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    Clinical Trial Results:
    A randomised, multi-centre, open-label, phase III study of adjuvant lapatinib, trastuzumab, their sequence and their combination in patients with HER2/ErbB2 positive primary breast cancer

    Summary
    EudraCT number
    		 2006-000562-36
    Trial protocol
    		 IE   HU   FR   GB   SK   EE   CZ   DK   BE   DE   GR   NL   IT   ES   SI   BG   AT  
    Global end of trial date
    01 Jul 2021

    Results information
    Results version number
    		 v2(current)
    This version publication date
    06 Apr 2025
    First version publication date
    02 Jul 2022
    Other versions
    		 v1
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CLAP016B2301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00490139
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    Novartis Campus, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    01 Jul 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Jul 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to compare disease-free survival (DFS) in patients with Human Epidermal Growth Factor Receptor 2 (HER2) overexpressing and/or amplified breast cancer randomized to trastuzumab for one year (Trastuzumab arm) versus lapatinib for one year (Lapatinib arm; this arm was discontinued prior to the primary analysis due to futility) versus weekly trastuzumab (12 or 18 weeks, according to assigned design) followed by a six-week washout period followed by lapatinib (28 or 34 weeks, according to assigned design; Trastuzumab followed by Lapatinib arm) versus trastuzumab in combination with lapatinib for one year (Lapatinib plus Trastuzumab arm).
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 May 2007
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 64
    Country: Number of subjects enrolled
    Australia: 181
    Country: Number of subjects enrolled
    Austria: 5
    Country: Number of subjects enrolled
    Belgium: 231
    Country: Number of subjects enrolled
    Brazil: 98
    Country: Number of subjects enrolled
    Bulgaria: 26
    Country: Number of subjects enrolled
    Canada: 42
    Country: Number of subjects enrolled
    Chile: 108
    Country: Number of subjects enrolled
    China: 441
    Country: Number of subjects enrolled
    Czechia: 116
    Country: Number of subjects enrolled
    Denmark: 187
    Country: Number of subjects enrolled
    Estonia: 4
    Country: Number of subjects enrolled
    France: 410
    Country: Number of subjects enrolled
    Germany: 1375
    Country: Number of subjects enrolled
    Greece: 56
    Country: Number of subjects enrolled
    Hong Kong: 56
    Country: Number of subjects enrolled
    Hungary: 134
    Country: Number of subjects enrolled
    India: 201
    Country: Number of subjects enrolled
    Ireland: 52
    Country: Number of subjects enrolled
    Israel: 47
    Country: Number of subjects enrolled
    Italy: 371
    Country: Number of subjects enrolled
    Japan: 142
    Country: Number of subjects enrolled
    Korea, Republic of: 353
    Country: Number of subjects enrolled
    Mexico: 31
    Country: Number of subjects enrolled
    Netherlands: 87
    Country: Number of subjects enrolled
    New Zealand: 41
    Country: Number of subjects enrolled
    Norway: 40
    Country: Number of subjects enrolled
    Pakistan: 204
    Country: Number of subjects enrolled
    Peru: 143
    Country: Number of subjects enrolled
    Philippines: 150
    Country: Number of subjects enrolled
    Poland: 176
    Country: Number of subjects enrolled
    Romania: 105
    Country: Number of subjects enrolled
    Russian Federation: 324
    Country: Number of subjects enrolled
    Singapore: 25
    Country: Number of subjects enrolled
    Slovakia: 53
    Country: Number of subjects enrolled
    Slovenia: 20
    Country: Number of subjects enrolled
    South Africa: 168
    Country: Number of subjects enrolled
    Spain: 267
    Country: Number of subjects enrolled
    Switzerland: 56
    Country: Number of subjects enrolled
    Taiwan: 374
    Country: Number of subjects enrolled
    Thailand: 172
    Country: Number of subjects enrolled
    Ukraine: 85
    Country: Number of subjects enrolled
    United Kingdom: 243
    Country: Number of subjects enrolled
    United States: 917
    Worldwide total number of subjects
    8381
    EEA total number of subjects
    3715
    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)
    7526
    From 65 to 84 years
    855
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 This study was conducted in 969 centers in 44 countries worldwide.

    Pre-assignment
    Screening details
    		 Based on the IDMC results from 18 August 2011, any patient enrolled onto Lapatinib arm were considered for a new treatment strategy based on discussion with their physician.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Lapatinib plus Trastuzumab
    Arm description
    		 Participants received treatment per one of three designs and adjuvant radiotherapy / adjuvant anti-estrogen therapy when clinically indicated. * Design 1: oral lapatinib (OL) 1000 milligrams (mg) daily with trastuzumab (tras) (8 milligrams per kilogram [mg/kg] intravenous [IV] loading dose [LD], followed by 6 mg/kg IV every 3 weeks [E3W]) for 52 weeks (wks). * Design 2: OL 750 mg daily plus wkly tras (4 mg/kg LD, followed by 2 mg/kg IV) concomitantly (conc.) with wkly paclitaxel (pac) 80 mg per squared meter (mg/m^2) IV or docetaxel (doc) 75 mg/m^2 IV E3W for 12 wks. After completion of pac or doc, par. received OL at an increased dose of 1000 mg daily in combination with tras (6 mg/kg without a LD) E3W for 40 wks. * Design 2B: OL 750 mg plus wkly tras (4 mg/kg IV LD, followed by 2 mg/kg IV wkly) conc. with doc 75 mg/m^2 E3W and carboplatin (carb) AUC6 IV for 18 wks. After completion of doc and carb, par. received tras E3W (6 mg/kg without a LD) plus OL 1000 mg daily for 34 wks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lapatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Design 1: Oral lapatinib 1000 mg daily concurrent with trastuzumab 8 mg/kg IV loading dose followed by 6mg/kg IV every 3 weeks (52 weeks total). Design 2: Trastuzumab (4mg/kg loading dose followed by 2mg/kg IV weekly) concurrent with oral lapatinib 750 mg daily and either paclitaxel 80mg/m2 IV weekly for 12 weeks OR docetaxel 75mg/m2 every 21 days for 4 cycles (12 weeks). After completion of chemotherapy, the dose of lapatinib will be increased to 1000mg daily concurrently with trastuzumab every 3 weeks (6mg/kg without loading dose) for an additional 40 weeks (52 weeks total). Design 2B: Docetaxel 75mg/m2 and carboplatin AUC 6 every 3 weeks for 6 cycles (18 weeks) administered concurrently with oral lapatinib 750mg plus weekly trastuzumab (4mg/kg IV loading dose followed by 2mg/kg IV. After the completion of chemotherapy, trastuzumab will be administered every 3 weeks (6mg/kg without loading dose) concurrent with lapatinib 1000mg daily for an additional 40 weeks (52 weeks total).

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Design 2: Trastuzumab (4mg/kg loading dose followed by 2mg/kg IV weekly) concurrent with oral lapatinib 750 mg daily and either paclitaxel 80mg/m2 IV weekly for 12 weeks OR docetaxel 75mg/m2 every 21 days for 4 cycles (12 weeks). After completion of chemotherapy, the dose of lapatinib will be increased to 1000mg daily concurrently with trastuzumab every 3 weeks (6mg/kg without loading dose) for an additional 40 weeks (52 weeks total). Design 2B: Docetaxel 75mg/m2 and carboplatin AUC 6 every 3 weeks for 6 cycles (18 weeks) administered concurrently with oral lapatinib 750mg plus weekly trastuzumab (4mg/kg IV loading dose followed by 2mg/kg IV. After the completion of chemotherapy, trastuzumab will be administered every 3 weeks (6mg/kg without loading dose) concurrent with lapatinib 1000mg daily for an additional 40 weeks (52 weeks total).

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Design 2: Trastuzumab (4mg/kg loading dose followed by 2mg/kg IV weekly) concurrent with oral lapatinib 750 mg daily and either paclitaxel 80mg/m2 IV weekly for 12 weeks OR docetaxel 75mg/m2 every 21 days for 4 cycles (12 weeks). After completion of chemotherapy, the dose of lapatinib will be increased to 1000mg daily concurrently with trastuzumab every 3 weeks (6mg/kg without loading dose) for an additional 40 weeks (52 weeks total).

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Design 1: Oral lapatinib 1000 mg daily concurrent with trastuzumab 8 mg/kg IV loading dose followed by 6mg/kg IV every 3 weeks (52 weeks total). Design 2: Trastuzumab (4mg/kg loading dose followed by 2mg/kg IV weekly) concurrent with oral lapatinib 750 mg daily and either paclitaxel 80mg/m2 IV weekly for 12 weeks OR docetaxel 75mg/m2 every 21 days for 4 cycles (12 weeks). After completion of chemotherapy, the dose of lapatinib will be increased to 1000mg daily concurrently with trastuzumab every 3 weeks (6mg/kg without loading dose) for an additional 40 weeks (52 weeks total). Design 2B: Docetaxel 75mg/m2 and carboplatin AUC 6 every 3 weeks for 6 cycles (18 weeks) administered concurrently with oral lapatinib 750mg plus weekly trastuzumab (4mg/kg IV loading dose followed by 2mg/kg IV. After the completion of chemotherapy, trastuzumab will be administered every 3 weeks (6mg/kg without loading dose) concurrent with lapatinib 1000mg daily for an additional 40 weeks (52 weeks total).

    Arm title
    		 Trastuzumab followed by Lapatinib
    Arm description
    		 Participants received treatment per one of three designs and adjuvant radiotherapy / adjuvant anti-estrogen therapy when clinically indicated. * Design 1: weekly tras for 12 weeks (4 mg/kg IV loading dose, followed by 2 mg/kg IV weekly), followed by a 6-week washout period, followed by oral lap 1500 mg daily for 34 weeks. * Design 2: weekly tras (4 mg/kg IV loading dose, followed by 2 mg/kg IV) concomitantly with weekly paclitaxel 80 mg/m^2 IV or docetaxel 75 mg/m^2 IV every 3 weeks for 12 weeks, followed by a 6-week washout period, followed by oral lap 1500 mg daily for 34 weeks. * Design 2B: weekly tras (4 mg/kg IV loading dose, followed by 2 mg/kg IV weekly) concomitantly with docetaxel 75 mg/m^2 every 3 weeks and carboplatin AUC6 IV for 18 weeks, followed by a 6-week washout period, followed by oral lap 1500 mg daily for 28 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Design 1: Trastuzumab (4mg/kg IV loading dose followed by 2mg/kg IV weekly) for 12 weeks followed by a 6 week treatment-free interval followed by oral lapatinib 1500mg daily for 34 weeks (52 weeks total). Design 2: Trastuzumab (4mg/kg IV loading dose followed by 2mg/kg IV weekly) for 12 weeks administered concomitantly and either paclitaxel 80mg/m2 IV weekly for 12 weeks OR docetaxel 75mg/m2 every 21 days for 4 cycles; followed by a 6 week treatment-free interval followed by oral lapatinib 1500mg daily for 34 weeks (52 weeks total). Design 2B: Docetaxel 75mg/m2 and carboplatin AUC 6 every 3 weeks for 6 cycles (18 weeks) administered concomitantly with trastuzumab (4mg/kg IV loading dose followed by 2mg/kg IV weekly) followed by a 6 week treatment-free interval followed by oral lapatinib 1500 mg daily for 28 weeks (52 weeks total).

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Design 2: Trastuzumab (4mg/kg IV loading dose followed by 2mg/kg IV weekly) for 12 weeks administered concomitantly and either paclitaxel 80mg/m2 IV weekly for 12 weeks OR docetaxel 75mg/m2 every 21 days for 4 cycles; followed by a 6 week treatment-free interval followed by oral lapatinib 1500mg daily for 34 weeks (52 weeks total). Design 2B: Docetaxel 75mg/m2 and carboplatin AUC 6 every 3 weeks for 6 cycles (18 weeks) administered concomitantly with trastuzumab (4mg/kg IV loading dose followed by 2mg/kg IV weekly) followed by a 6 week treatment-free interval followed by oral lapatinib 1500 mg daily for 28 weeks (52 weeks total).

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Design 2: Trastuzumab (4mg/kg IV loading dose followed by 2mg/kg IV weekly) for 12 weeks administered concomitantly and either paclitaxel 80mg/m2 IV weekly for 12 weeks OR docetaxel 75mg/m2 every 21 days for 4 cycles; followed by a 6 week treatment-free interval followed by oral lapatinib 1500mg daily for 34 weeks (52 weeks total).

