709 (0.42%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 3
    Sudden Death
         subjects affected / exposed
    14 / 709 (1.97%)
         occurrences causally related to treatment / all
    0 / 14
         deaths causally related to treatment / all
    0 / 14
    Systemic Inflammatory Response Syndrome
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Withdrawal Syndrome
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Immune system disorders
    Amyloidosis
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Endometriosis
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Uterine Haemorrhage
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vaginal Haemorrhage
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute Pulmonary Oedema
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Asthma
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Acute Respiratory Failure
         subjects affected / exposed
    5 / 709 (0.71%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 5
    Chronic Obstructive Pulmonary Disease
         subjects affected / exposed
    2 / 709 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Chronic Respiratory Failure
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Dyspnoea
         subjects affected / exposed
    18 / 709 (2.54%)
         occurrences causally related to treatment / all
    0 / 21
         deaths causally related to treatment / all
    0 / 0
    Dyspnoea Exertional
         subjects affected / exposed
    2 / 709 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Haemoptysis
         subjects affected / exposed
    10 / 709 (1.41%)
         occurrences causally related to treatment / all
    1 / 13
         deaths causally related to treatment / all
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypersensitivity Pneumonitis
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Lower Respiratory Tract Inflammation
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypoxia
         subjects affected / exposed
    4 / 709 (0.56%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Lupus Pneumonitis
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pleuritic Pain
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pleurisy
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary Alveolar Haemorrhage
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Pulmonary Arterial Hypertension
         subjects affected / exposed
    169 / 709 (23.84%)
         occurrences causally related to treatment / all
    2 / 220
         deaths causally related to treatment / all
    1 / 66
    Pulmonary Artery Dilatation
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary Artery Aneurysm
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    8 / 709 (1.13%)
         occurrences causally related to treatment / all
    0 / 12
         deaths causally related to treatment / all
    0 / 4
    Pulmonary Hypertension
         subjects affected / exposed
    2 / 709 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    Pulmonary Oedema
         subjects affected / exposed
    2 / 709 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    Pulmonary Mass
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory Distress
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory Failure
         subjects affected / exposed
    4 / 709 (0.56%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    Psychiatric disorders
    Acute Psychosis
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Drug Dependence
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Anxiety
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Major Depression
         subjects affected / exposed
    2 / 709 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Suicide Attempt
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Bile Duct Stone
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cholecystitis
         subjects affected / exposed
    2 / 709 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Cardiac Cirrhosis
         subjects affected / exposed
    2 / 709 (0.28%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    Cholecystitis Acute
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cirrhosis Alcoholic
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Cholelithiasis
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Drug-Induced Liver Injury
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatic Failure
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Jaundice
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Activated Partial Thromboplastin Time Prolonged
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Anticoagulation Drug Level above Therapeutic
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood Uric Acid Increased
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Biopsy Kidney
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Catheterisation Cardiac
         subjects affected / exposed
    2 / 709 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Haemoglobin Decreased
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    International Normalised Ratio Increased
         subjects affected / exposed
    2 / 709 (0.28%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Investigation
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    N-Terminal Prohormone Brain Natriuretic Peptide Increased
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Precancerous Cells Present
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Transplant Evaluation
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Prothrombin Time Prolonged
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Weight Decreased
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Accident
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Anaesthetic Complication
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Ankle Fracture
         subjects affected / exposed
    3 / 709 (0.42%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Fall
         subjects affected / exposed
    8 / 709 (1.13%)
         occurrences causally related to treatment / all
    0 / 8
         deaths causally related to treatment / all
    0 / 1
    Contusion
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Concussion
         subjects affected / exposed
    2 / 709 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Head Injury
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fractured Sacrum
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Femoral Neck Fracture
         subjects affected / exposed
    2 / 709 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Humerus Fracture
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intentional Overdose
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Jaw Fracture
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Joint Dislocation
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pelvic Fracture
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Poisoning
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Radius Fracture
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Post Procedural Haemorrhage
         subjects affected / exposed
    2 / 709 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Reactive Gastropathy
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Road Traffic Accident
         subjects affected / exposed
    2 / 709 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Rib Fracture
