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    Clinical Trial Results:
    A Phase III Trial Evaluating the Role of Exemestane Plus GnRH Analogue as Adjuvant Therapy for Premenopausal Women with Endocrine Responsive Breast Cancer.

    Summary
    EudraCT number
    		 2004-000168-28
    Trial protocol
    		 SE   BE   DE  
    Global end of trial date

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 May 2021
    First version publication date
    19 May 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    IBCSG25-02/BIG3-02 TEXT
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00066703
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    IBCSG
    Sponsor organisation address
    Effingerstrasse 40, Bern, Switzerland, 3008
    Public contact
    IBCSG Coordinating Center, IBCSG, +41 31389 93 91, regulatoryoffice@ibcsg.org
    Scientific contact
    IBCSG Coordinating Center, IBCSG, +41 31389 93 91, regulatoryoffice@ibcsg.org
    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
    Interim
    Date of interim/final analysis
    31 Aug 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Aug 2013
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    Compare the disease-free survival, breast cancer-free interval, distant recurrence-free interval and overall survival of premenopausal women with endocrine-responsive breast cancer when treated with triptorelin and exemestane vs triptorelin and tamoxifen. Compare the quality of life, including late side effects of early menopause, of patients treated with these regimens.
    Protection of trial subjects
    In compliance with GDPR. Adverse events were reported and in case of adverse events and treatment-related toxicities management guidance was provided in the study protocol to treat trial subjects in adequately manner. The safety of the trial treatment was regularly reviewed by the IBCSG Data Safety Monitoring Committee (DSMC).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 Aug 2003
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 11 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Slovenia: 29
    Country: Number of subjects enrolled
    Sweden: 11
    Country: Number of subjects enrolled
    Belgium: 92
    Country: Number of subjects enrolled
    Germany: 39
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    Australia: 249
    Country: Number of subjects enrolled
    Egypt: 6
    Country: Number of subjects enrolled
    Hungary: 189
    Country: Number of subjects enrolled
    India: 28
    Country: Number of subjects enrolled
    Italy: 866
    Country: Number of subjects enrolled
    Peru: 121
    Country: Number of subjects enrolled
    Switzerland: 165
    Country: Number of subjects enrolled
    South Africa: 7
    Country: Number of subjects enrolled
    United States: 739
    Country: Number of subjects enrolled
    Canada: 127
    Worldwide total number of subjects
    2672
    EEA total number of subjects
    1230
    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)
    2672
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Final accrual for TEXT was 2672 patients (target: 2639) from 182 centers.

    Pre-assignment
    Screening details
    		 This trial used a web-based randomization system. Each Participating Group determined how its Participating Centers will access the randomization system, either through a Group Randomization Center, or directly from the Participating Center.

    Period 1
    Period 1 title
    Overall study
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 T+OFS
    Arm description
    		 Ovarian function suppression (OFS) by triptorelin (GnRH analogue) 3.75mg by im injection q28 days for 5 years plus tamoxifen 20mg orally daily for 5 years. Tamoxifen (T) begins after the completion of adjuvant chemotherapy if given, or approximately 6-8 weeks after the initiation of triptorelin. Bilateral oophorectomy or ovarian irradiation was allowed after at least 6 months of triptorelin.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Tamoxifen
    Investigational medicinal product code
    Other name
    Nolvadex
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    20mg orally daily for 5 years. Tamoxifen (T) begins after the completion of adjuvant chemotherapy if given, or approximately 6-8 weeks after the initiation of triptorelin.

    Investigational medicinal product name
    Triptorelin
    Investigational medicinal product code
    Other name
    GnRH analogue, Trelstar Depot, Decapeptyl Depot
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    3.75mg by im injection q28 days for 5 years

    Arm title
    		 E+OFS
    Arm description
    		 Ovarian function suppression (OFS) by triptorelin (GnRH analogue) 3.75mg by im injection q28 days for 5 years plus exemestane 25mg orally daily for 5 years. Exemestane (E) begins after the completion of adjuvant chemotherapy if given, or approximately 6-8 weeks after the initiation of triptorelin. Bilateral oophorectomy or ovarian irradiation was allowed after at least 6 months of triptorelin.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Exemestane
    Investigational medicinal product code
    Other name
    Aromasin
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    25mg orally daily for 5 years. Exemestane (E) begins after the completion of adjuvant chemotherapy if given, or approximately 6-8 weeks after the initiation of triptorelin.