    Investigational medicinal product name
    Lapatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Design 1: Trastuzumab (4mg/kg IV loading dose followed by 2mg/kg IV weekly) for 12 weeks followed by a 6 week treatment-free interval followed by oral lapatinib 1500mg daily for 34 weeks (52 weeks total). Design 2: Trastuzumab (4mg/kg IV loading dose followed by 2mg/kg IV weekly) for 12 weeks administered concomitantly and either paclitaxel 80mg/m2 IV weekly for 12 weeks OR docetaxel 75mg/m2 every 21 days for 4 cycles; followed by a 6 week treatment-free interval followed by oral lapatinib 1500mg daily for 34 weeks (52 weeks total). Design 2B: Docetaxel 75mg/m2 and carboplatin AUC 6 every 3 weeks for 6 cycles (18 weeks) administered concomitantly with trastuzumab (4mg/kg IV loading dose followed by 2mg/kg IV weekly) followed by a 6 week treatment-free interval followed by oral lapatinib 1500 mg daily for 28 weeks (52 weeks total).

    Arm title
    		 Lapatinib
    Arm description
    		 Participants received treatment per one of three designs and adjuvant radiotherapy / adjuvant anti-estrogen therapy when clinically indicated. * Design 1: oral lap 1500 mg daily for 52 weeks. * Design 2: oral lap 750 mg daily concomitantly with weekly paclitaxel 80 mg/m^2 IV or docetaxel 75 mg/m^2 IV every 3 weeks, for 12 weeks. After completion of paclitaxel or docetaxel, participants received oral lap at an increased dose of 1500 mg daily for 40 weeks. * Design 2B: oral lap 750 mg daily concomitantly with docetaxel 75 mg/m^2 every 3 weeks and carboplatin AUC6 IV, for 18 weeks. After completion of docetaxel and carboplatin, oral lap was given at an increased dose of 1500 mg for 34 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lapatinid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Design 1: Lapatinib 1500mg oral daily for a total of 52 weeks. Design 2: Either paclitaxel 80mg/m2 IV weekly for 12 weeks OR docetaxel 75mg/m2 IV every 3 weeks for 4 cycles administered concomitantly with oral lapatinib at 750mg daily. After completion of chemotherapy, oral lapatinib administered at 1500mg daily for an additional 40 weeks (52 weeks total). Design 2B: Docetaxel 75mg/m2 and carboplatin AUC 6 every 3 weeks for 6 cycles (18 weeks) administered concomitantly with oral lapatinib at 750mg daily. After completion of chemotherapy, the dose of lapatinib will be increased to 1500mg oral daily for an additional 40 weeks (52 weeks total).

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Design 2: Either paclitaxel 80mg/m2 IV weekly for 12 weeks OR docetaxel 75mg/m2 IV every 3 weeks for 4 cycles administered concomitantly with oral lapatinib at 750mg daily. After completion of chemotherapy, oral lapatinib administered at 1500mg daily for an additional 40 weeks (52 weeks total). Design 2B: Docetaxel 75mg/m2 and carboplatin AUC 6 every 3 weeks for 6 cycles (18 weeks) administered concomitantly with oral lapatinib at 750mg daily. After completion of chemotherapy, the dose of lapatinib will be increased to 1500mg oral daily for an additional 40 weeks (52 weeks total).

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Design 2: Either paclitaxel 80mg/m2 IV weekly for 12 weeks OR docetaxel 75mg/m2 IV every 3 weeks for 4 cycles administered concomitantly with oral lapatinib at 750mg daily. After completion of chemotherapy, oral lapatinib administered at 1500mg daily for an additional 40 weeks (52 weeks total).

    Arm title
    		 Trastuzumab
    Arm description
    		 Participants received treatment per one of three designs and adjuvant radiotherapy / adjuvant anti-estrogen therapy when clinically indicated. * Design 1: tras 8 mg/kg IV LD, followed by 6 mg/kg IV every 3 weeks for 52 weeks. * Design 2: weekly tras (4 mg/kg IV LD, followed by 2 mg/kg IV weekly) concomitantly with weekly paclitaxel 80 mg/m^2 IV or docetaxel 75 mg/m^2 IV every 3 weeks, for 12 weeks. After completion of paclitaxel or docetaxel, participants received tras (6 mg/kg without a LD every 3 weeks for 40 weeks. * Design 2B: weekly tras (4 mg/kg IV LD, followed by 2 mg/kg IV weekly) concomitantly with docetaxel 75 mg/m^2 every 3 weeks and carboplatin AUC6 IV, for 18 weeks. After completion of docetaxel and carboplatin, participants received tras every 3 weeks (6 mg/kg without a LD) for 34 weeks. "
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Design 1: Trastuzumab 8mg/kg IV loading dose followed by 6mg/kg IV every 3 weeks for a total of 52 weeks. Design 2: Either paclitaxel 80mg/m2 IV weekly for 12 weeks OR docetaxel 75mg/m2 IV every 3 weeks for 4 cycles administered concomitantly with trastuzumab 4mg/kg IV loading dose followed by 2mg/kg IV weekly. After completion of chemotherapy, trastuzumab administered every 3 weeks (6mg/kg IV without loading dose) for an additional 40 weeks (52 weeks total). Design 2B: Docetaxel 75mg/m2 and carboplatin AUC 6 every 3 weeks for 6 cycles (18 weeks) administered concomitantly with trastuzumab 4mg/kg IV loading dose followed by 2mg/kg IV weekly. After completion of chemotherapy, trastuzumab (6mg/kg without loading dose) every 3 weeks for an additional 40 weeks (52 weeks total).

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Design 2: Either paclitaxel 80mg/m2 IV weekly for 12 weeks OR docetaxel 75mg/m2 IV every 3 weeks for 4 cycles administered concomitantly with trastuzumab 4mg/kg IV loading dose followed by 2mg/kg IV weekly. After completion of chemotherapy, trastuzumab administered every 3 weeks (6mg/kg IV without loading dose) for an additional 40 weeks (52 weeks total). Design 2B: Docetaxel 75mg/m2 and carboplatin AUC 6 every 3 weeks for 6 cycles (18 weeks) administered concomitantly with trastuzumab 4mg/kg IV loading dose followed by 2mg/kg IV weekly. After completion of chemotherapy, trastuzumab (6mg/kg without loading dose) every 3 weeks for an additional 40 weeks (52 weeks total).

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Design 2: Either paclitaxel 80mg/m2 IV weekly for 12 weeks OR docetaxel 75mg/m2 IV every 3 weeks for 4 cycles administered concomitantly with trastuzumab 4mg/kg IV loading dose followed by 2mg/kg IV weekly. After completion of chemotherapy, trastuzumab administered every 3 weeks (6mg/kg IV without loading dose) for an additional 40 weeks (52 weeks total).

    Number of subjects in period 1
    		Lapatinib plus Trastuzumab Trastuzumab followed by Lapatinib Lapatinib Trastuzumab
    Started
    2093
    2091
    2100
    2097
    Safety population
    2061
    2076
    2056
    2076
    Completed
    1132
    1184
    1179
    1192
    Not completed
    961
    907
    921
    905
         Consent withdrawn by subject
    333
    322
    396
    295
         Data unavailable due to regulatory issues
    98
    96
    85
    95
         Data unavailable due to lapsed ethical consent
    14
    13
    14
    14
         Patient did not sign ICF 12
    169
    176
    139
    167
         Lost to follow-up
    249
    216
    205
    229
         Other reasons as defined per protocol
    98
    84
    82
    105

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Lapatinib plus Trastuzumab
    Reporting group description
    		 Participants received treatment per one of three designs and adjuvant radiotherapy / adjuvant anti-estrogen therapy when clinically indicated. * Design 1: oral lapatinib (OL) 1000 milligrams (mg) daily with trastuzumab (tras) (8 milligrams per kilogram [mg/kg] intravenous [IV] loading dose [LD], followed by 6 mg/kg IV every 3 weeks [E3W]) for 52 weeks (wks). * Design 2: OL 750 mg daily plus wkly tras (4 mg/kg LD, followed by 2 mg/kg IV) concomitantly (conc.) with wkly paclitaxel (pac) 80 mg per squared meter (mg/m^2) IV or docetaxel (doc) 75 mg/m^2 IV E3W for 12 wks. After completion of pac or doc, par. received OL at an increased dose of 1000 mg daily in combination with tras (6 mg/kg without a LD) E3W for 40 wks. * Design 2B: OL 750 mg plus wkly tras (4 mg/kg IV LD, followed by 2 mg/kg IV wkly) conc. with doc 75 mg/m^2 E3W and carboplatin (carb) AUC6 IV for 18 wks. After completion of doc and carb, par. received tras E3W (6 mg/kg without a LD) plus OL 1000 mg daily for 34 wks.

    Reporting group title
    Trastuzumab followed by Lapatinib
    Reporting group description
    		 Participants received treatment per one of three designs and adjuvant radiotherapy / adjuvant anti-estrogen therapy when clinically indicated. * Design 1: weekly tras for 12 weeks (4 mg/kg IV loading dose, followed by 2 mg/kg IV weekly), followed by a 6-week washout period, followed by oral lap 1500 mg daily for 34 weeks. * Design 2: weekly tras (4 mg/kg IV loading dose, followed by 2 mg/kg IV) concomitantly with weekly paclitaxel 80 mg/m^2 IV or docetaxel 75 mg/m^2 IV every 3 weeks for 12 weeks, followed by a 6-week washout period, followed by oral lap 1500 mg daily for 34 weeks. * Design 2B: weekly tras (4 mg/kg IV loading dose, followed by 2 mg/kg IV weekly) concomitantly with docetaxel 75 mg/m^2 every 3 weeks and carboplatin AUC6 IV for 18 weeks, followed by a 6-week washout period, followed by oral lap 1500 mg daily for 28 weeks.

    Reporting group title
    Lapatinib
    Reporting group description
    		 Participants received treatment per one of three designs and adjuvant radiotherapy / adjuvant anti-estrogen therapy when clinically indicated. * Design 1: oral lap 1500 mg daily for 52 weeks. * Design 2: oral lap 750 mg daily concomitantly with weekly paclitaxel 80 mg/m^2 IV or docetaxel 75 mg/m^2 IV every 3 weeks, for 12 weeks. After completion of paclitaxel or docetaxel, participants received oral lap at an increased dose of 1500 mg daily for 40 weeks. * Design 2B: oral lap 750 mg daily concomitantly with docetaxel 75 mg/m^2 every 3 weeks and carboplatin AUC6 IV, for 18 weeks. After completion of docetaxel and carboplatin, oral lap was given at an increased dose of 1500 mg for 34 weeks.