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin Laceration
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Soft Tissue Injury
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal Compression Fracture
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Subcutaneous Haematoma
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal Fracture
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Toxicity to Various Agents
         subjects affected / exposed
    3 / 709 (0.42%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Traumatic Haematoma
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Upper Limb Fracture
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular Pseudoaneurysm
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Congenital, familial and genetic disorders
    Dermoid Cyst
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemorrhagic Arteriovenous Malformation
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Acute Coronary Syndrome
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Acute Myocardial Infarction
         subjects affected / exposed
    4 / 709 (0.56%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    Acute Right Ventricular Failure
         subjects affected / exposed
    11 / 709 (1.55%)
         occurrences causally related to treatment / all
    0 / 11
         deaths causally related to treatment / all
    0 / 11
    Angina Pectoris
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Aortic Valve Stenosis
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Arrhythmia
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    17 / 709 (2.40%)
         occurrences causally related to treatment / all
    0 / 23
         deaths causally related to treatment / all
    0 / 0
    Atrial Tachycardia
         subjects affected / exposed
    2 / 709 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Atrial Flutter
         subjects affected / exposed
    8 / 709 (1.13%)
         occurrences causally related to treatment / all
    0 / 10
         deaths causally related to treatment / all
    0 / 1
    Atrioventricular Block
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Atrioventricular Block Second Degree
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Atrioventricular Block Complete
         subjects affected / exposed
    3 / 709 (0.42%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Cardiac Arrest
         subjects affected / exposed
    13 / 709 (1.83%)
         occurrences causally related to treatment / all
    0 / 13
         deaths causally related to treatment / all
    0 / 13
    Cardiac Failure
         subjects affected / exposed
    8 / 709 (1.13%)
         occurrences causally related to treatment / all
    0 / 12
         deaths causally related to treatment / all
    0 / 2
    Cardiac Failure Acute
         subjects affected / exposed
    2 / 709 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cardiac Failure Congestive
         subjects affected / exposed
    4 / 709 (0.56%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    Cardiac Failure Chronic
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Cardiopulmonary Failure
         subjects affected / exposed
    8 / 709 (1.13%)
         occurrences causally related to treatment / all
    0 / 8
         deaths causally related to treatment / all
    0 / 8
    Cardiogenic Shock
         subjects affected / exposed
    9 / 709 (1.27%)
         occurrences causally related to treatment / all
    0 / 9
         deaths causally related to treatment / all
    0 / 8
    Cardio-Respiratory Arrest
         subjects affected / exposed
    5 / 709 (0.71%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 5
    Cardiorenal Syndrome
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiovascular Insufficiency
         subjects affected / exposed
    2 / 709 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    Chronic Left Ventricular Failure
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Chronic Right Ventricular Failure
         subjects affected / exposed
    2 / 709 (0.28%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Cor Pulmonale
         subjects affected / exposed
    2 / 709 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cor Pulmonale Acute
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Myocardial Infarction
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Left Ventricular Failure
         subjects affected / exposed
    4 / 709 (0.56%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    Coronary Artery Disease
         subjects affected / exposed
    2 / 709 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pericardial Effusion
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Right Ventricular Dysfunction
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Right Ventricular Failure
         subjects affected / exposed
    93 / 709 (13.12%)
         occurrences causally related to treatment / all
    1 / 163
         deaths causally related to treatment / all
    0 / 39
    Supraventricular Tachycardia
         subjects affected / exposed
    4 / 709 (0.56%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    Tricuspid Valve Incompetence
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ventricular Tachyarrhythmia
         subjects affected / exposed
    2 / 709 (0.28%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Cerebral Infarction
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Carotid Artery Occlusion
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intracranial Haematoma
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Headache
         subjects affected / exposed
    4 / 709 (0.56%)
         occurrences causally related to treatment / all
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    Ischaemic Stroke
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Presyncope
         subjects affected / exposed
    3 / 709 (0.42%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Syncope
         subjects affected / exposed
    18 / 709 (2.54%)
         occurrences causally related to treatment / all
    0 / 25
         deaths causally related to treatment / all
    0 / 0
    Vocal Cord Paralysis
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Transient Ischaemic Attack
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    9 / 709 (1.27%)
         occurrences causally related to treatment / all
    0 / 10
         deaths causally related to treatment / all
    0 / 1
    Anaemia Vitamin B12 Deficiency
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bone Marrow Failure
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood Loss Anaemia
         subjects affected / exposed
    2 / 709 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Disseminated Intravascular Coagulation
         subjects affected / exposed
    2 / 709 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Immune Thrombocytopenic Purpura
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Iron Deficiency Anaemia
         subjects affected / exposed
    2 / 709 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    2 / 709 (0.28%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Pseudolymphoma
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Lymphadenopathy Mediastinal
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Diabetic Retinopathy
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Astigmatism
