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    Clinical Trial Results:
    Monotherapy vs Dual Therapy for the Initial Treatment of Hypertension (Pathway-1): a Randomised Double-blind Controlled Trial

    Summary
    EudraCT number
    2008-007749-29
    Trial protocol
    GB  
    Global end of trial date
    31 Jan 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    19 Feb 2020
    First version publication date
    19 Feb 2020
    Other versions
    Summary report(s)
    Pathway 1 Publication

    Trial information

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    Trial identification
    Sponsor protocol code
    Pathway 1
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00994617
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Cambridge University Hospitals NHS Foundation Trust & the University of Cambridge
    Sponsor organisation address
    R&D Department, Addenbrooke's Hospital, Hills Road, Cambridge, United Kingdom, CB2 0QQ
    Public contact
    Morris J Brown (Chief Investigator), William Harvey Research Institute, Queen Mary University of London, morris.brown@qmul.ac.uk
    Scientific contact
    Morris J Brown (Chief Investigator), William Harvey Research Institute, Queen Mary University of London, morris.brown@qmul.ac.uk
    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
    04 Jan 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Jan 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Jan 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To test whether the current custom of initiating treatment for high blood pressure with a single drug is less effective in the short-term than initial combination therapy , and results in the eventual need for comparatively more drugs for lowereing blood pressure.
    Protection of trial subjects
    Serious Adverse Events were documented and reported to the Chief Investigator and to regulatory authorities, in accordance with local an national requirements. The study was approved by Cambridgeshire Research Ethics Committee and all participants gave written informed consent. A Study Steering Committee was responsible for evaluating and reporting the results of the trial.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    16 Feb 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 605
    Worldwide total number of subjects
    605
    EEA total number of subjects
    605
    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)
    471
    From 65 to 84 years
    134
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Participants were enrolled between Feb 2010 to Nov 2013. The trial was conducted in 11 secondary and 2 primary care centres in the United Kingdom

    Pre-assignment
    Screening details
    Patients aged 18-79 with a diagnosis of essential hypertension, systolic BP>150 mm Hg and diastolic BP>95 mm, and who were never treated or who had received 1 drug class in the previous year. 796 patients were screened, 191 excluded and 605 randomised.

    Pre-assignment period milestones
    Number of subjects started
    796 [1]
    Number of subjects completed
    605

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    not eligible: 191
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: We screened 796 patients and randomized 605 participants, 301 to initial monotherapy and 304 to initial combination therapy
    Period 1
    Period 1 title
    weeks 0-16/initial mono- and combo thera
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator
    Blinding implementation details
    Losartan and HCTZ tablets were reencapsulated in identical gelatin capsules. All patients receive two capsules throughout phase 1, in a double-dummy fashion, to maintain masking in the combination and monotherapy groups. In phases 2 and 3, losartan and HCTZ were provided in a single tablet, the identity of which was known to investigators and patients; however masking of the initial assignment was maintained until database loc

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    initial monotherapy
    Arm description
    301 patients were randomly assigned to initial monotherapy (losartan and HCTZ crossing over at 8 weeks)
    Arm type
    Experimental

    Investigational medicinal product name
    losartan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    losartan 50-100 mg crossing over hydrochlorothiazide (HCTZ) 12.5 -25 mg at 8 weeks

    Investigational medicinal product name
    hydrochlorothiazide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were randomly assigned to initial monotherapy (hydrochlorothiazide (HCTZ) 12.5 -25 mg and losartan 50-100 mg or crossing over at 8 weeks)

    Arm title
    initial combination therapy
    Arm description
    304 eligible participants received 50 mg losartan plus 12.5 mg HCTZ combination therapy. The successive dose permutations at every 4 weeks after initial assignment were losartan/HCTZ 50/25, 100/12.5, and 100/25 mg
    Arm type
    Active comparator

    Investigational medicinal product name
    losartan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    losartan 50 mg plus hydrochlorothiazide 12.5 mg. In this arm, the successful dose permutations at every 4 weeks after initial assignment were losartan/HCTZ 50/25, 100/12.5, and 100/25 mg.

    Investigational medicinal product name
    hydrochlorothiazide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    losartan 50 mg plus hydrochlorothiazide 12.5. In this arm, the successful dose permutations at every 4 weeks after initial assignment were losartan/HCTZ 50/25, 100/12.5, and 100/25 mg.