    Reporting group title
    Trastuzumab
    Reporting group description
    		 Participants received treatment per one of three designs and adjuvant radiotherapy / adjuvant anti-estrogen therapy when clinically indicated. * Design 1: tras 8 mg/kg IV LD, followed by 6 mg/kg IV every 3 weeks for 52 weeks. * Design 2: weekly tras (4 mg/kg IV LD, followed by 2 mg/kg IV weekly) concomitantly with weekly paclitaxel 80 mg/m^2 IV or docetaxel 75 mg/m^2 IV every 3 weeks, for 12 weeks. After completion of paclitaxel or docetaxel, participants received tras (6 mg/kg without a LD every 3 weeks for 40 weeks. * Design 2B: weekly tras (4 mg/kg IV LD, followed by 2 mg/kg IV weekly) concomitantly with docetaxel 75 mg/m^2 every 3 weeks and carboplatin AUC6 IV, for 18 weeks. After completion of docetaxel and carboplatin, participants received tras every 3 weeks (6 mg/kg without a LD) for 34 weeks. "

    Reporting group values
    		 Lapatinib plus Trastuzumab Trastuzumab followed by Lapatinib Lapatinib Trastuzumab Total
    Number of subjects
    		 2093 2091 2100 2097 8381
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 1879 1877 1889 1881 7526
        From 65-84 years
    		 214 214 211 216 855
        85 years and over
    		 0 0 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 2091 2086 2098 2097 8372
        Male
    		 2 5 2 0 9
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    		 48 45 47 47 187
        Asian: Central/South
    		 107 103 110 109 429
        Asian: East
    		 311 312 299 314 1236
        Asian: Japanese
    		 33 36 33 43 145
        Asian: South East
    		 95 92 107 89 383
        Black or African American
    		 38 30 43 25 136
        Native Hawaiian or Other Pacific
    		 2 4 4 5 15
        White: Arabic
    		 53 52 62 69 236
        White: Caucasian
    		 1392 1402 1372 1382 5548
        Other Race
    		 14 14 23 14 65
        Unknown/Missing
    		 0 1 0 0 1
    Axillary Lymph Node Status
    Axillary Lymph Node Status was categorized as: a) Not applicable (neoadjuvant chemotherapy); b) Node negative (no neoadjuvant chemotherapy); c) 1-3 positive nodes (no neoadjuvant chemotherapy); d) >= 4 positive nodes (no neoadjuvant chemotherapy)
    Units: Subjects
        Not applicable (neoadjuvant chemotherapy)
    		 168 170 167 181 686
        Node negative (no neoadjuvant chemotherapy)
    		 845 842 841 844 3372
        1-3 positive nodes (no neoadjuvant chemotherapy)
    		 617 617 620 603 2457
        >= 4 positive nodes (no neoadjuvant chemotherapy)
    		 463 462 472 469 1866
    Timing of Chemotherapy
    Timing of (neo)adjuvant chemotherapy was defined as follows: Design 1 – sequentially (all chemotherapy completed prior to randomization) versus Design 2 – concurrently with targeted therapy (taxane medication administered with targeted treatment after randomization). Subjects treated concurrently but without anthracycline (Design 2B) were regarded as part of Design 2 for all stratified analyses.
    Units: Subjects
        Sequential
    		 1155 1143 1168 1147 4613
        Concurrent
    		 938 948 932 950 3768
    Hormone Receptor (HR) Status
    HR status was determined from the percentage of Estrogen Receptor (ER) and Progesterone Receptor (PgR) cells stained positive: a) Positive: if the percentage of cells stained positive is >= 1% for either ER or PgR; b) Negative: if the percentage of cells stained positive is < 1% for both ER and PgR
    Units: Subjects
        Negative
    		 890 886 903 897 3576
        Positive
    		 1203 1205 1197 1200 4805
    GenderNIH
    Units: Subjects
        Female
    		 2091 2086 2098 2097 8372
        Male
    		 2 5 2 0 9
    AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    		 50.9 ( 10.23 ) 50.8 ( 10.32 ) 51.2 ( 10.18 ) 51.0 ( 10.25 ) -

    End points

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    End points reporting groups
    Reporting group title
    Lapatinib plus Trastuzumab
    Reporting group description
    		 Participants received treatment per one of three designs and adjuvant radiotherapy / adjuvant anti-estrogen therapy when clinically indicated. * Design 1: oral lapatinib (OL) 1000 milligrams (mg) daily with trastuzumab (tras) (8 milligrams per kilogram [mg/kg] intravenous [IV] loading dose [LD], followed by 6 mg/kg IV every 3 weeks [E3W]) for 52 weeks (wks). * Design 2: OL 750 mg daily plus wkly tras (4 mg/kg LD, followed by 2 mg/kg IV) concomitantly (conc.) with wkly paclitaxel (pac) 80 mg per squared meter (mg/m^2) IV or docetaxel (doc) 75 mg/m^2 IV E3W for 12 wks. After completion of pac or doc, par. received OL at an increased dose of 1000 mg daily in combination with tras (6 mg/kg without a LD) E3W for 40 wks. * Design 2B: OL 750 mg plus wkly tras (4 mg/kg IV LD, followed by 2 mg/kg IV wkly) conc. with doc 75 mg/m^2 E3W and carboplatin (carb) AUC6 IV for 18 wks. After completion of doc and carb, par. received tras E3W (6 mg/kg without a LD) plus OL 1000 mg daily for 34 wks.

    Reporting group title
    Trastuzumab followed by Lapatinib
    Reporting group description
    		 Participants received treatment per one of three designs and adjuvant radiotherapy / adjuvant anti-estrogen therapy when clinically indicated. * Design 1: weekly tras for 12 weeks (4 mg/kg IV loading dose, followed by 2 mg/kg IV weekly), followed by a 6-week washout period, followed by oral lap 1500 mg daily for 34 weeks. * Design 2: weekly tras (4 mg/kg IV loading dose, followed by 2 mg/kg IV) concomitantly with weekly paclitaxel 80 mg/m^2 IV or docetaxel 75 mg/m^2 IV every 3 weeks for 12 weeks, followed by a 6-week washout period, followed by oral lap 1500 mg daily for 34 weeks. * Design 2B: weekly tras (4 mg/kg IV loading dose, followed by 2 mg/kg IV weekly) concomitantly with docetaxel 75 mg/m^2 every 3 weeks and carboplatin AUC6 IV for 18 weeks, followed by a 6-week washout period, followed by oral lap 1500 mg daily for 28 weeks.

    Reporting group title
    Lapatinib
    Reporting group description
    		 Participants received treatment per one of three designs and adjuvant radiotherapy / adjuvant anti-estrogen therapy when clinically indicated. * Design 1: oral lap 1500 mg daily for 52 weeks. * Design 2: oral lap 750 mg daily concomitantly with weekly paclitaxel 80 mg/m^2 IV or docetaxel 75 mg/m^2 IV every 3 weeks, for 12 weeks. After completion of paclitaxel or docetaxel, participants received oral lap at an increased dose of 1500 mg daily for 40 weeks. * Design 2B: oral lap 750 mg daily concomitantly with docetaxel 75 mg/m^2 every 3 weeks and carboplatin AUC6 IV, for 18 weeks. After completion of docetaxel and carboplatin, oral lap was given at an increased dose of 1500 mg for 34 weeks.

    Reporting group title
    Trastuzumab
    Reporting group description
    		 Participants received treatment per one of three designs and adjuvant radiotherapy / adjuvant anti-estrogen therapy when clinically indicated. * Design 1: tras 8 mg/kg IV LD, followed by 6 mg/kg IV every 3 weeks for 52 weeks. * Design 2: weekly tras (4 mg/kg IV LD, followed by 2 mg/kg IV weekly) concomitantly with weekly paclitaxel 80 mg/m^2 IV or docetaxel 75 mg/m^2 IV every 3 weeks, for 12 weeks. After completion of paclitaxel or docetaxel, participants received tras (6 mg/kg without a LD every 3 weeks for 40 weeks. * Design 2B: weekly tras (4 mg/kg IV LD, followed by 2 mg/kg IV weekly) concomitantly with docetaxel 75 mg/m^2 every 3 weeks and carboplatin AUC6 IV, for 18 weeks. After completion of docetaxel and carboplatin, participants received tras every 3 weeks (6 mg/kg without a LD) for 34 weeks. "

    Primary: Disease-Free Survival (DFS) at the Primary Analysis

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    End point title
    		 Disease-Free Survival (DFS) at the Primary Analysis
    End point description
    Disease-Free Survival (DFS) was defined as the interval between randomization and the date of first occurrence of disease recurrence (local, regional or distant), a contralateral invasive breast cancer, a second primary cancer or death without recurrence. Only deaths occurring in participants whose clinical follow-up was ongoing at the time of death and who had no recurrence, contralateral breast cancer (CBC) or second primary malignancy (SPM) reported prior to death were considered as death without recurrence. DFS was estimated using the Kaplan Meier method. The percentile data values presented here indicate the percentage (95, 90, 85, 80 and 75 percent) of participants who had disease free survival for the indicated years.
    End point type
    Primary
    End point timeframe
    From randomization until the date of the first occurrence of disease recurrence, a contralateral invasive breast cancer, a second primary cancer, or death from any cause (median follow-up of 4.5 years)
    End point values
    		 Lapatinib plus Trastuzumab Trastuzumab followed by Lapatinib Lapatinib Trastuzumab
    Number of subjects analysed
    2093
    2091
    2100
    2097
    Units: Years
    number (not applicable)
        95th Percentile
    1.9
    1.3
    1.0
    1.5
        90th Percentile
    3.2
    2.8
    1.8
    2.6
        85th Percentile
    5.1
    4.8
    2.8
    4.2
        80th Percentile
    6.1
    999
    999
    5.6
        75th Percentile
    6.1
    999
    999
    999
    Statistical analysis title
    		 DFS at the Primary Analysis
    Comparison groups
    Trastuzumab followed by Lapatinib v Trastuzumab
    Number of subjects included in analysis
    4188
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.61
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.81
         upper limit
    		 1.13
    Statistical analysis title
    		 DFS at the Primary Analysis
    Comparison groups
    Lapatinib plus Trastuzumab v Trastuzumab
    Number of subjects included in analysis
    4190
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.048
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.71
         upper limit
    		 1

    Secondary: Disease-Free Survival (DFS) at the 10-Year Follow-Up

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    End point title
    		 Disease-Free Survival (DFS) at the 10-Year Follow-Up
    End point description
    Disease-Free Survival (DFS) was defined as the interval between randomization and the date of first occurrence of disease recurrence (local, regional or distant), a contralateral invasive breast cancer, a second primary cancer or death without recurrence. Only deaths occurring in participants whose clinical follow-up was ongoing at the time of death and who had no recurrence, contralateral breast cancer (CBC) or second primary malignancy (SPM) reported prior to death were considered as death without recurrence. DFS was estimated using the Kaplan Meier method. The percentile data values presented here indicate the percentage (95, 90, 85 and 80 percent) of participants who had disease free survival for the indicated years.
    End point type
    Secondary
    End point timeframe
    From randomization until the date of the first occurrence of disease recurrence, a contralateral invasive breast cancer, a second primary cancer, or death from any cause, assessed up to approximately 10 years
    End point values
    		 Lapatinib plus Trastuzumab Trastuzumab followed by Lapatinib Lapatinib Trastuzumab
    Number of subjects analysed
    2093
    2091
    0 [1]
    2097
    Units: Years
    number (not applicable)
        95th Percentile
    1.89
    1.27
    1.49
        90th Percentile
    3.21
    2.80
    2.63
        85th Percentile
    5.92
    4.85
    4.43
        80th Percentile
    8.99
    9.18
    7.42
    Notes
    [1] - The Lapatinib alone arm was discontinued prior to primary analysis due to futility.
    Statistical analysis title
    		 DFS at the 10-Year Follow-Up
    Comparison groups
    Trastuzumab followed by Lapatinib v Trastuzumab
    Number of subjects included in analysis
    4188
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.914
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 1.05
    Statistical analysis title
    		 DFS at the 10-Year Follow-Up
    Comparison groups
    Lapatinib plus Trastuzumab v Trastuzumab
    Number of subjects included in analysis
    4190
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.887
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.77
         upper limit
    		 1.02

    Secondary: Overall Survival (OS) at the Primary Analysis

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    End point title
    		 Overall Survival (OS) at the Primary Analysis
    End point description
    Overall Survival (OS) was defined as the time from randomization until death due to any cause. Participants who had not died were censored at the last date they were known to be alive, or date of withdrawal of consent. OS was calculated in years as (date of death minus the date of randomization +1) divided by 365.25. The percentile data values presented here indicate the percentage (99, 98, 97, 96, 95 and 90 percent) of participants who survived for the indicated years.
    End point type
    Secondary
    End point timeframe
    From randomization until death due to any cause (median follow-up of 4.5 years)
    End point values
    		 Lapatinib plus Trastuzumab Trastuzumab followed by Lapatinib Lapatinib Trastuzumab
    Number of subjects analysed
    2093
    2091
    0 [2]
    2097
    Units: Years
    number (not applicable)
        99th Percentile
    1.7
    1.2
    1.7
        98th Percentile
    2.2
    1.6
    2.1
        97th Percentile
    2.8
    2.2
    2.6
        96th Percentile
    3.4
    2.9
    3.0
        95th Percentile
    3.9
    3.7
    3.6
        90th Percentile
    999
    999
    5.9
    Notes
    [2] - The Lapatinib alone arm was discontinued prior to primary analysis due to futility.
    Statistical analysis title
    		 OS at the Primary Analysis
    Comparison groups
    Trastuzumab followed by Lapatinib v Trastuzumab
    Number of subjects included in analysis
    4188
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.433
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.71
         upper limit
    		 1.16
    Statistical analysis title
    		 OS at the Primary Analysis
    Comparison groups
    Lapatinib plus Trastuzumab v Trastuzumab
    Number of subjects included in analysis
    4190
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.078
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 1.03