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Glaucoma
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal Distension
         subjects affected / exposed
    2 / 709 (0.28%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Abdominal Hernia
         subjects affected / exposed
    2 / 709 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Abdominal Pain
         subjects affected / exposed
    4 / 709 (0.56%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    Abdominal Wall Haematoma
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Abdominal Pain Lower
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Chronic Gastritis
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ascites
         subjects affected / exposed
    6 / 709 (0.85%)
         occurrences causally related to treatment / all
    0 / 9
         deaths causally related to treatment / all
    0 / 1
    Colitis
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
         subjects affected / exposed
    12 / 709 (1.69%)
         occurrences causally related to treatment / all
    3 / 13
         deaths causally related to treatment / all
    0 / 2
    Constipation
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diverticular Perforation
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Enterocolitis
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastritis Haemorrhagic
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastric Ulcer
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal Haemorrhage
         subjects affected / exposed
    9 / 709 (1.27%)
         occurrences causally related to treatment / all
    0 / 9
         deaths causally related to treatment / all
    0 / 2
    Gastrointestinal Motility Disorder
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ileus Paralytic
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intestinal Haemorrhage
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Large Intestinal Haemorrhage
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Large Intestine Polyp
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Melaena
         subjects affected / exposed
    2 / 709 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 709 (0.28%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Obstructive Pancreatitis
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oesophageal Haemorrhage
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatitis Acute
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rectal Haemorrhage
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 709 (0.42%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Upper Gastrointestinal Haemorrhage
         subjects affected / exposed
    2 / 709 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Skin and subcutaneous tissue disorders
    Skin Necrosis
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin Ulcer
         subjects affected / exposed
    2 / 709 (0.28%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Chronic Kidney Disease
         subjects affected / exposed
    3 / 709 (0.42%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Acute Kidney Injury
         subjects affected / exposed
    6 / 709 (0.85%)
         occurrences causally related to treatment / all
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    Cystitis Haemorrhagic
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Glomerulonephritis Chronic
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ischaemic Nephropathy
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haematuria
         subjects affected / exposed
    2 / 709 (0.28%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Lupus Nephritis
         subjects affected / exposed
    2 / 709 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Renal Failure
         subjects affected / exposed
    4 / 709 (0.56%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Proteinuria
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal Haematoma
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tubulointerstitial Nephritis
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal Impairment
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary Retention
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Endocrine disorders
    Adrenocortical Insufficiency Acute
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Basedow's Disease
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyperthyroidism
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Thyroiditis Subacute
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    2 / 709 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Fracture Malunion
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Mixed Connective Tissue Disease
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haematoma Muscle
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neck Pain
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rheumatoid Arthritis
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Systemic Lupus Erythematosus
         subjects affected / exposed
    2 / 709 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Still's Disease
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    Systemic Scleroderma
         subjects affected / exposed
    2 / 709 (0.28%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Abscess Bacterial
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Abscess Limb
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Appendicitis
         subjects affected / exposed
    3 / 709 (0.42%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Anal Abscess
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Actinomycotic Pulmonary Infection
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bacterial Abdominal Infection
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Atypical Pneumonia
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Appendicitis Perforated
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Bacterial Sepsis
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Bronchitis
         subjects affected / exposed
    11 / 709 (1.55%)
         occurrences causally related to treatment / all
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    Cellulitis
         subjects affected / exposed
    6 / 709 (0.85%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    Clostridium Difficile Colitis
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Colonic Abscess
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Corona Virus Infection
         subjects affected / exposed
    4 / 709 (0.56%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    Complicated Appendicitis
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dengue Fever
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Disseminated Tuberculosis
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Empyema
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Endocarditis
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Enterobacter Sepsis
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Erysipelas
         subjects affected / exposed
    2 / 709 (0.28%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Escherichia Sepsis
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    3 / 709 (0.42%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Escherichia Urinary Tract Infection
         subjects affected / exposed
    2 / 709 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis Norovirus