    Number of subjects in period 1
    initial monotherapy initial combination therapy
    Started
    301
    304
    Completed
    287
    299
    Not completed
    14
    5
         not eligible
    14
    5
    Period 2
    Period 2 title
    weeks 16-32 (combination therapy)
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Arm title
    Losartan and HCTZ combo
    Arm description
    After 16 weeks (start of period 2) all 586 participants in the intention-to-treat population received the combination of losartan 100 mg plus HCTZ 12.5 mg. At week 24, all partcipants were force-titrated to losartan 100 mh plus HCTZ 25 mg
    Arm type
    Experimental

    Investigational medicinal product name
    losartan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    After 16 weeks (start of period 2) all 586 participants in the intention-to-treat population received the combination of losartan 100 mg with HCTZ orally

    Investigational medicinal product name
    hydrochlorothiazide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    After 16 weeks (start of period 2) all 586 participants in the intention-to-treat population received the combination of losartan 100 mg plus HCTZ 12.5 mg. At week 24, all partcipants were force-titrated to losartan 100 mh plus HCTZ 25 mg

    Number of subjects in period 2
    Losartan and HCTZ combo
    Started
    586
    Completed
    586
    Period 3
    Period 3 title
    weeks 33-52 (combination therapy)
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Single blind
    Roles blinded
    Subject
    Blinding implementation details
    Single blind add-on (amplodipine 10mg, doxazosin 4mg)

    Arms
    Arm title
    Losartan and HCTZ combo
    Arm description
    At week 32 (start of phase 3) all participants received 100 mg losartan plus 25 mg HCTZ. 5/10 mg amlodipline ( with or without 4/8 mg doxazosin) was added if systolic BP was >140 mm Hg or diastolic was >90 mm Hg.
    Arm type
    Active comparator

    Investigational medicinal product name
    losartan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    At week 32 (start of phase 3) all participants received 100 mg losartan plus 25 mg HCTZ. 5/10 mg amlodipline ( with or without 4/8 mg doxazosin) was added if systolic BP was >140 mm Hg or diastolic was >90 mm Hg.

    Investigational medicinal product name
    hydrochlorothiazide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    At week 32 (start of phase 3) all participants received 100 mg losartan plus 25 mg HCTZ. 5/10 mg amlodipline ( with or without 4/8 mg doxazosin) was added if systolic BP was >140 mm Hg or diastolic was >90 mm Hg.

    Number of subjects in period 3
    Losartan and HCTZ combo
    Started
    586
    Completed
    432
    Not completed
    154
         not eligible
    154

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    initial monotherapy
    Reporting group description
    301 patients were randomly assigned to initial monotherapy (losartan and HCTZ crossing over at 8 weeks)

    Reporting group title
    initial combination therapy
    Reporting group description
    304 eligible participants received 50 mg losartan plus 12.5 mg HCTZ combination therapy. The successive dose permutations at every 4 weeks after initial assignment were losartan/HCTZ 50/25, 100/12.5, and 100/25 mg

    Reporting group values
    initial monotherapy initial combination therapy Total
    Number of subjects
    301 304 605
    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
        arithmetic mean (standard deviation)
    53.9 ± 12.0 54.2 ± 12.0 -
    Gender categorical
    Units: Subjects
        Female
    103 113 216
        Male
    198 191 389
    Subject analysis sets

    Subject analysis set title
    monotherapy (HCTZ first)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    151 participants were assigned first to 12.5 mg HCTZ plus 50 mg losartan treatment during weeks 0-16. The participants crossed over at 6 weeks to the alternative drug at the lower dose, which was again force dose-titrated to twice the dose after a further 4 weeks

    Subject analysis set title
    monotherapy (losartan first)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    150 participants were assigned first to 50 mg losartan or 12.5-25 mg HCTZ during weeks 0-16 (the participants crossed over at 8 weeks to the alternative drug at the lower dose, which was again forced dose-titrated to twice the dose after a further 4 weeks)

    Subject analysis sets values
    monotherapy (HCTZ first) monotherapy (losartan first)
    Number of subjects
    151
    150
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    53.4 ± 11.9
    54.5 ± 12.1
    Gender categorical
    Units: Subjects
        Female
    55
    48
        Male
    96
    102

    End points

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    End points reporting groups
    Reporting group title
    initial monotherapy
    Reporting group description
    301 patients were randomly assigned to initial monotherapy (losartan and HCTZ crossing over at 8 weeks)

    Reporting group title
    initial combination therapy
    Reporting group description
    304 eligible participants received 50 mg losartan plus 12.5 mg HCTZ combination therapy. The successive dose permutations at every 4 weeks after initial assignment were losartan/HCTZ 50/25, 100/12.5, and 100/25 mg
    Reporting group title
    Losartan and HCTZ combo
    Reporting group description
    After 16 weeks (start of period 2) all 586 participants in the intention-to-treat population received the combination of losartan 100 mg plus HCTZ 12.5 mg. At week 24, all partcipants were force-titrated to losartan 100 mh plus HCTZ 25 mg
    Reporting group title
    Losartan and HCTZ combo
    Reporting group description
    At week 32 (start of phase 3) all participants received 100 mg losartan plus 25 mg HCTZ. 5/10 mg amlodipline ( with or without 4/8 mg doxazosin) was added if systolic BP was >140 mm Hg or diastolic was >90 mm Hg.