    Secondary: Overall Survival (OS) at the 10-Year Follow-Up

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    End point title
    		 Overall Survival (OS) at the 10-Year Follow-Up
    End point description
    Overall Survival (OS) was defined as the time from randomization until death due to any cause. Participants who had not died were censored at the last date they were known to be alive, or date of withdrawal of consent. OS was calculated in years as (date of death minus the date of randomization +1) divided by 365.25. The percentile data values presented here indicate the percentage (99, 98, 95 and 90 percent) of participants who survived for the indicated years.
    End point type
    Secondary
    End point timeframe
    From randomization until death due to any cause, assessed up to approximately 10 years
    End point values
    		 Lapatinib plus Trastuzumab Trastuzumab followed by Lapatinib Lapatinib Trastuzumab
    Number of subjects analysed
    2093
    2091
    0 [3]
    2097
    Units: Years
    number (not applicable)
        99th Percentile
    1.68
    1.17
    1.75
        98th Percentile
    2.19
    1.60
    2.07
        95th Percentile
    3.92
    3.52
    3.65
        90th Percentile
    8.31
    8.49
    6.72
    Notes
    [3] - The Lapatinib alone arm was discontinued prior to primary analysis due to futility.
    Statistical analysis title
    		 OS at the 10-Year Follow-Up
    Comparison groups
    Trastuzumab followed by Lapatinib v Trastuzumab
    Number of subjects included in analysis
    4188
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.863
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.71
         upper limit
    		 1.04
    Statistical analysis title
    		 OS at the 10-Year Follow-Up
    Comparison groups
    Lapatinib plus Trastuzumab v Trastuzumab
    Number of subjects included in analysis
    4190
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.853
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 1.03

    Secondary: Analysis of Time to Distant Recurrence (TTDR)

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    End point title
    		 Analysis of Time to Distant Recurrence (TTDR)
    End point description
    Time to Distant Recurrence (TTDR) was defined as the the time from randomization to first distant breast cancer recurrence, ignoring locoregional recurrences and second primary cancers, (including contralateral breast cancers and non-breast second malignancies ) and counting deaths without recurrence as a competing risk.
    End point type
    Secondary
    End point timeframe
    From randomization until the date of the first occurrence of distant recurrence, assessed up to approximately 10 years
    End point values
    		 Lapatinib plus Trastuzumab Trastuzumab followed by Lapatinib Lapatinib Trastuzumab
    Number of subjects analysed
    2093
    2091
    0 [4]
    2097
    Units: Participants
        Distant recurrence
    213
    238
    250
        Death as a competing risk
    45
    41
    54
        Censored
    1835
    1812
    1793
    Notes
    [4] - The Lapatinib alone arm was discontinued prior to primary analysis due to futility.
    Statistical analysis title
    		 Time to Distant Recurrence (TTDR)
    Comparison groups
    Trastuzumab followed by Lapatinib v Trastuzumab
    Number of subjects included in analysis
    4188
    Analysis specification
    Pre-specified
    Analysis type
    		 [5]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.968
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.81
         upper limit
    		 1.16
    Notes
    [5] - Time to distant recurrence was analyzed using competing risks methodology with death (without event) as a competing risk.
    Statistical analysis title
    		 Time to Distant Recurrence (TTDR)
    Comparison groups
    Lapatinib plus Trastuzumab v Trastuzumab
    Number of subjects included in analysis
    4190
    Analysis specification
    Pre-specified
    Analysis type
    		 [6]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.852
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.71
         upper limit
    		 1.02
    Notes
    [6] - Time to distant recurrence was analyzed using competing risks methodology with death (without event) as a competing risk.

    Secondary: Analysis of Time to Recurrence (TTR)

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    End point title
    		 Analysis of Time to Recurrence (TTR)
    End point description
    Time to Recurrence (TTR) was defined as the the time from randomization to breast cancer recurrence, ignoring second primary cancers (including contralateral breast cancers and non-breast second malignancies) and counting deaths without recurrence as a competing risk.
    End point type
    Secondary
    End point timeframe
    From randomization until the date of the first occurrence of a disease recurrence, assessed up to approximately 10 years
    End point values
    		 Lapatinib plus Trastuzumab Trastuzumab followed by Lapatinib Lapatinib Trastuzumab
    Number of subjects analysed
    2093
    2091
    0 [7]
    2097
    Units: Participants
        Local, regional, or distant recurrence
    243
    275
    298
        Death as a competing risk
    43
    38
    46
        Censored
    1807
    1778
    1753
    Notes
    [7] - The Lapatinib alone arm was discontinued prior to primary analysis due to futility.
    Statistical analysis title
    		 Time to Recurrence (TTR)
    Comparison groups
    Trastuzumab followed by Lapatinib v Trastuzumab
    Number of subjects included in analysis
    4188
    Analysis specification
    Pre-specified
    Analysis type
    		 [8]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.79
         upper limit
    		 1.1
    Notes
    [8] - Time to recurrence was analyzed using competing risks methodology with death (without event) as a competing risk.
    Statistical analysis title
    		 Time to Recurrence (TTR)
    Comparison groups
    Lapatinib plus Trastuzumab v Trastuzumab
    Number of subjects included in analysis
    4190
    Analysis specification
    Pre-specified
    Analysis type
    		 [9]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.811
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 0.96
    Notes
    [9] - Time to recurrence was analyzed using competing risks methodology with death (without event) as a competing risk.

    Secondary: Analysis of Time to Central Nervous System (CNS) Recurrence

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    End point title
    		 Analysis of Time to Central Nervous System (CNS) Recurrence
    End point description
    Time to Central Nervous System (CNS) recurrence was defined as the time from randomization to first CNS recurrence. Both brain metastasis and meningitis carcinomatosa were considered.
    End point type
    Secondary
    End point timeframe
    From randomization until the first central nervous system recurrence, assessed up to approximately 10 years
    End point values
    		 Lapatinib plus Trastuzumab Trastuzumab followed by Lapatinib Lapatinib Trastuzumab
    Number of subjects analysed
    2093
    2091
    0 [10]
    2097
    Units: Participants
        CNS recurrence
    91
    91
    95
        Death as a competing risk
    114
    117
    142
        Censored
    1888
    1883
    1860
    Notes
    [10] - The Lapatinib alone arm was discontinued prior to primary analysis due to futility.
    Statistical analysis title
    		 Time to CNS Recurrence
    Comparison groups
    Trastuzumab followed by Lapatinib v Trastuzumab
    Number of subjects included in analysis
    4188
    Analysis specification
    Pre-specified
    Analysis type
    		 [11]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.74
         upper limit
    		 1.31
    Notes
    [11] - Time to CNS recurrence was analyzed using competing risks methodology with death (without event) as a competing risk.
    Statistical analysis title
    		 Time to CNS Recurrence
    Comparison groups
    Lapatinib plus Trastuzumab v Trastuzumab
    Number of subjects included in analysis
    4190
    Analysis specification
    Pre-specified
    Analysis type
    		 [12]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.986
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.74
         upper limit
    		 1.31
    Notes
    [12] - Time to CNS recurrence was analyzed using competing risks methodology with death (without event) as a competing risk.

    Secondary: Cumulative incidence of brain metastases

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    End point title
    		 Cumulative incidence of brain metastases
    End point description
    The cumulative incidence of brain metastases as the first site of breast cancer recurrence among treatment arms was assessed using a hierarchy of primary type and location of first DFS event in cases where more than one event was identified simultaneously. Because diagnostic procedures for different types of recurrence could not be performed on exactly the same day, any diagnoses noted within a two month (60 day) period of the first reported event was considered as identified simultaneously for purposes of defining the type of the first event and the date of event was be regarded as the earliest of the relevant events.
    End point type
    Secondary
    End point timeframe
    From randomization until the date of the first occurrence of a disease recurrence, assessed up to approximately 10 years
    End point values
    		 Lapatinib plus Trastuzumab Trastuzumab followed by Lapatinib Lapatinib Trastuzumab
    Number of subjects analysed
    2093
    2091
    0 [13]
    2097
    Units: Participants
    50
    52
    48
    Notes
    [13] - The Lapatinib alone arm was discontinued prior to primary analysis due to futility.
    No statistical analyses for this end point

    Post-hoc: All collected deaths

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    End point title
    		 All collected deaths
    End point description
    Pre-treatment deaths were collected from day of participant’s informed consent to the day before first dose of study medication. On-treatment deaths were collected from first dose of study medication to 30 days after last dose of study medication (on-treatment), up to approximately 56 weeks. ​ Deaths were collected in the post treatment survival follow up from 31 days after last dose of study medication until the end of the study, up to approximately 10 years.
    End point type
    Post-hoc
    End point timeframe
    Pre-treatment deaths: Up to 14 days prior to treatment. On-treatment deaths: Up to 56 weeks. Post-treatment deaths: up to 10 years.
    End point values
    		 Lapatinib plus Trastuzumab Trastuzumab followed by Lapatinib Lapatinib Trastuzumab
    Number of subjects analysed
    2093
    2091
    2100
    2097
    Units: Participants
        Pre-treatment deaths
    1
    2
    1
    2
        On-treatment deaths
    6
    5
    12
    3
        Post-treatment deaths
    189
    190
    250
    228
        All deaths
    196
    197
    263
    233
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events (AEs) were collected from first dose of study medication until the last dose plus 30 days post-treat follow-up, assessed up to approximately 56 weeks.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    Lapatinib plus Trastuzumab
    Reporting group description
    		 Lapatinib plus Trastuzumab: Events up to 30 days post-treatment

    Reporting group title
    Lapatinib
    Reporting group description
    		 Lapatinib: Events up to 30 days post-treatment

    Reporting group title
    Trastuzumab
    Reporting group description
    		 Trastuzumab: Events up to 30 days post-treatment

    Reporting group title
    Trastuzumab followed by Lapatinib
    Reporting group description
    		 Trastuzumab followed by Lapatinib: Events up to 30 days post-treatment