    Investigational medicinal product name
    Triptorelin
    Investigational medicinal product code
    Other name
    GnRH analogue, Trelstar Depot, Decapeptyl Depot
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    3.75mg by im injection q28 days for 5 years

    Number of subjects in period 1
    		T+OFS E+OFS
    Started
    1334
    1338
    Completed
    1328
    1332
    Not completed
    6
    6
         Consent withdrawn by subject
    4
    3
         Center not compliant with protocol procedure
    2
    1
         Protocol deviation
    -
    2
    Period 2
    Period 2 title
    ITT analysis
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 T+OFS
    Arm description
    		 Ovarian function suppression (OFS) by triptorelin (GnRH analogue) 3.75mg by im injection q28 days for 5 years plus tamoxifen 20mg orally daily for 5 years. Tamoxifen (T) begins after the completion of adjuvant chemotherapy if given, or approximately 6-8 weeks after the initiation of triptorelin. Bilateral oophorectomy or ovarian irradiation was allowed after at least 6 months of triptorelin.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Tamoxifen
    Investigational medicinal product code
    Other name
    Nolvadex
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    20mg orally daily for 5 years. Tamoxifen (T) begins after the completion of adjuvant chemotherapy if given, or approximately 6-8 weeks after the initiation of triptorelin.

    Investigational medicinal product name
    Triptorelin
    Investigational medicinal product code
    Other name
    GnRH analogue, Trelstar Depot, Decapeptyl Depot
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    3.75mg by im injection q28 days for 5 years

    Arm title
    		 E+OFS
    Arm description
    		 Ovarian function suppression (OFS) by triptorelin (GnRH analogue) 3.75mg by im injection q28 days for 5 years plus exemestane 25mg orally daily for 5 years. Exemestane (E) begins after the completion of adjuvant chemotherapy if given, or approximately 6-8 weeks after the initiation of triptorelin. Bilateral oophorectomy or ovarian irradiation was allowed after at least 6 months of triptorelin.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Exemestane
    Investigational medicinal product code
    Other name
    Aromasin
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    25mg orally daily for 5 years. Exemestane (E) begins after the completion of adjuvant chemotherapy if given, or approximately 6-8 weeks after the initiation of triptorelin.

    Investigational medicinal product name
    Triptorelin
    Investigational medicinal product code
    Other name
    GnRH analogue, Trelstar Depot, Decapeptyl Depot
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    3.75mg by im injection q28 days for 5 years

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Baseline characteristics were only reported for Intention-to-treat population.
    Number of subjects in period 2 [2]
    		T+OFS E+OFS
    Started
    1328
    1332
    Completed
    1328
    1332
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Intention-to-treat population, excludes 12 patients in total - 7 patients who withdrew consent, 2 patients with protocol deviations and 3 patients from centers not compliant with protocol procedures.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    T+OFS
    Reporting group description
    		 Ovarian function suppression (OFS) by triptorelin (GnRH analogue) 3.75mg by im injection q28 days for 5 years plus tamoxifen 20mg orally daily for 5 years. Tamoxifen (T) begins after the completion of adjuvant chemotherapy if given, or approximately 6-8 weeks after the initiation of triptorelin. Bilateral oophorectomy or ovarian irradiation was allowed after at least 6 months of triptorelin.

    Reporting group title
    E+OFS
    Reporting group description
    		 Ovarian function suppression (OFS) by triptorelin (GnRH analogue) 3.75mg by im injection q28 days for 5 years plus exemestane 25mg orally daily for 5 years. Exemestane (E) begins after the completion of adjuvant chemotherapy if given, or approximately 6-8 weeks after the initiation of triptorelin. Bilateral oophorectomy or ovarian irradiation was allowed after at least 6 months of triptorelin.

    Reporting group values
    		 T+OFS E+OFS Total
    Number of subjects
    		 1328 1332 2660
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 44 (40 to 46) 43 (39 to 46) -
    Gender categorical
    Units: Subjects
        Female
    		 1328 1332 2660
        Male
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    T+OFS
    Reporting group description
    		 Ovarian function suppression (OFS) by triptorelin (GnRH analogue) 3.75mg by im injection q28 days for 5 years plus tamoxifen 20mg orally daily for 5 years. Tamoxifen (T) begins after the completion of adjuvant chemotherapy if given, or approximately 6-8 weeks after the initiation of triptorelin. Bilateral oophorectomy or ovarian irradiation was allowed after at least 6 months of triptorelin.