    Subject analysis set title
    monotherapy (HCTZ first)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    151 participants were assigned first to 12.5 mg HCTZ plus 50 mg losartan treatment during weeks 0-16. The participants crossed over at 6 weeks to the alternative drug at the lower dose, which was again force dose-titrated to twice the dose after a further 4 weeks

    Subject analysis set title
    monotherapy (losartan first)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    150 participants were assigned first to 50 mg losartan or 12.5-25 mg HCTZ during weeks 0-16 (the participants crossed over at 8 weeks to the alternative drug at the lower dose, which was again forced dose-titrated to twice the dose after a further 4 weeks)

    Primary: Mean reduction from baseline HSBP over weeks 0 - 32

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    End point title
    Mean reduction from baseline HSBP over weeks 0 - 32
    End point description
    There were two primary analysis in a hierarchy. The comparison between groups of the endpoints averaged over weeks 0-32, phase 1-2, was tested first. If, and only if, this was statistically significant was the second comparison made of the endpoint observed at week 32 in isolation.
    End point type
    Primary
    End point timeframe
    Measured at 32 weeks after randomization (average). We test the superiority between losartan plus HCTZ (initial combination group) and the mean of each monotherapy arm
    End point values
    initial monotherapy initial combination therapy
    Number of subjects analysed
    301
    304
    Units: mm Hg
        least squares mean (confidence interval 95%)
    -14.8 (-15.8 to -13.8)
    -19.7 (-20.7 to -18.7)
    Statistical analysis title
    Mean change from baseline HSBP
    Statistical analysis description
    A sample size of 268 in each group had 90% power to detect a change in HSBP means of 4 mm HG, assuming a common SD of 12 mm Hg using a 2-group t test with α=0.01. We used mix-effect models with unstructured covariances for repeated measures within a patient, adjusting for prescribed baselines covariates. Least squares means were estimated. BP control and response rates were analysed using log regression. χ2 tests were used to compare adverse event rates, and Fisher exact P values are given.
    Comparison groups
    initial monotherapy v initial combination therapy
    Number of subjects included in analysis
    605
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -4.88
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.04
         upper limit
    -3.73
    Variability estimate
    Standard deviation

    Primary: Change from baseline HSBP at week 32 in isolation

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    End point title
    Change from baseline HSBP at week 32 in isolation
    End point description
    There were two primary analysis in a hierarchy. The comparison between groups of the endpoints averaged over weeks 0-32, phase 1-2, was tested first. If, and only if, this was statistically significant was the second comparison made of the endpoint observed at week 32 in isolation.
    End point type
    Primary
    End point timeframe
    The second primary end point (measured only if the first hypothesis was positive) is the reduction from baseline in HSBP at 32 week, a point in the study when all participants were receiving the same combination treatment (losartan + HCTZ)
    End point values
    initial monotherapy initial combination therapy
    Number of subjects analysed
    287
    299
    Units: mm Hg
        least squares mean (confidence interval 95%)
    -23.4 (-24.8 to -22.0)
    -22.2 (-23.6 to -20.8)
    Statistical analysis title
    reduction in mean HSBP at week 32
    Statistical analysis description
    We used mixed-effect models with unstructured covariances for repeated measures within a patient. We adjusted for prespecified baseline covariates (sex, age etc.). Least square means estimated from these models are presented. Arithmetic mean of last 18 home BP measurements was used to calculate home BP.
    Comparison groups
    initial monotherapy v initial combination therapy
    Number of subjects included in analysis
    586
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    1.22
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.38
         upper limit
    2.82
    Variability estimate
    Standard deviation

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Timeframe for AE
    Adverse event reporting additional description
    AE additional description
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Combination
    Reporting group description
    -