    Serious adverse events
    		 Lapatinib plus Trastuzumab Lapatinib Trastuzumab Trastuzumab followed by Lapatinib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    379 / 2061 (18.39%)
    394 / 2056 (19.16%)
    251 / 2076 (12.09%)
    299 / 2076 (14.40%)
         number of deaths (all causes)
    6
    12
    3
    5
         number of deaths resulting from adverse events
    2
    3
    3
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    ADENOCARCINOMA OF COLON
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ACUTE LYMPHOCYTIC LEUKAEMIA
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    ACUTE PROMYELOCYTIC LEUKAEMIA
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GASTROINTESTINAL CARCINOMA
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GASTROINTESTINAL STROMAL TUMOUR
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HAEMANGIOMA
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BENIGN BREAST NEOPLASM
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BENIGN OVARIAN TUMOUR
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GASTRIC CANCER
         subjects affected / exposed
    0 / 2061 (0.00%)
    2 / 2056 (0.10%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BORDERLINE OVARIAN TUMOUR
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BREAST CANCER
         subjects affected / exposed
    3 / 2061 (0.15%)
    3 / 2056 (0.15%)
    4 / 2076 (0.19%)
    3 / 2076 (0.14%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    BREAST CANCER IN SITU
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COLON CANCER
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    2 / 2076 (0.10%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ENDOMETRIAL ADENOCARCINOMA
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BLADDER NEOPLASM
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INTRADUCTAL PAPILLOMA OF BREAST
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INTRADUCTAL PROLIFERATIVE BREAST LESION
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    2 / 2076 (0.10%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LEIOMYOMA
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LEIOMYOSARCOMA
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MENINGIOMA BENIGN
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LIPOMA
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MALIGNANT MELANOMA
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MELANOCYTIC NAEVUS
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MENINGIOMA
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LENTIGO MALIGNA
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    METASTASES TO CENTRAL NERVOUS SYSTEM
         subjects affected / exposed
    1 / 2061 (0.05%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    NEUROENDOCRINE TUMOUR
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    OVARIAN ADENOMA
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    OVARIAN CANCER
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    OVARIAN GERM CELL TERATOMA BENIGN
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RECTAL CANCER
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PANCREATIC CARCINOMA
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    PAPILLARY THYROID CANCER
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PARATHYROID TUMOUR BENIGN
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PLASMA CELL MYELOMA
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    OVARIAN NEOPLASM
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    SMALL CELL LUNG CANCER
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    SQUAMOUS CELL CARCINOMA OF THE VULVA
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SUPERFICIAL SPREADING MELANOMA STAGE UNSPECIFIED
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    THYROID CANCER
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    2 / 2076 (0.10%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    TRANSITIONAL CELL CARCINOMA
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    UTERINE CANCER
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    UTERINE LEIOMYOMA
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    1 / 2076 (0.05%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    HYPERTENSION
         subjects affected / exposed
    2 / 2061 (0.10%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    2 / 2076 (0.10%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPOTENSION
         subjects affected / exposed
    2 / 2061 (0.10%)
    2 / 2056 (0.10%)
    3 / 2076 (0.14%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
    0 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    JUGULAR VEIN THROMBOSIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPERTENSIVE CRISIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CIRCULATORY COLLAPSE
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DEEP VEIN THROMBOSIS
         subjects affected / exposed
    2 / 2061 (0.10%)
    2 / 2056 (0.10%)
    0 / 2076 (0.00%)
    2 / 2076 (0.10%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    EMBOLISM VENOUS
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    FLUSHING
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    VENOUS THROMBOSIS LIMB
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    VASCULAR INSUFFICIENCY
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    THROMBOSIS
         subjects affected / exposed
    2 / 2061 (0.10%)
    1 / 2056 (0.05%)
    2 / 2076 (0.10%)
    2 / 2076 (0.10%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SUPERFICIAL VEIN THROMBOSIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SUBCLAVIAN VEIN THROMBOSIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RHEUMATOID VASCULITIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ORTHOSTATIC HYPOTENSION
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    ADVERSE DRUG REACTION
         subjects affected / exposed
    2 / 2061 (0.10%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ASTHENIA
         subjects affected / exposed
    2 / 2061 (0.10%)
    4 / 2056 (0.19%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    4 / 5
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CHEST PAIN
         subjects affected / exposed
    1 / 2061 (0.05%)
    2 / 2056 (0.10%)
    1 / 2076 (0.05%)
    4 / 2076 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
    0 / 1
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CHILLS
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    2 / 2076 (0.10%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CHRONIC FATIGUE SYNDROME
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DEATH
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    GRANULOMA
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    FAT NECROSIS
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    FATIGUE
         subjects affected / exposed
    5 / 2061 (0.24%)
    7 / 2056 (0.34%)
    2 / 2076 (0.10%)
    2 / 2076 (0.10%)
         occurrences causally related to treatment / all
    5 / 5
    6 / 7
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    FEELING COLD
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GENERAL PHYSICAL HEALTH DETERIORATION
         subjects affected / exposed
    0 / 2061 (0.00%)
    2 / 2056 (0.10%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DEVICE RELATED THROMBOSIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    IMPAIRED HEALING
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    IMPLANT SITE THROMBOSIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INFLAMMATION
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LIPOGRANULOMA
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MALAISE
         subjects affected / exposed
    1 / 2061 (0.05%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PERIPHERAL SWELLING
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    NECROSIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    NON-CARDIAC CHEST PAIN
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    OEDEMA
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    OEDEMA PERIPHERAL
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    2 / 2076 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MUCOSAL INFLAMMATION
         subjects affected / exposed
    2 / 2061 (0.10%)
    3 / 2056 (0.15%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PYREXIA
         subjects affected / exposed
    11 / 2061 (0.53%)
    13 / 2056 (0.63%)
    5 / 2076 (0.24%)
    16 / 2076 (0.77%)
         occurrences causally related to treatment / all
    6 / 13
    4 / 13
    4 / 5
    8 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SUDDEN DEATH
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Immune system disorders
    SARCOIDOSIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ANAPHYLACTIC REACTION
         subjects affected / exposed
    3 / 2061 (0.15%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ANAPHYLACTOID REACTION
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DRUG HYPERSENSITIVITY
         subjects affected / exposed
    1 / 2061 (0.05%)
    2 / 2056 (0.10%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPERSENSITIVITY
         subjects affected / exposed
    4 / 2061 (0.19%)
    1 / 2056 (0.05%)
    4 / 2076 (0.19%)
    4 / 2076 (0.19%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 1
    3 / 4
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    BREAST HAEMATOMA
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ADENOMYOSIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BREAST CALCIFICATIONS
         subjects affected / exposed
    1 / 2061 (0.05%)
    1 / 2056 (0.05%)
    1 / 2076 (0.05%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BREAST DISORDER
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BREAST FIBROSIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BREAST INFLAMMATION
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BREAST NECROSIS
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BREAST SWELLING
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ENDOMETRIAL HYPERPLASIA
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    UTERINE POLYP
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    OVARIAN CYST
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    3 / 2076 (0.14%)
    4 / 2076 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    OVARIAN CYST RUPTURED
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PELVIC PAIN
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    POSTMENOPAUSAL HAEMORRHAGE
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INTERMENSTRUAL BLEEDING
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    VAGINAL HAEMORRHAGE
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    ACUTE RESPIRATORY DISTRESS SYNDROME
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ATELECTASIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BRONCHIECTASIS
         subjects affected / exposed
    1 / 2061 (0.05%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BRONCHOSPASM
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HAEMOPTYSIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DYSPHONIA
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DYSPNOEA
         subjects affected / exposed
    4 / 2061 (0.19%)
    2 / 2056 (0.10%)
    6 / 2076 (0.29%)
    3 / 2076 (0.14%)
         occurrences causally related to treatment / all
    2 / 4
    2 / 2
    2 / 6
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DYSPNOEA EXERTIONAL
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    EPISTAXIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COUGH
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPOXIA
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INTERSTITIAL LUNG DISEASE
         subjects affected / exposed
    2 / 2061 (0.10%)
    2 / 2056 (0.10%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LARYNGEAL OEDEMA
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LUNG CONSOLIDATION
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LUNG DISORDER
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    3 / 2076 (0.14%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PNEUMOTHORAX
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PLEURAL EFFUSION
         subjects affected / exposed
    2 / 2061 (0.10%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PLEURISY
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PLEURITIC PAIN
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    2 / 2076 (0.10%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PNEUMONITIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    2 / 2056 (0.10%)
    5 / 2076 (0.24%)
    4 / 2076 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    3 / 5
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LUNG INFILTRATION
         subjects affected / exposed
    1 / 2061 (0.05%)
    1 / 2056 (0.05%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PULMONARY EMBOLISM
         subjects affected / exposed
    2 / 2061 (0.10%)
    6 / 2056 (0.29%)
    2 / 2076 (0.10%)
    4 / 2076 (0.19%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 6
    1 / 2
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    PULMONARY GRANULOMA
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PULMONARY MASS
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PULMONARY OEDEMA
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PULMONARY THROMBOSIS
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RESPIRATORY FAILURE
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Psychiatric disorders
    RESTLESSNESS
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SCHIZOPHRENIA
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SUICIDE ATTEMPT
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    1 / 2076 (0.05%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ABNORMAL BEHAVIOUR
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MENTAL DISORDER
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COMPLETED SUICIDE
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    DEPRESSION
         subjects affected / exposed
    3 / 2061 (0.15%)
    1 / 2056 (0.05%)
    3 / 2076 (0.14%)
    2 / 2076 (0.10%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    INSOMNIA
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MAJOR DEPRESSION
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ALCOHOL WITHDRAWAL SYNDROME
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    THROMBOSIS IN DEVICE
         subjects affected / exposed
    1 / 2061 (0.05%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DEVICE DISLOCATION
         subjects affected / exposed
    2 / 2061 (0.10%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DEVICE EXPULSION
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    BLOOD BILIRUBIN INCREASED
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    AMYLASE INCREASED
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BLOOD ALKALINE PHOSPHATASE INCREASED
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BLOOD CREATININE INCREASED
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    2 / 2076 (0.10%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BLOOD MAGNESIUM DECREASED
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    2 / 2076 (0.10%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BLOOD POTASSIUM DECREASED
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BLOOD UREA INCREASED
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BLOOD URINE PRESENT
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ELECTROCARDIOGRAM ST SEGMENT DEPRESSION
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COAGULATION TEST ABNORMAL
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE STATUS WORSENED
         subjects affected / exposed
    1 / 2061 (0.05%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    EJECTION FRACTION DECREASED
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ELECTROCARDIOGRAM ABNORMAL
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ELECTROCARDIOGRAM QT PROLONGED
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BODY TEMPERATURE INCREASED
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ELECTROCARDIOGRAM T WAVE INVERSION
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GAMMA-GLUTAMYLTRANSFERASE INCREASED
         subjects affected / exposed
    2 / 2061 (0.10%)
    3 / 2056 (0.15%)
    0 / 2076 (0.00%)
    4 / 2076 (0.19%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 3
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INTERNATIONAL NORMALISED RATIO INCREASED
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LIPASE
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LIVER FUNCTION TEST INCREASED
         subjects affected / exposed
    1 / 2061 (0.05%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PLATELET COUNT DECREASED
         subjects affected / exposed
    2 / 2061 (0.10%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    WEIGHT DECREASED
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LIPASE INCREASED
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    CONTUSION
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ALCOHOL POISONING
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    ANKLE FRACTURE
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    2 / 2076 (0.10%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CARBON MONOXIDE POISONING
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    CONCUSSION
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    FIBULA FRACTURE
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    FOOT FRACTURE
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    FOREIGN BODY
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    FRACTURE
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    FRACTURED COCCYX
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LOWER LIMB FRACTURE
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HUMERUS FRACTURE
         subjects affected / exposed
    1 / 2061 (0.05%)
    1 / 2056 (0.05%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INFUSION RELATED REACTION
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LIGAMENT INJURY
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LIGAMENT SPRAIN
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HIP FRACTURE
         subjects affected / exposed
    1 / 2061 (0.05%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MULTIPLE INJURIES
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PELVIC FRACTURE
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RADIATION FIBROSIS - LUNG
         subjects affected / exposed
    0 / 2061 (0.00%)
    2 / 2056 (0.10%)
    1 / 2076 (0.05%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RADIATION PNEUMONITIS
         subjects affected / exposed
    1 / 2061 (0.05%)
    2 / 2056 (0.10%)
    1 / 2076 (0.05%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RADIATION SKIN INJURY
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    3 / 2076 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RADIUS FRACTURE
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RIB FRACTURE
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    2 / 2076 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ROAD TRAFFIC ACCIDENT
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    SEROMA
         subjects affected / exposed
    1 / 2061 (0.05%)
    1 / 2056 (0.05%)
    1 / 2076 (0.05%)
    2 / 2076 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SPINAL COMPRESSION FRACTURE
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SPINAL FRACTURE
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    STERNAL FRACTURE
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SUBDURAL HAEMORRHAGE
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    THERMAL BURN
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    TIBIA FRACTURE
         subjects affected / exposed
    1 / 2061 (0.05%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    UPPER LIMB FRACTURE
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    2 / 2076 (0.10%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    WRIST FRACTURE
         subjects affected / exposed
    0 / 2061 (0.00%)
    2 / 2056 (0.10%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    WOUND COMPLICATION
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    GILBERT'S SYNDROME