    Reporting group title
    E+OFS
    Reporting group description
    		 Ovarian function suppression (OFS) by triptorelin (GnRH analogue) 3.75mg by im injection q28 days for 5 years plus exemestane 25mg orally daily for 5 years. Exemestane (E) begins after the completion of adjuvant chemotherapy if given, or approximately 6-8 weeks after the initiation of triptorelin. Bilateral oophorectomy or ovarian irradiation was allowed after at least 6 months of triptorelin.
    Reporting group title
    T+OFS
    Reporting group description
    		 Ovarian function suppression (OFS) by triptorelin (GnRH analogue) 3.75mg by im injection q28 days for 5 years plus tamoxifen 20mg orally daily for 5 years. Tamoxifen (T) begins after the completion of adjuvant chemotherapy if given, or approximately 6-8 weeks after the initiation of triptorelin. Bilateral oophorectomy or ovarian irradiation was allowed after at least 6 months of triptorelin.

    Reporting group title
    E+OFS
    Reporting group description
    		 Ovarian function suppression (OFS) by triptorelin (GnRH analogue) 3.75mg by im injection q28 days for 5 years plus exemestane 25mg orally daily for 5 years. Exemestane (E) begins after the completion of adjuvant chemotherapy if given, or approximately 6-8 weeks after the initiation of triptorelin. Bilateral oophorectomy or ovarian irradiation was allowed after at least 6 months of triptorelin.

    Primary: Disease-free Survival

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    End point title
    		 Disease-free Survival
    End point description
    Estimated percentage of patients alive and disease-free at 5 years from randomization, where disease-free survival is defined as the time from randomization to the first appearance of one of the following: invasive breast cancer recurrence at local, regional, or distant site, invasive contralateral breast cancer, second (non-breast) invasive cancer, or death without cancer event; or censored at date of last follow up.
    End point type
    Primary
    End point timeframe
    5-year estimate reported at a median follow-up of 72 months
    End point values
    		 T+OFS E+OFS
    Number of subjects analysed
    1328
    1332
    Units: Percentage of participants
        number (confidence interval 95%)
    87.3 (85.7 to 88.7)
    91.1 (89.7 to 92.3)
    Statistical analysis title
    		 Statistical analysis primary endpoint
    Comparison groups
    T+OFS v E+OFS
    Number of subjects included in analysis
    2660
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0002
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.717
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.602
         upper limit
    		 0.855

    Secondary: Breast Cancer-free Interval

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    End point title
    		 Breast Cancer-free Interval
    End point description
    Estimated percentage of patients alive and disease-free at 5 years from randomization, where breast cancer-free interval is defined as the time from randomization to the invasive breast cancer recurrence at local, regional, or distant site, or invasive contralateral breast cancer; or censored at date of last follow up.
    End point type
    Secondary
    End point timeframe
    5-year estimate reported at a median follow-up of 72 months
    End point values
    		 T+OFS E+OFS
    Number of subjects analysed
    1328
    1332
    Units: Percentage of participants
        number (confidence interval 95%)
    88.8 (87.3 to 90.1)
    92.8 (91.6 to 93.9)
    Statistical analysis title
    		 Breast Cancer-free Interval
    Comparison groups
    T+OFS v E+OFS
    Number of subjects included in analysis
    2660
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.664
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.548
         upper limit
    		 0.804

    Secondary: Distant Recurrence-free Interval

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    End point title
    		 Distant Recurrence-free Interval
    End point description
    Estimated percentage of patients alive and disease-free at 5 years from randomization, where distant recurrence-free interval is defined as the time from randomization to breast cancer recurrence at a distant site; or censored at date of last follow-up
    End point type
    Secondary
    End point timeframe
    5-year estimates reported at a median follow-up of 72 months
    End point values
    		 T+OFS E+OFS
    Number of subjects analysed
    1328
    1332
    Units: Percentage of participants
        number (confidence interval 95%)
    92 (90.7 to 93.1)
    93.8 (92.7 to 94.8)
    Statistical analysis title
    		 Distant Recurrence-free Interval
    Comparison groups
    T+OFS v E+OFS
    Number of subjects included in analysis
    2660
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.02
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.624
         upper limit
    		 0.967