    Reporting group title
    Monotherapy
    Reporting group description
    -

    Serious adverse events
    Combination Monotherapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 304 (3.62%)
    10 / 301 (3.32%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Endometrial cancer stage II
    Additional description: Endometrial cancer stage II
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic neoplasm
    Additional description: Metastatic neoplasm
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Rectal cancer
    Additional description: Rectal cancer
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Glomerular filtration rate decreased
    Additional description: Glomerular filtration rate decreased
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test abnormal
    Additional description: Liver function test abnormal
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Circulatory collapse
    Additional description: Circulatory collapse
         subjects affected / exposed
    2 / 304 (0.66%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
    Additional description: Hypotension
         subjects affected / exposed
    2 / 304 (0.66%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
    Additional description: Atrial fibrillation
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
    Additional description: Coronary artery disease
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachyarrhythmia
    Additional description: Tachyarrhythmia
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Cardiac pacemaker insertion
    Additional description: Cardiac pacemaker insertion
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystectomy
    Additional description: Cholecystectomy
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal stone removal
    Additional description: Renal stone removal
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rotator cuff repair
    Additional description: Rotator cuff repair
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Loss of consciousness
    Additional description: Loss of consciousness
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Thrombocytopenic purpura
    Additional description: Thrombocytopenic purpura
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
    Additional description: Cholecystitis
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
    Additional description: Nephrolithiasis
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
    Additional description: Renal colic
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Diverticulitis
    Additional description: Diverticulitis
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
    Additional description: Lower respiratory tract infection
         subjects affected / exposed
    1 / 304 (0.33%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
    Additional description: Urinary tract infection
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
    Additional description: Dehydration
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (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
    Combination Monotherapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    278 / 304 (91.45%)
    265 / 301 (88.04%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Angiomyolipoma
    Additional description: Angiomyolipoma
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Benign neoplasm of eyelid
    Additional description: Benign neoplasm of eyelid
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Bowen's disease
    Additional description: Bowen's disease
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Melanocytic naevus
    Additional description: Melanocytic naevus
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Oral neoplasm
    Additional description: Oral neoplasm
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Skin papilloma
    Additional description: Skin papilloma
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Vascular disorders
    Aortic aneurysm
    Additional description: Aortic aneurysm
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Aortic stenosis
    Additional description: Aortic stenosis
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Circulatory collapse
    Additional description: Circulatory collapse
         subjects affected / exposed
    2 / 304 (0.66%)
    0 / 301 (0.00%)
         occurrences all number
    2
    0
    Deep vein thrombosis
    Additional description: Deep vein thrombosis
         subjects affected / exposed
    1 / 304 (0.33%)
    1 / 301 (0.33%)
         occurrences all number
    1
    1
    Flushing
    Additional description: Flushing
         subjects affected / exposed
    5 / 304 (1.64%)
    1 / 301 (0.33%)
         occurrences all number
    5
    1
    Hot flush
    Additional description: Hot flush
         subjects affected / exposed
    4 / 304 (1.32%)
    3 / 301 (1.00%)
         occurrences all number
    8
    3
    Hypotension
    Additional description: Hypotension
         subjects affected / exposed
    4 / 304 (1.32%)
    7 / 301 (2.33%)
         occurrences all number
    4
    7
    Orthostatic hypotension
    Additional description: Orthostatic hypotension
         subjects affected / exposed
    11 / 304 (3.62%)
    10 / 301 (3.32%)
         occurrences all number
    15
    12
    Peripheral coldness
    Additional description: Peripheral coldness
         subjects affected / exposed
    5 / 304 (1.64%)
    2 / 301 (0.66%)
         occurrences all number
    5
    2
    Raynaud's phenomenon
    Additional description: Raynaud's phenomenon
         subjects affected / exposed
    3 / 304 (0.99%)
    1 / 301 (0.33%)
         occurrences all number
    3
    1
    Varicose vein
    Additional description: Varicose vein
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Vein disorder
    Additional description: Vein disorder
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Surgical and medical procedures
    Acrochordon excision
    Additional description: Acrochordon excision
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Bartholin's cyst removal
    Additional description: Bartholin's cyst removal
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Bladder neck operation
    Additional description: Bladder neck operation
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Cataract operation
    Additional description: Cataract operation
         subjects affected / exposed
    1 / 304 (0.33%)
    2 / 301 (0.66%)
         occurrences all number
    1
    3
    Colostomy