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    CARDIAC FAILURE
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    CARDIAC ARREST
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    ATRIOVENTRICULAR BLOCK COMPLETE
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ATRIAL THROMBOSIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ATRIAL TACHYCARDIA
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ATRIAL FIBRILLATION
         subjects affected / exposed
    5 / 2061 (0.24%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    4 / 2076 (0.19%)
         occurrences causally related to treatment / all
    3 / 5
    0 / 0
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ARRHYTHMIA
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ANGINA PECTORIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ACUTE MYOCARDIAL INFARCTION
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CARDIAC FAILURE CONGESTIVE
         subjects affected / exposed
    24 / 2061 (1.16%)
    7 / 2056 (0.34%)
    19 / 2076 (0.92%)
    6 / 2076 (0.29%)
         occurrences causally related to treatment / all
    24 / 24
    4 / 7
    19 / 19
    6 / 6
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    1 / 1
    0 / 0
    ACUTE CORONARY SYNDROME
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    MYOCARDIAL INFARCTION
         subjects affected / exposed
    2 / 2061 (0.10%)
    1 / 2056 (0.05%)
    2 / 2076 (0.10%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LEFT VENTRICULAR DYSFUNCTION
         subjects affected / exposed
    3 / 2061 (0.15%)
    4 / 2056 (0.19%)
    4 / 2076 (0.19%)
    5 / 2076 (0.24%)
         occurrences causally related to treatment / all
    3 / 3
    3 / 4
    4 / 4
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INTRACARDIAC THROMBUS
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CORONARY ARTERY DISEASE
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CARDIOMYOPATHY
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CARDIAC VENTRICULAR THROMBOSIS
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MYOCARDIAL ISCHAEMIA
         subjects affected / exposed
    2 / 2061 (0.10%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    SUPRAVENTRICULAR TACHYCARDIA
         subjects affected / exposed
    2 / 2061 (0.10%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PERICARDITIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    1 / 2076 (0.05%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PERICARDIAL EFFUSION
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PALPITATIONS
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    VENTRICULAR ARRHYTHMIA
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    VENTRICULAR EXTRASYSTOLES
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    VENTRICULAR TACHYCARDIA
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    AMYOTROPHIC LATERAL SCLEROSIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BRAIN HYPOXIA
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    CEREBELLAR ATAXIA
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CEREBROVASCULAR ACCIDENT
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DIZZINESS
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    EPILEPSY
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    FACIAL PARALYSIS
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HEADACHE
         subjects affected / exposed
    2 / 2061 (0.10%)
    3 / 2056 (0.15%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPOTONIA
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PERIPHERAL SENSORY NEUROPATHY
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MIGRAINE
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MOTOR NEURONE DISEASE
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    NEUROPATHY PERIPHERAL
         subjects affected / exposed
    0 / 2061 (0.00%)
    2 / 2056 (0.10%)
    1 / 2076 (0.05%)
    4 / 2076 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    1 / 1
    4 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PERIPHERAL MOTOR NEUROPATHY
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INTRACRANIAL ANEURYSM
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    POLYNEUROPATHY
         subjects affected / exposed
    0 / 2061 (0.00%)
    2 / 2056 (0.10%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    QUADRIPARESIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SEIZURE
         subjects affected / exposed
    2 / 2061 (0.10%)
    3 / 2056 (0.15%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SEROTONIN SYNDROME
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SOMNOLENCE
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SYNCOPE
         subjects affected / exposed
    2 / 2061 (0.10%)
    3 / 2056 (0.15%)
    5 / 2076 (0.24%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 3
    3 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    TRANSIENT GLOBAL AMNESIA
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SUBARACHNOID HAEMORRHAGE
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    LEUKOPENIA
         subjects affected / exposed
    20 / 2061 (0.97%)
    13 / 2056 (0.63%)
    7 / 2076 (0.34%)
    4 / 2076 (0.19%)
         occurrences causally related to treatment / all
    23 / 23
    13 / 13
    7 / 7
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    THROMBOCYTOPENIA
         subjects affected / exposed
    2 / 2061 (0.10%)
    2 / 2056 (0.10%)
    7 / 2076 (0.34%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
    7 / 7
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PANCYTOPENIA
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    NEUTROPENIA
         subjects affected / exposed
    37 / 2061 (1.80%)
    36 / 2056 (1.75%)
    20 / 2076 (0.96%)
    21 / 2076 (1.01%)
         occurrences causally related to treatment / all
    49 / 49
    37 / 37
    24 / 24
    25 / 25
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    IRON DEFICIENCY ANAEMIA
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ANAEMIA
         subjects affected / exposed
    7 / 2061 (0.34%)
    13 / 2056 (0.63%)
    7 / 2076 (0.34%)
    6 / 2076 (0.29%)
         occurrences causally related to treatment / all
    7 / 8
    11 / 13
    5 / 8
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    EOSINOPHILIA
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    FEBRILE NEUTROPENIA
         subjects affected / exposed
    10 / 2061 (0.49%)
    12 / 2056 (0.58%)
    3 / 2076 (0.14%)
    6 / 2076 (0.29%)
         occurrences causally related to treatment / all
    9 / 10
    12 / 13
    2 / 3
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    AGRANULOCYTOSIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    VERTIGO POSITIONAL
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    VERTIGO
         subjects affected / exposed
    2 / 2061 (0.10%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    2 / 2076 (0.10%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    TINNITUS
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    DIPLOPIA
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RETINAL DETACHMENT
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    2 / 2076 (0.10%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PERIORBITAL OEDEMA
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL PAIN LOWER
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    1 / 2061 (0.05%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ANAL FISSURE
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ANAL HAEMORRHAGE
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COLITIS
         subjects affected / exposed
    4 / 2061 (0.19%)
    1 / 2056 (0.05%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ABDOMINAL MASS
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ABDOMINAL DISTENSION
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ABDOMINAL PAIN
         subjects affected / exposed
    6 / 2061 (0.29%)
    4 / 2056 (0.19%)
    2 / 2076 (0.10%)
    4 / 2076 (0.19%)
         occurrences causally related to treatment / all
    5 / 7
    3 / 4
    0 / 2
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GASTRITIS EROSIVE
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CONSTIPATION
         subjects affected / exposed
    0 / 2061 (0.00%)
    2 / 2056 (0.10%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DIARRHOEA
         subjects affected / exposed
    53 / 2061 (2.57%)
    44 / 2056 (2.14%)
    9 / 2076 (0.43%)
    6 / 2076 (0.29%)
         occurrences causally related to treatment / all
    56 / 58
    46 / 48
    6 / 9
    5 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DUODENAL ULCER
         subjects affected / exposed
    1 / 2061 (0.05%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DYSPEPSIA
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DYSPHAGIA
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ENTERITIS
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ENTEROCOLITIS
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    EPIPLOIC APPENDAGITIS
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GASTRIC HAEMORRHAGE
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GASTRIC ULCER
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GASTRITIS
         subjects affected / exposed
    2 / 2061 (0.10%)
    1 / 2056 (0.05%)
    2 / 2076 (0.10%)
    2 / 2076 (0.10%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GASTROINTESTINAL OBSTRUCTION
         subjects affected / exposed
    1 / 2061 (0.05%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GASTROINTESTINAL PERFORATION
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GASTROINTESTINAL TOXICITY
         subjects affected / exposed
    1 / 2061 (0.05%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GASTROINTESTINAL ULCER
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LOWER GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ILEUS
         subjects affected / exposed
    1 / 2061 (0.05%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INTESTINAL HAEMORRHAGE
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INTESTINAL OBSTRUCTION
         subjects affected / exposed
    2 / 2061 (0.10%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LARGE INTESTINE PERFORATION
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HAEMORRHOIDS
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    4 / 2076 (0.19%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    NAUSEA
         subjects affected / exposed
    5 / 2061 (0.24%)
    7 / 2056 (0.34%)
    6 / 2076 (0.29%)
    3 / 2076 (0.14%)
         occurrences causally related to treatment / all
    4 / 5
    6 / 7
    6 / 7
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    OESOPHAGITIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PANCREATITIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    1 / 2076 (0.05%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PANCREATITIS ACUTE
         subjects affected / exposed
    1 / 2061 (0.05%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    REFLUX GASTRITIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    STOMATITIS
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    UPPER GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    VOLVULUS
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    VOMITING
         subjects affected / exposed
    9 / 2061 (0.44%)
    9 / 2056 (0.44%)
    8 / 2076 (0.39%)
    3 / 2076 (0.14%)
         occurrences causally related to treatment / all
    8 / 10
    8 / 9
    4 / 8
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SMALL INTESTINAL OBSTRUCTION
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    BILE DUCT STENOSIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BILIARY COLIC
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    2 / 2076 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CHOLECYSTITIS
         subjects affected / exposed
    3 / 2061 (0.15%)
    2 / 2056 (0.10%)
    3 / 2076 (0.14%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HEPATIC FUNCTION ABNORMAL
         subjects affected / exposed
    1 / 2061 (0.05%)
    4 / 2056 (0.19%)
    0 / 2076 (0.00%)
    4 / 2076 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 4
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    CHOLELITHIASIS
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DRUG-INDUCED LIVER INJURY
         subjects affected / exposed
    2 / 2061 (0.10%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GALLBLADDER OBSTRUCTION
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HEPATIC FAILURE
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CHOLECYSTITIS ACUTE
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HEPATIC LESION
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HEPATITIS
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HEPATOTOXICITY
         subjects affected / exposed
    3 / 2061 (0.15%)
    5 / 2056 (0.24%)
    0 / 2076 (0.00%)
    3 / 2076 (0.14%)
         occurrences causally related to treatment / all
    3 / 3
    5 / 5
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPERBILIRUBINAEMIA
         subjects affected / exposed
    5 / 2061 (0.24%)
    18 / 2056 (0.88%)
    1 / 2076 (0.05%)
    12 / 2076 (0.58%)
         occurrences causally related to treatment / all
    5 / 5
    18 / 19
    0 / 1
    12 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPERTRANSAMINASAEMIA
         subjects affected / exposed
    74 / 2061 (3.59%)
    86 / 2056 (4.18%)
    11 / 2076 (0.53%)
    55 / 2076 (2.65%)
         occurrences causally related to treatment / all
    95 / 98
    101 / 104
    6 / 12
    67 / 74
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    JAUNDICE
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    2 / 2076 (0.10%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    ERYTHEMA
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ACNE
         subjects affected / exposed
    2 / 2061 (0.10%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ANGIODERMATITIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ANGIOEDEMA
         subjects affected / exposed
    0 / 2061 (0.00%)
    2 / 2056 (0.10%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CUTANEOUS VASCULITIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DERMATITIS ACNEIFORM
         subjects affected / exposed
    0 / 2061 (0.00%)
    2 / 2056 (0.10%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RASH
         subjects affected / exposed
    4 / 2061 (0.19%)
    7 / 2056 (0.34%)
    0 / 2076 (0.00%)
    4 / 2076 (0.19%)
         occurrences causally related to treatment / all
    4 / 4
    7 / 7
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PRURITUS
         subjects affected / exposed
    1 / 2061 (0.05%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SKIN NECROSIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SKIN SWELLING
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SKIN ULCER
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RASH MACULO-PAPULAR
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PHOTOSENSITIVITY REACTION
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PALMAR-PLANTAR ERYTHRODYSAESTHESIA SYNDROME
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    NAIL DISORDER
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPERTROPHIC SCAR
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    EXFOLIATIVE RASH
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    TOXIC EPIDERMAL NECROLYSIS
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    URTICARIA
         subjects affected / exposed
    1 / 2061 (0.05%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    ACUTE KIDNEY INJURY
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CALCULUS URINARY
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    NEPHRITIC SYNDROME
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    NEPHROLITHIASIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    2 / 2076 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RENAL COLIC
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RENAL FAILURE
         subjects affected / exposed
    1 / 2061 (0.05%)
    2 / 2056 (0.10%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    URINARY BLADDER HAEMORRHAGE
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    URETHRAL OBSTRUCTION
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    HYPOTHYROIDISM
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPERPARATHYROIDISM
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GOITRE
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    AUTOIMMUNE THYROIDITIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    3 / 2076 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BACK PAIN
         subjects affected / exposed
    4 / 2061 (0.19%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MYALGIA
         subjects affected / exposed
    2 / 2061 (0.10%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CHEST WALL NECROSIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COSTOCHONDRITIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LUMBAR SPINAL STENOSIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MUSCULOSKELETAL CHEST PAIN
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BONE PAIN
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MYOSITIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    OSTEOARTHRITIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    OSTEOPOROSIS
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PAIN IN EXTREMITY
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SCLERODERMA
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SYNOVIAL CYST
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SYNOVITIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SPONDYLOLISTHESIS
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    ABDOMINAL WALL ABSCESS
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ABSCESS
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ACUTE HEPATITIS B
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ACUTE SINUSITIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    AMOEBIC DYSENTERY
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BACTERIAL INFECTION
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ANAL INFECTION
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ANTIBIOTIC ASSOCIATED COLITIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ATYPICAL PNEUMONIA
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BACTERAEMIA
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ANAL ABSCESS
         subjects affected / exposed
    1 / 2061 (0.05%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BREAST CELLULITIS
         subjects affected / exposed
    1 / 2061 (0.05%)
    3 / 2056 (0.15%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BRONCHITIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    2 / 2076 (0.10%)
    2 / 2076 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BRONCHITIS VIRAL
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CATHETER SITE CELLULITIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CELLULITIS
         subjects affected / exposed
    15 / 2061 (0.73%)
    7 / 2056 (0.34%)
    5 / 2076 (0.24%)
    14 / 2076 (0.67%)
         occurrences causally related to treatment / all
    5 / 16
    1 / 7
    0 / 5
    10 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DEVICE RELATED INFECTION
         subjects affected / exposed
    8 / 2061 (0.39%)
    4 / 2056 (0.19%)
    3 / 2076 (0.14%)
    2 / 2076 (0.10%)
         occurrences causally related to treatment / all
    1 / 8
    1 / 4
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CHLAMYDIAL INFECTION
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CLOSTRIDIUM DIFFICILE INFECTION
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CONJUNCTIVITIS
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CYSTITIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CHEST WALL ABSCESS
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DIARRHOEA INFECTIOUS
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DIVERTICULITIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ERYSIPELAS
         subjects affected / exposed
    6 / 2061 (0.29%)
    4 / 2056 (0.19%)
    3 / 2076 (0.14%)
    4 / 2076 (0.19%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 4
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GASTRIC INFECTION