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis Clostridial
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal Infection
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    H1n1 Influenza
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Herpes Zoster
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemorrhagic Pneumonia
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Haematoma Infection
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infective Tenosynovitis
         subjects affected / exposed
    2 / 709 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Infection
         subjects affected / exposed
    2 / 709 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Influenza
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lower Respiratory Tract Infection
         subjects affected / exposed
    8 / 709 (1.13%)
         occurrences causally related to treatment / all
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    Lung Infection
         subjects affected / exposed
    5 / 709 (0.71%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    Nasopharyngitis
         subjects affected / exposed
    2 / 709 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Otitis Media Bacterial
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Peritonitis Bacterial
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Peritonitis
         subjects affected / exposed
    3 / 709 (0.42%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    Pneumonia
         subjects affected / exposed
    50 / 709 (7.05%)
         occurrences causally related to treatment / all
    0 / 58
         deaths causally related to treatment / all
    0 / 10
    Pneumonia Bacterial
         subjects affected / exposed
    2 / 709 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Pneumonia Viral
         subjects affected / exposed
    3 / 709 (0.42%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Postoperative Wound Infection
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyelonephritis Acute
         subjects affected / exposed
    2 / 709 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pyoderma
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Sepsis
         subjects affected / exposed
    10 / 709 (1.41%)
         occurrences causally related to treatment / all
    0 / 11
         deaths causally related to treatment / all
    0 / 4
    Rhinitis
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory Tract Infection
         subjects affected / exposed
    4 / 709 (0.56%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 1
    Septic Shock
         subjects affected / exposed
    3 / 709 (0.42%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 3
    Sialoadenitis
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Soft Tissue Infection
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Staphylococcal Sepsis
         subjects affected / exposed
    2 / 709 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Tracheobronchitis
         subjects affected / exposed
    2 / 709 (0.28%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    4 / 709 (0.56%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    4 / 709 (0.56%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Viral Infection
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Viral Upper Respiratory Tract Infection
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Wound Infection
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Fluid Overload
         subjects affected / exposed
    3 / 709 (0.42%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Fluid Retention
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypoproteinaemia
         subjects affected / exposed
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Selexipag
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    598 / 709 (84.34%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    49 / 709 (6.91%)
         occurrences all number
    54
    Hypotension
         subjects affected / exposed
    38 / 709 (5.36%)
         occurrences all number
    48
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    43 / 709 (6.06%)
         occurrences all number
    48
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    71 / 709 (10.01%)
         occurrences all number
    88
    Headache
         subjects affected / exposed
    328 / 709 (46.26%)
         occurrences all number
    469
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    65 / 709 (9.17%)
         occurrences all number
    78
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    44 / 709 (6.21%)
         occurrences all number
    48
    Oedema Peripheral
         subjects affected / exposed
    90 / 709 (12.69%)
         occurrences all number
    104
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    209 / 709 (29.48%)
         occurrences all number
    274
    Nausea
         subjects affected / exposed
    135 / 709 (19.04%)
         occurrences all number
    171
    Vomiting
         subjects affected / exposed
    74 / 709 (10.44%)
         occurrences all number
    90
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    80 / 709 (11.28%)
         occurrences all number
    96
    Dyspnoea
         subjects affected / exposed
    76 / 709 (10.72%)
         occurrences all number
    99
    Pulmonary Arterial Hypertension
         subjects affected / exposed
    68 / 709 (9.59%)
         occurrences all number
    77
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    65 / 709 (9.17%)
         occurrences all number
    75
    Myalgia
         subjects affected / exposed
    68 / 709 (9.59%)
         occurrences all number
    92
    Pain in Extremity
         subjects affected / exposed
    78 / 709 (11.00%)
         occurrences all number
    97
    Pain in Jaw
         subjects affected / exposed
    130 / 709 (18.34%)
         occurrences all number
    153
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    59 / 709 (8.32%)
         occurrences all number
    76
    Urinary Tract Infection
         subjects affected / exposed
    42 / 709 (5.92%)
         occurrences all number
    54
    Upper Respiratory Tract Infection
         subjects affected / exposed
    84 / 709 (11.85%)
         occurrences all number
    130
    Nasopharyngitis
         subjects affected / exposed
    88 / 709 (12.41%)
         occurrences all number
    125
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    44 / 709 (6.21%)
         occurrences all number
    54

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Mar 2010
    The purpose of this amendment was: the double-blind studies AC-065A301 and AC-065A302 (2009-014490-41) were merged into a single study and all references were replaced by the reference to the merged protocol AC-065A302; subjects who experienced a Critical Event Committee (CEC)-confirmed clinical worsening event during study AC-065A302 could only enter study AC-065A303 after their Week 16 visit of study AC-065A302 and after written approval from the sponsor. These restrictions were removed; a time limit of 2 weeks after the last visit in study AC-065A302 was introduced for entering study AC-065A303; and clarification that prostacyclin and prostanoid therapy were prohibited not only during studyAC-065A303 but also during the transition period between study AC-065A302 and study AC-065A303.