    Additional description: Colostomy
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Dental cleaning
    Additional description: Dental cleaning
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Dental implantation
    Additional description: Dental implantation
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    2
    0
    Dental operation
    Additional description: Dental operation
         subjects affected / exposed
    1 / 304 (0.33%)
    1 / 301 (0.33%)
         occurrences all number
    1
    1
    Endodontic procedure
    Additional description: Endodontic procedure
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Eye laser surgery
    Additional description: Eye laser surgery
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    2
    Fasciectomy
    Additional description: Fasciectomy
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Gallbladder operation
    Additional description: Gallbladder operation
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Gingival operation
    Additional description: Gingival operation
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Hernia repair
    Additional description: Hernia repair
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Hip arthroplasty
    Additional description: Hip arthroplasty
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Hysterectomy
    Additional description: Hysterectomy
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Inguinal hernia repair
    Additional description: Inguinal hernia repair
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    2
    0
    Injection
    Additional description: Injection
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Intestinal operation
    Additional description: Intestinal operation
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Lesion excision
    Additional description: Lesion excision
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Nasal polypectomy
    Additional description: Nasal polypectomy
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Nasal septal operation
    Additional description: Nasal septal operation
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Removal of internal fixation
    Additional description: Removal of internal fixation
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Shoulder operation
    Additional description: Shoulder operation
         subjects affected / exposed
    0 / 304 (0.00%)
    2 / 301 (0.66%)
         occurrences all number
    0
    2
    Skin lesion excision
    Additional description: Skin lesion excision
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Tooth extraction
    Additional description: Tooth extraction
         subjects affected / exposed
    2 / 304 (0.66%)
    2 / 301 (0.66%)
         occurrences all number
    2
    3
    Tooth repair
    Additional description: Tooth repair
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    2
    0
    Tympanoplasty
    Additional description: Tympanoplasty
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Wisdom teeth removal
    Additional description: Wisdom teeth removal
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Adverse drug reaction
    Additional description: Adverse drug reaction
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Adverse reaction
    Additional description: Adverse reaction
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Asthenia
    Additional description: Asthenia
         subjects affected / exposed
    3 / 304 (0.99%)
    4 / 301 (1.33%)
         occurrences all number
    3
    4
    Chest discomfort
    Additional description: Chest discomfort
         subjects affected / exposed
    7 / 304 (2.30%)
    12 / 301 (3.99%)
         occurrences all number
    8
    12
    Chest pain
    Additional description: Chest pain
         subjects affected / exposed
    8 / 304 (2.63%)
    10 / 301 (3.32%)
         occurrences all number
    12
    12
    Chills
    Additional description: Chills
         subjects affected / exposed
    2 / 304 (0.66%)
    2 / 301 (0.66%)
         occurrences all number
    2
    2
    Crepitations
    Additional description: Crepitations
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Drug resistance
    Additional description: Drug resistance
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Facial pain
    Additional description: Facial pain
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Fatigue
    Additional description: Fatigue
         subjects affected / exposed
    45 / 304 (14.80%)
    34 / 301 (11.30%)
         occurrences all number
    53
    39
    Feeling abnormal
    Additional description: Feeling abnormal
         subjects affected / exposed
    3 / 304 (0.99%)
    1 / 301 (0.33%)
         occurrences all number
    3
    1
    Feeling cold
    Additional description: Feeling cold
         subjects affected / exposed
    2 / 304 (0.66%)
    0 / 301 (0.00%)
         occurrences all number
    2
    0
    Feeling hot
    Additional description: Feeling hot
         subjects affected / exposed
    2 / 304 (0.66%)
    1 / 301 (0.33%)
         occurrences all number
    2
    1
    Influenza like illness
    Additional description: Influenza like illness
         subjects affected / exposed
    13 / 304 (4.28%)
    6 / 301 (1.99%)
         occurrences all number
    13
    6
    Irritability
    Additional description: Irritability
         subjects affected / exposed
    1 / 304 (0.33%)
    3 / 301 (1.00%)
         occurrences all number
    1
    6
    Local swelling
    Additional description: Local swelling
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Malaise
    Additional description: Malaise
         subjects affected / exposed
    5 / 304 (1.64%)
    4 / 301 (1.33%)
         occurrences all number
    6
    4
    Non-cardiac chest pain
    Additional description: Non-cardiac chest pain
         subjects affected / exposed
    2 / 304 (0.66%)
    0 / 301 (0.00%)
         occurrences all number
    2
    0
    Oedema peripheral
    Additional description: Oedema peripheral
         subjects affected / exposed
    8 / 304 (2.63%)
    7 / 301 (2.33%)
         occurrences all number
    8
    7
    Pain
    Additional description: Pain
         subjects affected / exposed
    3 / 304 (0.99%)
    1 / 301 (0.33%)
         occurrences all number
    4
    1
    Pyrexia
    Additional description: Pyrexia
         subjects affected / exposed
    1 / 304 (0.33%)
    3 / 301 (1.00%)
         occurrences all number
    1
    6
    Sensation of foreign body
    Additional description: Sensation of foreign body