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Estimated percentage of patients alive at 8 years from randomization, where overall survival is defined as the time from randomization to death from any cause; or censored at date last known alive.
    End point type
    Secondary
    End point timeframe
    8-year estimates, reported at a median follow-up of 9 years
    End point values
    		 T+OFS E+OFS
    Number of subjects analysed
    1328
    1332
    Units: Percentage of participants
        number (confidence interval 95%)
    93.3 (92.1 to 94.3)
    93.4 (92.2 to 94.4)
    Statistical analysis title
    		 Overall Survival
    Comparison groups
    T+OFS v E+OFS
    Number of subjects included in analysis
    2660
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.84
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.79
         upper limit
    		 1.22

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Assessed every 3 months for the first year, then every 6 months until year 6. Reported at a median follow-up of 72 months.
    Adverse event reporting additional description
    Targeted adverse events and other grade 3 or higher adverse events were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 NCI CTCAE
    Dictionary version
    3.0
    Reporting groups
    Reporting group title
    T+OFS
    Reporting group description
    		 Ovarian function suppression (OFS) by triptorelin (GnRH analogue) 3.75mg by im injection q28 days for 5 years plus tamoxifen 20mg orally daily for 5 years. Tamoxifen (T) begins after the completion of adjuvant chemotherapy if given, or approximately 6-8 weeks after the initiation of triptorelin. Bilateral oophorectomy or ovarian irradiation was allowed after at least 6 months of triptorelin.

    Reporting group title
    E+OFS
    Reporting group description
    		 Ovarian function suppression (OFS) by triptorelin (GnRH analogue) 3.75mg by im injection q28 days for 5 years plus exemestane 25mg orally daily for 5 years. Exemestane (E) begins after the completion of adjuvant chemotherapy if given, or approximately 6-8 weeks after the initiation of triptorelin. Bilateral oophorectomy or ovarian irradiation was allowed after at least 6 months of triptorelin.