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GASTROENTERITIS
         subjects affected / exposed
    3 / 2061 (0.15%)
    3 / 2056 (0.15%)
    1 / 2076 (0.05%)
    3 / 2076 (0.14%)
         occurrences causally related to treatment / all
    1 / 3
    2 / 3
    1 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GASTROENTERITIS VIRAL
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GASTROINTESTINAL INFECTION
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    H1N1 INFLUENZA
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HEPATITIS B
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HEPATITIS C
         subjects affected / exposed
    1 / 2061 (0.05%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    DEVICE RELATED SEPSIS
         subjects affected / exposed
    2 / 2061 (0.10%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HEPATITIS VIRAL
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HERPES ZOSTER
         subjects affected / exposed
    1 / 2061 (0.05%)
    3 / 2056 (0.15%)
    0 / 2076 (0.00%)
    2 / 2076 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 3
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    IMPLANT SITE CELLULITIS
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INFECTED CYST
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INFECTED LYMPHOCELE
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LOCALISED INFECTION
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INFECTIVE EXACERBATION OF CHRONIC OBSTRUCTIVE AIRWAYS DISEASE
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INFLUENZA
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INTERVERTEBRAL DISCITIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LARGE INTESTINE INFECTION
         subjects affected / exposed
    1 / 2061 (0.05%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LARYNGITIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INFECTION
         subjects affected / exposed
    2 / 2061 (0.10%)
    2 / 2056 (0.10%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LOWER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    3 / 2061 (0.15%)
    1 / 2056 (0.05%)
    1 / 2076 (0.05%)
    2 / 2076 (0.10%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LYMPH GLAND INFECTION
         subjects affected / exposed
    1 / 2061 (0.05%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LYMPH NODE ABSCESS
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LYMPHANGITIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MALARIA
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    NEUTROPENIC SEPSIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MENINGITIS VIRAL
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    NAIL INFECTION
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    NASOPHARYNGITIS
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    NEUROBORRELIOSIS
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MASTITIS
         subjects affected / exposed
    2 / 2061 (0.10%)
    6 / 2056 (0.29%)
    2 / 2076 (0.10%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 6
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    OESOPHAGEAL CANDIDIASIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    OESOPHAGEAL INFECTION
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    OSTEOMYELITIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    OTITIS MEDIA
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    2 / 2076 (0.10%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    OVARIAN ABSCESS
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PNEUMONIA ASPIRATION
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PERITONITIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PHARYNGITIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PNEUMOCYSTIS JIROVECII INFECTION
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    14 / 2061 (0.68%)
    9 / 2056 (0.44%)
    10 / 2076 (0.48%)
    11 / 2076 (0.53%)
         occurrences causally related to treatment / all
    8 / 14
    2 / 9
    4 / 11
    2 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    PARONYCHIA
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PNEUMONIA CYTOMEGALOVIRAL
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    POST PROCEDURAL INFECTION
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    POSTOPERATIVE WOUND INFECTION
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PYELONEPHRITIS
         subjects affected / exposed
    2 / 2061 (0.10%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SKIN INFECTION
         subjects affected / exposed
    2 / 2061 (0.10%)
    2 / 2056 (0.10%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    0 / 2061 (0.00%)
    2 / 2056 (0.10%)
    0 / 2076 (0.00%)
    2 / 2076 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SEPSIS
         subjects affected / exposed
    1 / 2061 (0.05%)
    5 / 2056 (0.24%)
    5 / 2076 (0.24%)
    3 / 2076 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 5
    3 / 5
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    SIALOADENITIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SINUSITIS
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    2 / 2076 (0.10%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PYELONEPHRITIS ACUTE
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    TUBERCULOUS PLEURISY
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SOFT TISSUE INFECTION
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    STAPHYLOCOCCAL BACTERAEMIA
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    STAPHYLOCOCCAL INFECTION
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    TUBERCULOSIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    STREPTOCOCCAL SEPSIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SUBCUTANEOUS ABSCESS
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    1 / 2076 (0.05%)
    2 / 2076 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SUPERINFECTION
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    TOOTH INFECTION
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    STREPTOCOCCAL INFECTION
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    UPPER RESPIRATORY TRACT INFECTION BACTERIAL
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    URINARY TRACT INFECTION
         subjects affected / exposed
    2 / 2061 (0.10%)
    2 / 2056 (0.10%)
    7 / 2076 (0.34%)
    6 / 2076 (0.29%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
    1 / 7
    4 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    UROSEPSIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    VIRAL INFECTION
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    WOUND INFECTION
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    1 / 2076 (0.05%)
    2 / 2076 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    WOUND INFECTION BACTERIAL
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    DEHYDRATION
         subjects affected / exposed
    11 / 2061 (0.53%)
    12 / 2056 (0.58%)
    4 / 2076 (0.19%)
    3 / 2076 (0.14%)
         occurrences causally related to treatment / all
    11 / 11
    11 / 13
    4 / 5
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DECREASED APPETITE
         subjects affected / exposed
    3 / 2061 (0.15%)
    3 / 2056 (0.15%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DIABETES MELLITUS
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    3 / 2076 (0.14%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPERCHOLESTEROLAEMIA
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPERGLYCAEMIA
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    1 / 2076 (0.05%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPERNATRAEMIA
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPERPHOSPHATASAEMIA
         subjects affected / exposed
    4 / 2061 (0.19%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    4 / 2076 (0.19%)
         occurrences causally related to treatment / all
    3 / 4
    1 / 1
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPOPHAGIA
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPOCALCAEMIA
         subjects affected / exposed
    2 / 2061 (0.10%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPOKALAEMIA
         subjects affected / exposed
    8 / 2061 (0.39%)
    9 / 2056 (0.44%)
    3 / 2076 (0.14%)
    1 / 2076 (0.05%)
         occurrences causally related to treatment / all
    9 / 9
    7 / 9
    2 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPOMAGNESAEMIA
         subjects affected / exposed
    1 / 2061 (0.05%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPONATRAEMIA
         subjects affected / exposed
    0 / 2061 (0.00%)
    1 / 2056 (0.05%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    HYPERURICAEMIA
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPOPHOSPHATAEMIA
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    0 / 2076 (0.00%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPOVOLAEMIA
         subjects affected / exposed
    1 / 2061 (0.05%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    METABOLIC ACIDOSIS
         subjects affected / exposed
    0 / 2061 (0.00%)
    0 / 2056 (0.00%)
    1 / 2076 (0.05%)
    0 / 2076 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Lapatinib plus Trastuzumab Lapatinib Trastuzumab Trastuzumab followed by Lapatinib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1930 / 2061 (93.64%)
    1887 / 2056 (91.78%)
    1649 / 2076 (79.43%)
    1862 / 2076 (89.69%)
    Vascular disorders
    HOT FLUSH
         subjects affected / exposed
    211 / 2061 (10.24%)
    190 / 2056 (9.24%)
    272 / 2076 (13.10%)
    225 / 2076 (10.84%)
         occurrences all number
    232
    199
    294
    240
    General disorders and administration site conditions
    PYREXIA
         subjects affected / exposed
    227 / 2061 (11.01%)
    132 / 2056 (6.42%)
    171 / 2076 (8.24%)
    188 / 2076 (9.06%)
         occurrences all number
    270
    158
    208
    222
    OEDEMA PERIPHERAL
         subjects affected / exposed
    144 / 2061 (6.99%)
    138 / 2056 (6.71%)
    160 / 2076 (7.71%)
    149 / 2076 (7.18%)
         occurrences all number
    158
    153
    184
    174
    MUCOSAL INFLAMMATION
         subjects affected / exposed
    227 / 2061 (11.01%)
    164 / 2056 (7.98%)
    114 / 2076 (5.49%)
    149 / 2076 (7.18%)
         occurrences all number
    265
    193
    126
    171
    FATIGUE
         subjects affected / exposed
    511 / 2061 (24.79%)
    443 / 2056 (21.55%)
    439 / 2076 (21.15%)
    515 / 2076 (24.81%)
         occurrences all number
    603
    502
    550
    615
    ASTHENIA
         subjects affected / exposed
    202 / 2061 (9.80%)
    175 / 2056 (8.51%)
    171 / 2076 (8.24%)
    178 / 2076 (8.57%)
         occurrences all number
    259
    208
    213
    218
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    219 / 2061 (10.63%)
    153 / 2056 (7.44%)
    242 / 2076 (11.66%)
    201 / 2076 (9.68%)
         occurrences all number
    252
    173
    282
    225
    DYSPNOEA
         subjects affected / exposed
    147 / 2061 (7.13%)
    103 / 2056 (5.01%)
    170 / 2076 (8.19%)
    146 / 2076 (7.03%)
         occurrences all number
    151
    106
    202
    155
    EPISTAXIS
         subjects affected / exposed
    319 / 2061 (15.48%)
    244 / 2056 (11.87%)
    165 / 2076 (7.95%)
    213 / 2076 (10.26%)
         occurrences all number
    363
    268
    179
    238
    Psychiatric disorders
    INSOMNIA
         subjects affected / exposed
    168 / 2061 (8.15%)
    152 / 2056 (7.39%)
    190 / 2076 (9.15%)
    172 / 2076 (8.29%)
         occurrences all number
    182
    163
    220
    187
    Injury, poisoning and procedural complications
    RADIATION SKIN INJURY
         subjects affected / exposed
    91 / 2061 (4.42%)
    82 / 2056 (3.99%)
    129 / 2076 (6.21%)
    127 / 2076 (6.12%)
         occurrences all number
    92
    82
    132
    129
    Cardiac disorders
    LEFT VENTRICULAR DYSFUNCTION
         subjects affected / exposed
    59 / 2061 (2.86%)
    45 / 2056 (2.19%)
    107 / 2076 (5.15%)
    46 / 2076 (2.22%)
         occurrences all number
    65
    49
    115
    52
    Nervous system disorders
    DIZZINESS
         subjects affected / exposed
    104 / 2061 (5.05%)
    115 / 2056 (5.59%)
    118 / 2076 (5.68%)
    127 / 2076 (6.12%)
         occurrences all number
    111
    122
    130
    138
    HEADACHE
         subjects affected / exposed
    192 / 2061 (9.32%)
    161 / 2056 (7.83%)
    262 / 2076 (12.62%)
    241 / 2076 (11.61%)
         occurrences all number
    227
    193
    314
    295
    NEUROPATHY PERIPHERAL
         subjects affected / exposed
    177 / 2061 (8.59%)
    173 / 2056 (8.41%)
    178 / 2076 (8.57%)
    183 / 2076 (8.82%)
         occurrences all number
    189
    185
    197
    192
    PARAESTHESIA
         subjects affected / exposed
    125 / 2061 (6.07%)
    107 / 2056 (5.20%)
    131 / 2076 (6.31%)
    110 / 2076 (5.30%)
         occurrences all number
    141
    114
    181
    131
    PERIPHERAL SENSORY NEUROPATHY
         subjects affected / exposed
    164 / 2061 (7.96%)
    162 / 2056 (7.88%)
    194 / 2076 (9.34%)
    159 / 2076 (7.66%)
         occurrences all number
    201
    175
    232
    177
    Blood and lymphatic system disorders
    LEUKOPENIA
         subjects affected / exposed
    174 / 2061 (8.44%)
    155 / 2056 (7.54%)
    168 / 2076 (8.09%)
    138 / 2076 (6.65%)
         occurrences all number
    300
    268
    295
    225
    ANAEMIA
         subjects affected / exposed
    226 / 2061 (10.97%)
    169 / 2056 (8.22%)
    223 / 2076 (10.74%)
    168 / 2076 (8.09%)
         occurrences all number
    255
    184
    253
    186
    NEUTROPENIA
         subjects affected / exposed
    233 / 2061 (11.31%)
    220 / 2056 (10.70%)
    179 / 2076 (8.62%)
    175 / 2076 (8.43%)
         occurrences all number
    396
    365
    292
    303
    Gastrointestinal disorders
    STOMATITIS
         subjects affected / exposed
    203 / 2061 (9.85%)
    161 / 2056 (7.83%)
    98 / 2076 (4.72%)
    141 / 2076 (6.79%)
         occurrences all number
    249
    185
    114
    159
    NAUSEA
         subjects affected / exposed
    393 / 2061 (19.07%)
    381 / 2056 (18.53%)
    285 / 2076 (13.73%)
    393 / 2076 (18.93%)
         occurrences all number
    504
    471
    387
    496
    DYSPEPSIA
         subjects affected / exposed
    174 / 2061 (8.44%)
    156 / 2056 (7.59%)
    116 / 2076 (5.59%)
    140 / 2076 (6.74%)
         occurrences all number
    181
    173
    124
    151
    CONSTIPATION
         subjects affected / exposed
    120 / 2061 (5.82%)
    135 / 2056 (6.57%)
    156 / 2076 (7.51%)
    184 / 2076 (8.86%)
         occurrences all number
    132
    143
    194
    211
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    137 / 2061 (6.65%)
    110 / 2056 (5.35%)
    78 / 2076 (3.76%)
    111 / 2076 (5.35%)
         occurrences all number
    160
    119
    86
    121
    ABDOMINAL PAIN
         subjects affected / exposed
    146 / 2061 (7.08%)
    148 / 2056 (7.20%)
    79 / 2076 (3.81%)
    108 / 2076 (5.20%)
         occurrences all number
    164
    164
    101
    120
    DIARRHOEA
         subjects affected / exposed
    1516 / 2061 (73.56%)
    1278 / 2056 (62.16%)
    399 / 2076 (19.22%)
    1039 / 2076 (50.05%)
         occurrences all number
    2752
    1973
    527
    1450
    VOMITING
         subjects affected / exposed
    251 / 2061 (12.18%)
    215 / 2056 (10.46%)
    151 / 2076 (7.27%)
    181 / 2076 (8.72%)
         occurrences all number
    334
    278
    180
    220
    Hepatobiliary disorders
    HYPERTRANSAMINASAEMIA
         subjects affected / exposed
    348 / 2061 (16.89%)
    366 / 2056 (17.80%)
    281 / 2076 (13.54%)
    378 / 2076 (18.21%)
         occurrences all number
    600
    657
    482
    637
    HYPERBILIRUBINAEMIA
         subjects affected / exposed
    96 / 2061 (4.66%)
    121 / 2056 (5.89%)
    31 / 2076 (1.49%)
    103 / 2076 (4.96%)
         occurrences all number
    133
    165
    39
    133
    Skin and subcutaneous tissue disorders
    PALMAR-PLANTAR ERYTHRODYSAESTHESIA SYNDROME
         subjects affected / exposed
    181 / 2061 (8.78%)
    126 / 2056 (6.13%)
    47 / 2076 (2.26%)
    105 / 2076 (5.06%)
         occurrences all number
    197
    130
    50
    111
    PRURITUS
         subjects affected / exposed
    316 / 2061 (15.33%)
    334 / 2056 (16.25%)
    134 / 2076 (6.45%)
    268 / 2076 (12.91%)
         occurrences all number
    380
    382
    145
    304
    ACNE
         subjects affected / exposed
    134 / 2061 (6.50%)
    112 / 2056 (5.45%)
    20 / 2076 (0.96%)
    138 / 2076 (6.65%)
         occurrences all number
    149
    123
    21
    144
    ALOPECIA
         subjects affected / exposed
    109 / 2061 (5.29%)
    110 / 2056 (5.35%)
    151 / 2076 (7.27%)
    135 / 2076 (6.50%)
         occurrences all number
    109
    111
    152
    137
    DERMATITIS ACNEIFORM
         subjects affected / exposed
    117 / 2061 (5.68%)
    124 / 2056 (6.03%)
    19 / 2076 (0.92%)
    96 / 2076 (4.62%)
         occurrences all number
    138
    146
    24
    106
    DRY SKIN
         subjects affected / exposed
    262 / 2061 (12.71%)
    280 / 2056 (13.62%)
    86 / 2076 (4.14%)
    244 / 2076 (11.75%)
         occurrences all number
    282
    305
    92
    265
    ERYTHEMA
         subjects affected / exposed
    122 / 2061 (5.92%)
    93 / 2056 (4.52%)
    87 / 2076 (4.19%)
    104 / 2076 (5.01%)
         occurrences all number
    149
    112
    99
    116
    NAIL DISORDER
         subjects affected / exposed
    359 / 2061 (17.42%)
    294 / 2056 (14.30%)
    220 / 2076 (10.60%)
    272 / 2076 (13.10%)
         occurrences all number
    384
    312
    231
    285
    RASH
         subjects affected / exposed
    771 / 2061 (37.41%)
    767 / 2056 (37.31%)
    223 / 2076 (10.74%)
    685 / 2076 (33.00%)
         occurrences all number
    1010
    959
    265
    862
    SKIN FISSURES
         subjects affected / exposed
    145 / 2061 (7.04%)
    123 / 2056 (5.98%)
    7 / 2076 (0.34%)
    98 / 2076 (4.72%)
         occurrences all number
    165
    139
    8
    103
    Musculoskeletal and connective tissue disorders
    MYALGIA
         subjects affected / exposed
    211 / 2061 (10.24%)
    174 / 2056 (8.46%)
    252 / 2076 (12.14%)
    214 / 2076 (10.31%)
         occurrences all number
    274
    231
    368
    289
    BONE PAIN
         subjects affected / exposed
    87 / 2061 (4.22%)
    91 / 2056 (4.43%)
    122 / 2076 (5.88%)
    109 / 2076 (5.25%)
         occurrences all number
    103
    107
    146
    130
    BACK PAIN
         subjects affected / exposed
    128 / 2061 (6.21%)
    119 / 2056 (5.79%)
    126 / 2076 (6.07%)
    133 / 2076 (6.41%)
         occurrences all number
    138
    124
    133
    140
    ARTHRALGIA
         subjects affected / exposed
    340 / 2061 (16.50%)
    320 / 2056 (15.56%)
    451 / 2076 (21.72%)
    348 / 2076 (16.76%)
         occurrences all number
    404
    366
    559
    415
    PAIN IN EXTREMITY
         subjects affected / exposed
    135 / 2061 (6.55%)
    98 / 2056 (4.77%)
    175 / 2076 (8.43%)
    125 / 2076 (6.02%)
         occurrences all number
    154
    109
    216
    140
    Infections and infestations
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    117 / 2061 (5.68%)
    93 / 2056 (4.52%)
    118 / 2076 (5.68%)
    96 / 2076 (4.62%)
         occurrences all number
    144
    107
    149
    113
    PARONYCHIA
         subjects affected / exposed
    262 / 2061 (12.71%)
    206 / 2056 (10.02%)
    22 / 2076 (1.06%)
    165 / 2076 (7.95%)
         occurrences all number
    323
    247
    26
    185
    NASOPHARYNGITIS
         subjects affected / exposed
    128 / 2061 (6.21%)
    96 / 2056 (4.67%)
    150 / 2076 (7.23%)
    111 / 2076 (5.35%)
         occurrences all number
    152
    108
    189
    128
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    223 / 2061 (10.82%)
    188 / 2056 (9.14%)
    142 / 2076 (6.84%)
    173 / 2076 (8.33%)
         occurrences all number
    268
    215
    173
    189
    HYPERPHOSPHATASAEMIA
         subjects affected / exposed
    81 / 2061 (3.93%)
    120 / 2056 (5.84%)
    76 / 2076 (3.66%)
    109 / 2076 (5.25%)
         occurrences all number
    95
    127
    87
    118