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Sensation of pressure
    Additional description: Sensation of pressure
         subjects affected / exposed
    0 / 304 (0.00%)
    2 / 301 (0.66%)
         occurrences all number
    0
    2
    Sluggishness
    Additional description: Sluggishness
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Swelling
    Additional description: Swelling
         subjects affected / exposed
    0 / 304 (0.00%)
    2 / 301 (0.66%)
         occurrences all number
    0
    2
    Thirst
    Additional description: Thirst
         subjects affected / exposed
    2 / 304 (0.66%)
    0 / 301 (0.00%)
         occurrences all number
    3
    0
    Vessel puncture site haematoma
    Additional description: Vessel puncture site haematoma
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Immune system disorders
    Drug hypersensitivity
    Additional description: Drug hypersensitivity
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Hypersensitivity
    Additional description: Hypersensitivity
         subjects affected / exposed
    2 / 304 (0.66%)
    0 / 301 (0.00%)
         occurrences all number
    3
    0
    Seasonal allergy
    Additional description: Seasonal allergy
         subjects affected / exposed
    5 / 304 (1.64%)
    4 / 301 (1.33%)
         occurrences all number
    5
    4
    Social circumstances
    Bereavement
    Additional description: Bereavement
         subjects affected / exposed
    0 / 304 (0.00%)
    2 / 301 (0.66%)
         occurrences all number
    0
    2
    Death of companion
    Additional description: Death of companion
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Death of relative
    Additional description: Death of relative
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Ex-tobacco user
    Additional description: Ex-tobacco user
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Family stress
    Additional description: Family stress
         subjects affected / exposed
    2 / 304 (0.66%)
    0 / 301 (0.00%)
         occurrences all number
    2
    0
    Stress at work
    Additional description: Stress at work
         subjects affected / exposed
    3 / 304 (0.99%)
    1 / 301 (0.33%)
         occurrences all number
    3
    1
    Reproductive system and breast disorders
    Breast tenderness
    Additional description: Breast tenderness
         subjects affected / exposed
    0 / 304 (0.00%)
    2 / 301 (0.66%)
         occurrences all number
    0
    3
    Dysmenorrhoea
    Additional description: Dysmenorrhoea
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    2
    Erectile dysfunction
    Additional description: Erectile dysfunction
         subjects affected / exposed
    12 / 304 (3.95%)
    13 / 301 (4.32%)
         occurrences all number
    14
    14
    Gynaecomastia
    Additional description: Gynaecomastia
         subjects affected / exposed
    0 / 304 (0.00%)
    2 / 301 (0.66%)
         occurrences all number
    0
    3
    Menorrhagia
    Additional description: Menorrhagia
         subjects affected / exposed
    0 / 304 (0.00%)
    2 / 301 (0.66%)
         occurrences all number
    0
    3
    Nipple disorder
    Additional description: Nipple disorder
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Prostatic intraepithelial neoplasia
    Additional description: Prostatic intraepithelial neoplasia
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Vaginal haemorrhage
    Additional description: Vaginal haemorrhage
         subjects affected / exposed
    0 / 304 (0.00%)
    2 / 301 (0.66%)
         occurrences all number
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Asthma
    Additional description: Asthma
         subjects affected / exposed
    4 / 304 (1.32%)
    1 / 301 (0.33%)
         occurrences all number
    4
    1
    Choking sensation
    Additional description: Choking sensation
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Cough
    Additional description: Cough
         subjects affected / exposed
    23 / 304 (7.57%)
    24 / 301 (7.97%)
         occurrences all number
    25
    29
    Dry throat
    Additional description: Dry throat
         subjects affected / exposed
    4 / 304 (1.32%)
    2 / 301 (0.66%)
         occurrences all number
    4
    2
    Dyspnoea
    Additional description: Dyspnoea
         subjects affected / exposed
    13 / 304 (4.28%)
    10 / 301 (3.32%)
         occurrences all number
    13
    11
    Dyspnoea exertional
    Additional description: Dyspnoea exertional
         subjects affected / exposed
    2 / 304 (0.66%)
    2 / 301 (0.66%)
         occurrences all number
    3
    6
    Epistaxis
    Additional description: Epistaxis
         subjects affected / exposed
    3 / 304 (0.99%)
    4 / 301 (1.33%)
         occurrences all number
    3
    4
    Increased upper airway secretion
    Additional description: Increased upper airway secretion
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Nasal congestion
    Additional description: Nasal congestion
         subjects affected / exposed
    6 / 304 (1.97%)
    7 / 301 (2.33%)
         occurrences all number
    6
    9
    Nasal discomfort
    Additional description: Nasal discomfort
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Nasal polyps
    Additional description: Nasal polyps
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Oropharyngeal blistering
    Additional description: Oropharyngeal blistering
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Oropharyngeal pain
    Additional description: Oropharyngeal pain
         subjects affected / exposed
    5 / 304 (1.64%)
    9 / 301 (2.99%)
         occurrences all number
    6
    10
    Productive cough
    Additional description: Productive cough
         subjects affected / exposed
    3 / 304 (0.99%)
    1 / 301 (0.33%)
         occurrences all number
    4
    1
    Rhinitis allergic
    Additional description: Rhinitis allergic
         subjects affected / exposed
    2 / 304 (0.66%)
    1 / 301 (0.33%)
         occurrences all number
    2
    1
    Rhinorrhoea
    Additional description: Rhinorrhoea
         subjects affected / exposed
    1 / 304 (0.33%)
    4 / 301 (1.33%)
         occurrences all number
    1
    5
    Sinus congestion
    Additional description: Sinus congestion
         subjects affected / exposed
    1 / 304 (0.33%)
    1 / 301 (0.33%)
         occurrences all number
    1
    1
    Sneezing
    Additional description: Sneezing
         subjects affected / exposed