    Serious adverse events
    		 T+OFS E+OFS
    Total subjects affected by serious adverse events
         subjects affected / exposed
    290 / 1328 (21.84%)
    295 / 1332 (22.15%)
         number of deaths (all causes)
    5
    5
         number of deaths resulting from adverse events
    3
    1
    Vascular disorders
    Deep Vein Thrombosis
         subjects affected / exposed
    12 / 1328 (0.90%)
    2 / 1332 (0.15%)
         occurrences causally related to treatment / all
    7 / 12
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    3 / 1328 (0.23%)
    3 / 1332 (0.23%)
         occurrences causally related to treatment / all
    1 / 4
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Pregnancy
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Allergic reaction/hypersensitivity
         subjects affected / exposed
    3 / 1328 (0.23%)
    3 / 1332 (0.23%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalized edema inclusive pleura effusion
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute sarcoidosis (Loefgren Syndrome)
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Cervical Changes
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervical Polyp
         subjects affected / exposed
    2 / 1328 (0.15%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial Hyperplasia
         subjects affected / exposed
    5 / 1328 (0.38%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial Polyp
         subjects affected / exposed
    6 / 1328 (0.45%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    6 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian Cyst
         subjects affected / exposed
    3 / 1328 (0.23%)
    3 / 1332 (0.23%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine adenomyosis and chronic cervicitis
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine Hemorrhage
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine Leiomyoma
         subjects affected / exposed
    1 / 1328 (0.08%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine Myoma
         subjects affected / exposed
    2 / 1328 (0.15%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine Prolapse
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal Bleeding
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal Prolapse
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign Lesion-Fibrosis (L Breast)
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibrocystic Breast
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mammary Duct Ectasia
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sclerosing adenosis (R breast)
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic Pansinusitis
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroglossal duct cyst
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    2 / 1328 (0.15%)
    4 / 1332 (0.30%)
         occurrences causally related to treatment / all
    2 / 2
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma exacerbation
         subjects affected / exposed
    1 / 1328 (0.08%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 1328 (0.08%)
    3 / 1332 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiation Pneumonitis
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Larynx Stricture requiring surgery
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Sudden death due to lethal dose of diphenhydramine
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ureter and vaginal cuff injury after hysterectomy and BSO
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial Fibrillation
         subjects affected / exposed
    2 / 1328 (0.15%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    0 / 1328 (0.00%)
    2 / 1332 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular arrhythmia
         subjects affected / exposed
    2 / 1328 (0.15%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular Tachycardia
         subjects affected / exposed
    1 / 1328 (0.08%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular fibrilation in context of allergic reaction
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac ischemia/infarction
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest Pain
         subjects affected / exposed
    4 / 1328 (0.30%)
    5 / 1332 (0.38%)
         occurrences causally related to treatment / all
    0 / 6
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congestive Heart Failure and Asthma Exacerbation
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Heart Failure
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    2 / 1328 (0.15%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischemic Heart Disease
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral and tricuspid valve disease requiring surgery
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral valve stenosis requiring surgery
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial Infarction
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular Insufficiency
         subjects affected / exposed
    2 / 1328 (0.15%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    8 / 1328 (0.60%)
    6 / 1332 (0.45%)
         occurrences causally related to treatment / all
    9 / 9
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial spasms R
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 1328 (0.08%)
    2 / 1332 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mood Alteration
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuronitis Vestibularis
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Panic attacks with dyspnoea and chest pain
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychogenic seizure
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychosis
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ethylic intoxication with depressive syndrome
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumboischialgia
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sensory neuropathy
         subjects affected / exposed
    0 / 1328 (0.00%)
    2 / 1332 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal Meningioma and Primary Lateral Sclerosis
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoidal bleeding
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal Ideation
         subjects affected / exposed
    2 / 1328 (0.15%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide Attempt
         subjects affected / exposed
    4 / 1328 (0.30%)
    3 / 1332 (0.23%)
         occurrences causally related to treatment / all
    1 / 4
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 1328 (0.00%)
    2 / 1332 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient Ischemic Attack
         subjects affected / exposed
    2 / 1328 (0.15%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Trigeminal neuralgia
         subjects affected / exposed
    2 / 1328 (0.15%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertigo
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anxiety and depression
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral contusion
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carpal Tunnel Syndrome
         subjects affected / exposed
    2 / 1328 (0.15%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bipolar disorder
         subjects affected / exposed
    2 / 1328 (0.15%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alcohol abuse
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular Accident
         subjects affected / exposed
    2 / 1328 (0.15%)
    4 / 1332 (0.30%)
         occurrences causally related to treatment / all
    1 / 2
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    6 / 1328 (0.45%)
    3 / 1332 (0.23%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polycythemia Vera
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral Hemorrhage
         subjects affected / exposed
    1 / 1328 (0.08%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gum bleeding under anticoagulation
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemoptoe
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Edema
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anemia
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract and Retinal Detachment
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central vein occlusion (L eye)
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal Detachment
         subjects affected / exposed
    0 / 1328 (0.00%)
    2 / 1332 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinopathy
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Thyroid Nodules
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon polyps
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 1328 (0.08%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhea
         subjects affected / exposed
    3 / 1328 (0.23%)
    5 / 1332 (0.38%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 1328 (0.00%)
    3 / 1332 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Esophageal Achalasia
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric Ulcer
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 1328 (0.08%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastro-eosphageal reflux disease
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemorrhoids
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea and Vomiting
         subjects affected / exposed
    2 / 1328 (0.15%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small bowel obstruction
         subjects affected / exposed
    1 / 1328 (0.08%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal bleeding
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Irritable bowel syndrome leading to rectal bleeding
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Terminal Ileitisv
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    3 / 1328 (0.23%)
    2 / 1332 (0.15%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal Perforation
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hemorrhoidal bleeding
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute/Recurrent Pancreatitis
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    6 / 1328 (0.45%)
    2 / 1332 (0.15%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Choledocholytiasis
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    4 / 1328 (0.30%)
    2 / 1332 (0.15%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gallbladder Sludge
         subjects affected / exposed
    2 / 1328 (0.15%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatopathy
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver disfunction
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Hemorrhagic cystitis due to cyclophosphamide
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydroureteronephrosis left
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mature cystic teratoma and endometrial polyp
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 1328 (0.00%)
    2 / 1332 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal calculi
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic due to lithiasis
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suspicion of junction syndrom (R ureter)
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Incontinence
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention due to opioids treatment
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperparathyroidism
         subjects affected / exposed
    1 / 1328 (0.08%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parotis Adenoma
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroid Adenoma
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroiditis
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain and arthralgia
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone fracture
         subjects affected / exposed
    17 / 1328 (1.28%)
    30 / 1332 (2.25%)
         occurrences causally related to treatment / all
    7 / 18
    17 / 30
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Discus Hernia
         subjects affected / exposed
    1 / 1328 (0.08%)
    2 / 1332 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Exacerbation of ankylosing spondylitis
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint pain
         subjects affected / exposed
    0 / 1328 (0.00%)
    3 / 1332 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthrosis
         subjects affected / exposed
    1 / 1328 (0.08%)
    2 / 1332 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periarthritis humero-scapularis requiring surgery
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polytrauma
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    R knee dislocation
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rheumatoid Arthritis
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rupture of achilles tendon L
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendinitis calcarea (L Shoulder)
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic injuries on the face
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    4 / 1328 (0.30%)
    2 / 1332 (0.15%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 1328 (0.08%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Elevated liver function tests
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess breast
         subjects affected / exposed
    0 / 1328 (0.00%)
    3 / 1332 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute Appendicitis
         subjects affected / exposed
    1 / 1328 (0.08%)
    3 / 1332 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast implant infection
         subjects affected / exposed
    5 / 1328 (0.38%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 1328 (0.08%)
    2 / 1332 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bruise of abdominal wall with abscess
         subjects affected / exposed
    5 / 1328 (0.38%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    10 / 1328 (0.75%)
    9 / 1332 (0.68%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile Neutropenia
         subjects affected / exposed
    19 / 1328 (1.43%)
    29 / 1332 (2.18%)
         occurrences causally related to treatment / all
    0 / 22
    0 / 30
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia during chemotherapy
         subjects affected / exposed
    2 / 1328 (0.15%)
    2 / 1332 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fever
         subjects affected / exposed
    4 / 1328 (0.30%)
    5 / 1332 (0.38%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 1328 (0.15%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gram negative sepsis
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 1328 (0.08%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection (L arm cellulitis) in neutropenia
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection around the port system
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection with normal ANC
         subjects affected / exposed
    1 / 1328 (0.08%)
    5 / 1332 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza A leading to pulmonary complications
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mastitis
         subjects affected / exposed
    1 / 1328 (0.08%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HIV infection
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pleural effusion due to infection
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 1328 (0.30%)
    2 / 1332 (0.15%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Port-A-Cath infection
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative infection after oophorectomy
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock from infection of breast implant
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcus aureus infection (catheter related)
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth Abscess
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    1 / 1328 (0.08%)
    3 / 1332 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Viral upper respiratory infection
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound Infection
         subjects affected / exposed
    1 / 1328 (0.08%)
    2 / 1332 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sigmoid colitis
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint Infection (Right wrist)
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection with neutropenia
         subjects affected / exposed
    3 / 1328 (0.23%)
    4 / 1332 (0.30%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes Mellitus
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercholesterolemia G3 and Hypertrigyceridemia G4
         subjects affected / exposed
    0 / 1328 (0.00%)
    1 / 1332 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycemia
         subjects affected / exposed
    0 / 1328 (0.00%)
    3 / 1332 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibromyalgia
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Accidental CO - intoxication
         subjects affected / exposed
    1 / 1328 (0.08%)
    0 / 1332 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 T+OFS E+OFS
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1293 / 1328 (97.36%)
    1298 / 1332 (97.45%)
    Vascular disorders
    Hot flashes/flushes
         subjects affected / exposed
    1081 / 1328 (81.40%)
    1076 / 1332 (80.78%)
         occurrences all number
    1081
    1076
    Hypertension
         subjects affected / exposed
    179 / 1328 (13.48%)
    213 / 1332 (15.99%)
         occurrences all number
    179
    213
    General disorders and administration site conditions
    Fatigue (asthenia, lethargy, malaise)
         subjects affected / exposed
    807 / 1328 (60.77%)
    760 / 1332 (57.06%)
         occurrences all number
    807
    760
    Injection site reaction/extravasation changes
         subjects affected / exposed
    99 / 1328 (7.45%)
    86 / 1332 (6.46%)
         occurrences all number
    99
    86
    Immune system disorders
    Allergic reaction/hypersensitivity (including drug fever)
         subjects affected / exposed
    56 / 1328 (4.22%)
    60 / 1332 (4.50%)
         occurrences all number
    56
    60
    Reproductive system and breast disorders
    Pain - Vagina
         subjects affected / exposed
    336 / 1328 (25.30%)
    374 / 1332 (28.08%)
         occurrences all number
    336
    374
    Vaginal dryness
         subjects affected / exposed
    611 / 1328 (46.01%)
    683 / 1332 (51.28%)
         occurrences all number
    611
    683
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    738 / 1328 (55.57%)
    714 / 1332 (53.60%)
         occurrences all number
    738
    714
    Libido
         subjects affected / exposed
    486 / 1328 (36.60%)
    555 / 1332 (41.67%)
         occurrences all number
    486
    555
    Mood alteration - depression
         subjects affected / exposed
    592 / 1328 (44.58%)
    610 / 1332 (45.80%)
         occurrences all number
    592
    610
    Injury, poisoning and procedural complications
    Fracture
         subjects affected / exposed
    57 / 1328 (4.29%)
    82 / 1332 (6.16%)
         occurrences all number
    57
    82
    Thrombosis/embolism (vascular access-related)
         subjects affected / exposed
    3 / 1328 (0.23%)
    3 / 1332 (0.23%)
         occurrences all number
    3
    3
    Cardiac disorders
    Cardiac-ischemia/infarction
         subjects affected / exposed
    2 / 1328 (0.15%)
    4 / 1332 (0.30%)
         occurrences all number
    2
    4
    Nervous system disorders
    Hemorrhage, CNS
         subjects affected / exposed
    12 / 1328 (0.90%)
    7 / 1332 (0.53%)
         occurrences all number
    12
    7
    CNS cerebrovascular ischemia
         subjects affected / exposed
    2 / 1328 (0.15%)
    1 / 1332 (0.08%)
         occurrences all number
    2
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    446 / 1328 (33.58%)
    478 / 1332 (35.89%)
         occurrences all number
    446
    478
    Skin and subcutaneous tissue disorders
    Sweating (diaphoresis)
         subjects affected / exposed
    752 / 1328 (56.63%)
    705 / 1332 (52.93%)
         occurrences all number
    752
    705
    Renal and urinary disorders
    Incontinence, urinary
         subjects affected / exposed
    232 / 1328 (17.47%)
    182 / 1332 (13.66%)
         occurrences all number
    232
    182
    Musculoskeletal and connective tissue disorders
    Osteoporosis
         subjects affected / exposed
    388 / 1328 (29.22%)
    588 / 1332 (44.14%)
         occurrences all number
    388
    588
    Pain - Joint
         subjects affected / exposed
    953 / 1328 (71.76%)
    1030 / 1332 (77.33%)
         occurrences all number
    953
    1030
    Metabolism and nutrition disorders
    Glucose, serum-high (hyperglycemia)
         subjects affected / exposed
    30 / 1328 (2.26%)
    31 / 1332 (2.33%)
         occurrences all number
    30
    31
    Pancreatic endocrine: glucose intolerance
         subjects affected / exposed
    16 / 1328 (1.20%)
    17 / 1332 (1.28%)
         occurrences all number
    16
    17