    20 Dec 2010
    The purpose of this amendment was: the precautionary wording regarding sun exposure was removed and the Independent Data Monitoring Committee reviewing unblinded safety data of Study AC-065A302 was also assigned the review of safety data from the study AC-065A303.
    19 Apr 2013
    The purpose of this amendment was: sample size was increased from 670 up to a maximum of 1150 and collection of safety data in the clinical database was extended to vital signs, body weight, concomitant medications, and laboratory results; guidance for management of subjects with liver impairment was provided; and eligibility of study AC-065A302 subjects to study AC-065A303 was extended to subjects with worsening of pulmonary arterial hypertension (PAH) during the treatment extension period of study AC-065A302.
    16 Mar 2015
    The purpose of this amendment was: the possibility to up-titrate selexipag at unscheduled visits (for subjects who had not reached the maximum allowed dose) was introduced; the overall duration of study AC-065A303 was changed from “until the approval of selexipag in PAH” to “until selexipag is commercially available”; temporary concomitant use of selexipag and intravenous (IV), subcutaneous (SC), or inhaled prostacyclin and prostacyclin analogs was allowed when deemed medically indicated for the subject; and a discontinuation criterion for subjects diagnosed with pulmonary venoocclusive disease (PVOD) was introduced.
    15 Jun 2016
    The purpose of this amendment was: disbandment of the Data Monitoring Committee involved in study AC-065A302 and Ophthalmology Safety Board as of 01 July 2016; and the reference to the selexipag Investigator Brochure (IB) Section 6 was replaced with the complete list of adverse events.
    25 Jan 2017
    The purpose of this amendment was: further to new drug-drug interaction study results, concomitant administration of strong cytochrome P450 (CYP)2C8 inhibitors such as gemfibrozil was to be avoided and in case of concomitant administration of rifampicin, dose adjustment of selexipag could be required.
    30 Jun 2017
    The purpose of this amendment was to: contraindication of strong CYP2C8 inhibitors such as gemfibrozil in accordance with IB Version 11 was added; and information on the lack of studies to determine the effect of moderate inhibitors of CYP2C8, and strong inhibitors of UGT1A3 and UGT2B7 on the exposure to selexipag or its active metabolite was added.
    06 Feb 2019
    The purpose of this amendment was: Guidance for concomitant administration of selexipag and moderate inhibitors of CYP2C8 was updated based on Phase 1 study AC-065-117, in accordance with IB Version 13; clinical information section was updated to include reference to the recently completed studies along with the results in accordance with IB Version 13; statistical section was updated according to International Council for Harmonisation E6 guideline; and the data collection section was updated to allow the use of a standard ballpoint pen to complete the Case Report Forms (CRF).

    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.
    The open-label, uncontrolled design, additional PAH-specific treatments in limited subjects for limited time, a variable study duration due to commercial selexipag availability and limitation of safety data reporting in China by 20-Dec-2019.
    For support, Contact us.
    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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