    1 / 304 (0.33%)
    1 / 301 (0.33%)
         occurrences all number
    1
    1
    Snoring
    Additional description: Snoring
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Throat irritation
    Additional description: Throat irritation
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Wheezing
    Additional description: Wheezing
         subjects affected / exposed
    2 / 304 (0.66%)
    3 / 301 (1.00%)
         occurrences all number
    2
    3
    Psychiatric disorders
    Abnormal dreams
    Additional description: Abnormal dreams
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Agitation
    Additional description: Agitation
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Anxiety
    Additional description: Anxiety
         subjects affected / exposed
    4 / 304 (1.32%)
    6 / 301 (1.99%)
         occurrences all number
    6
    6
    Bradyphrenia
    Additional description: Bradyphrenia
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    2
    Deja vu
    Additional description: Deja vu
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Depressed mood
    Additional description: Depressed mood
         subjects affected / exposed
    4 / 304 (1.32%)
    3 / 301 (1.00%)
         occurrences all number
    4
    3
    Depression
    Additional description: Depression
         subjects affected / exposed
    2 / 304 (0.66%)
    3 / 301 (1.00%)
         occurrences all number
    2
    3
    Disorientation
    Additional description: Disorientation
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Dissociation
    Additional description: Dissociation
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Emotional distress
    Additional description: Emotional distress
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Euphoric mood
    Additional description: Euphoric mood
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Insomnia
    Additional description: Insomnia
         subjects affected / exposed
    6 / 304 (1.97%)
    2 / 301 (0.66%)
         occurrences all number
    7
    2
    Libido decreased
    Additional description: Libido decreased
         subjects affected / exposed
    4 / 304 (1.32%)
    0 / 301 (0.00%)
         occurrences all number
    5
    0
    Loss of libido
    Additional description: Loss of libido
         subjects affected / exposed
    0 / 304 (0.00%)
    2 / 301 (0.66%)
         occurrences all number
    0
    2
    Mood altered
    Additional description: Mood altered
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Mood swings
    Additional description: Mood swings
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Nervousness
    Additional description: Nervousness
         subjects affected / exposed
    2 / 304 (0.66%)
    0 / 301 (0.00%)
         occurrences all number
    2
    0
    Panic attack
    Additional description: Panic attack
         subjects affected / exposed
    2 / 304 (0.66%)
    2 / 301 (0.66%)
         occurrences all number
    2
    2
    Sleep disorder
    Additional description: Sleep disorder
         subjects affected / exposed
    5 / 304 (1.64%)
    4 / 301 (1.33%)
         occurrences all number
    5
    5
    Stress
    Additional description: Stress
         subjects affected / exposed
    3 / 304 (0.99%)
    2 / 301 (0.66%)
         occurrences all number
    3
    2
    Terminal insomnia
    Additional description: Terminal insomnia
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Investigations
    Alanine aminotransferase increased
    Additional description: Alanine aminotransferase increased
         subjects affected / exposed
    1 / 304 (0.33%)
    2 / 301 (0.66%)
         occurrences all number
    1
    2
    Arthroscopy
    Additional description: Arthroscopy
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Aspartate aminotransferase increased
    Additional description: Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 304 (0.33%)
    2 / 301 (0.66%)
         occurrences all number
    1
    3
    Aspiration joint
    Additional description: Aspiration joint
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Biopsy prostate
    Additional description: Biopsy prostate
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Biopsy skin
    Additional description: Biopsy skin
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Blood albumin abnormal
    Additional description: Blood albumin abnormal
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Blood albumin increased
    Additional description: Blood albumin increased
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Blood bicarbonate increased
    Additional description: Blood bicarbonate increased
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Blood calcium increased
    Additional description: Blood calcium increased
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Blood creatinine increased
    Additional description: Blood creatinine increased
         subjects affected / exposed
    1 / 304 (0.33%)
    1 / 301 (0.33%)
         occurrences all number
    1
    2
    Blood glucose abnormal
    Additional description: Blood glucose abnormal
         subjects affected / exposed
    1 / 304 (0.33%)
    2 / 301 (0.66%)
         occurrences all number
    2
    3
    Blood glucose increased
    Additional description: Blood glucose increased
         subjects affected / exposed
    5 / 304 (1.64%)
    4 / 301 (1.33%)
         occurrences all number
    7
    6
    Blood parathyroid hormone increased
    Additional description: Blood parathyroid hormone increased
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Blood potassium abnormal
    Additional description: Blood potassium abnormal
         subjects affected / exposed
    0 / 304 (0.00%)
    3 / 301 (1.00%)
         occurrences all number
    0
    3
    Blood potassium decreased
    Additional description: Blood potassium decreased
         subjects affected / exposed
    4 / 304 (1.32%)
    5 / 301 (1.66%)
         occurrences all number
    5
    6
    Blood pressure decreased
    Additional description: Blood pressure decreased
         subjects affected / exposed
    1 / 304 (0.33%)
    1 / 301 (0.33%)
         occurrences all number
    1
    1
    Blood pressure increased
    Additional description: Blood pressure increased
         subjects affected / exposed
    1 / 304 (0.33%)
    1 / 301 (0.33%)
         occurrences all number
    1
    1
    Blood sodium abnormal
    Additional description: Blood sodium abnormal
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    3
    0