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Oct 2005
    1. Modified the eligibility and other sections to include patients with bilateral breast cancer. 2. Modified/clarified eligibility requirements including: a. Defining a premenopausal group that does not require estradiol testing; b. Clarifying definitions of surgical margins; c. Defining eligible prior malignancies. 3. Clarified timing of randomization with respect to surgery, radiotherapy, and chemotherapy. 4. Clarified that trastuzumab is allowed prior to and/or concurrent with protocol treatment. 5. Included new findings about exemestane efficacy and side effects in postmenopausal women. 6. Added details of treatment administration. 7. Clarified pathology requirements and central review. 8. Administrative corrections and updates.
    25 Jul 2008
    1. Re-opened enrollment for an additional 600 patients (target accrual: 2639). 2. Added translational research investigations which involved a one-time blood sample for genotyping.
    24 Aug 2011
    1. Modified the statistical analysis plan to combine data available from SOFT and TEXT for the comparison of OFS + exemestane versus OFS + tamoxifen for a primary analysis with a data cut-off anticipated for the third quarter of 2013 at 5 years’ median follow-up. 2. Included breast cancer-free interval (BCFI) and distant recurrence-free interval (DRFI) as secondary endpoints replacing systemic disease free survival. 3. Added targeted adverse event information on diabetes and collection of anti-diabetic concomitant medications. Increased risk of diabetes has been suggested by epidemiologic studies in men being treated with GnRH agonists for prostate cancer. Glucose intolerance (diabetes) and hyperglycemia were added to the case report forms as targeted adverse events.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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