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Apr 2008
    Amendment No. 01: Implementation of additional monitoring of liver enzymes and associated criteria for study drug discontinuation, modification of the study inclusion/ exclusion criteria, provide clarification to the length of follow up, and permitted chemotherapy regimens. To provide clarification regarding the dosing of study therapy and the management of AEs.
    14 Aug 2008
    Amendment No. 02: Implementation of a lower starting dose of lapatinib (750 mg) during chemotherapy only in the Lap+Tras arm of Design 2 to diminish the chance of diarrhea occurrence. To allow patients randomized in the Tras-Lap arm of both designs to receive lapatinib after the occurrence of a secondary cardiac endpoint during trastuzumab administration only if LVEF after the washout period (6 weeks) and prior to lapatinib administration is ≥50%. To clarify the extent and nature of future translational research studies and provide revised timelines for circulating tumor cell collection.
    12 Feb 2009
    Amendment No. 03: Inclusion of statement indicating the possible accrual imbalance between Design 1 and Design 2 and possible future need to close screening to a design.
    19 Mar 2009
    Amendment No. 04: To allow the inclusion of docetaxel in Design 2, implement an additional interim analysis for analyses at 400, 700 and 1000 DFS events with final analysis after 1388 DFS events, and allow the use of Breast MRI scans instead of mammograms.
    20 Nov 2009
    Amendment No. 05: Inclusion of Design 2B and associated updates to enrollment (maximum sample size of 8400 patients) and revised timelines for circulating tumor cell collection.
    27 Jan 2010
    Amendment No. 06: Reduction of lapatinib dose when used concurrently with chemotherapy in the Lap arm and the Lap+Tras arm of Designs 2 and 2B to diminish the chance of diarrhea occurrence.
    29 Mar 2010
    Amendment No. 07: To clarify statistical plans for interim and final analyses, include the collection of a FFPE tumor block for future research, to update additional medicines added to the prohibited medications list for patients taking lapatinib.
    02 Aug 2010
    Amendment No. 08: To add a new statistical section entitled “Registration Strategy for ALTTO – June 2010”, and thus support the modification of the analysis plan by the sponsor at the time (GSK). Inclusion of a statement clarifying that after completion of study treatment, patients enrolled in this study may receive anti-cancer therapy in other trials only if the trial has been approved by the Steering Committee. Clarification regarding the reporting of post-study treatment long-term AEs, Grade 4 neutropenia/leukopenia as an SAE, diarrhea management in lapatinib-containing arms, and the dose adjustments of trastuzumab and chemotherapy due to substantial weight changes and overweight/obese patients. Inclusion of the collection of a FNA sample will be allowed for certain patients.
    28 Oct 2010
    Amendment No. 09: Add NCI/CTEP recommendation for the calculation of the carboplatin dose and to add the maximum dose of carboplatin based on the target area under the curve (AUC) 6 is 900 mg.
    17 Oct 2011
    Amendment No. 10: To implement the recommendations by the ALTTO Steering Committee due to the IDMC meeting (August 18, 2011). Guidance for patient withdrawal from the study while allowing for collection of OS information, patients who were considered lost to follow-up, regarding prohibited medications and future trial medications. Clarification of diarrhea management, assessments beyond study treatment completion to determine secondary cardiac event, lobular carcinoma in situ and ductal carcinoma in situ reporting.
    18 Mar 2016
    Amendment No. 11: To update the assessment schedule, specify that after the patient completed the 10-year follow-up post randomization, only drug-related SAEs were to be reported, add the definition of EOS for clarity purposes, add details regarding explorative subgroup analyses of DFS for specific risk factors, allow broader use of the previously collected pharmacogenetic samples and the previously generated genetic data, and to implement changes in secondary endpoints.
    05 Jul 2016
    Amendment No. 12: To delete or replace references to GSK or its staff with that of Novartis and its authorized agents to align with the change of sponsorship, and to make administrative changes to align with study-specific processes and procedures. As the burden on patients was reduced by decreasing the number of procedures that required a physical visit to the site, the optional collection of samples at the time of relapse was also deleted.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com for complete trial results.
    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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