    Blood sodium decreased
    Additional description: Blood sodium decreased
         subjects affected / exposed
    1 / 304 (0.33%)
    1 / 301 (0.33%)
         occurrences all number
    1
    1
    Blood test abnormal
    Additional description: Blood test abnormal
         subjects affected / exposed
    2 / 304 (0.66%)
    6 / 301 (1.99%)
         occurrences all number
    3
    7
    Blood triglycerides increased
    Additional description: Blood triglycerides increased
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Blood urea abnormal
    Additional description: Blood urea abnormal
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Blood urea increased
    Additional description: Blood urea increased
         subjects affected / exposed
    7 / 304 (2.30%)
    4 / 301 (1.33%)
         occurrences all number
    15
    6
    Blood uric acid increased
    Additional description: Blood uric acid increased
         subjects affected / exposed
    4 / 304 (1.32%)
    3 / 301 (1.00%)
         occurrences all number
    7
    4
    Body temperature increased
    Additional description: Body temperature increased
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Colonoscopy
    Additional description: Colonoscopy
         subjects affected / exposed
    2 / 304 (0.66%)
    0 / 301 (0.00%)
         occurrences all number
    2
    0
    Computerised tomogram
    Additional description: Computerised tomogram
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Cystoscopy
    Additional description: Cystoscopy
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Exercise test
    Additional description: Exercise test
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Free prostate-specific antigen increased
    Additional description: Free prostate-specific antigen increased
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Glomerular filtration rate decreased
    Additional description: Glomerular filtration rate decreased
         subjects affected / exposed
    2 / 304 (0.66%)
    0 / 301 (0.00%)
         occurrences all number
    2
    0
    Glycosylated haemoglobin increased
    Additional description: Glycosylated haemoglobin increased
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Haematocrit decreased
    Additional description: Haematocrit decreased
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    2
    0
    Haemoglobin decreased
    Additional description: Haemoglobin decreased
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Heart rate increased
    Additional description: Heart rate increased
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Heart rate irregular
    Additional description: Heart rate irregular
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Intraocular pressure increased
    Additional description: Intraocular pressure increased
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Liver function test abnormal
    Additional description: Liver function test abnormal
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Lymphocyte count abnormal
    Additional description: Lymphocyte count abnormal
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Mean cell haemoglobin concentration abnormal
    Additional description: Mean cell haemoglobin concentration abnormal
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Mean cell haemoglobin increased
    Additional description: Mean cell haemoglobin increased
         subjects affected / exposed
    2 / 304 (0.66%)
    3 / 301 (1.00%)
         occurrences all number
    4
    3
    Mean cell volume increased
    Additional description: Mean cell volume increased
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Myelocyte present
    Additional description: Myelocyte present
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Pulse pressure increased
    Additional description: Pulse pressure increased
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    2
    0
    Red blood cell count decreased
    Additional description: Red blood cell count decreased
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    2
    0
    Red cell distribution width increased
    Additional description: Red cell distribution width increased
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Sigmoidoscopy
    Additional description: Sigmoidoscopy
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Urine colour abnormal
    Additional description: Urine colour abnormal
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Urine potassium increased
    Additional description: Urine potassium increased
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Urine sodium increased
    Additional description: Urine sodium increased
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Weight increased
    Additional description: Weight increased
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    White blood cell count increased
    Additional description: White blood cell count increased
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Arthropod bite
    Additional description: Arthropod bite
         subjects affected / exposed
    1 / 304 (0.33%)
    4 / 301 (1.33%)
         occurrences all number
    1
    5
    Arthropod sting
    Additional description: Arthropod sting
         subjects affected / exposed
    2 / 304 (0.66%)
    1 / 301 (0.33%)
         occurrences all number
    2
    1
    Back injury
    Additional description: Back injury
         subjects affected / exposed
    0 / 304 (0.00%)
    2 / 301 (0.66%)
         occurrences all number
    0
    2
    Cartilage injury
    Additional description: Cartilage injury
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Contusion
    Additional description: Contusion
         subjects affected / exposed
    3 / 304 (0.99%)
    1 / 301 (0.33%)
         occurrences all number
    3
    1
    Ear injury
    Additional description: Ear injury
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Epicondylitis
    Additional description: Epicondylitis
         subjects affected / exposed
    2 / 304 (0.66%)
    0 / 301 (0.00%)
         occurrences all number
    2
    0
    Excoriation
    Additional description: Excoriation
         subjects affected / exposed
    0 / 304 (0.00%)
    2 / 301 (0.66%)
         occurrences all number
    0
    2
    Eye injury
    Additional description: Eye injury
         subjects affected / exposed
    2 / 304 (0.66%)
    0 / 301 (0.00%)
         occurrences all number
    2
    0
    Fall
    Additional description: Fall
         subjects affected / exposed
    4 / 304 (1.32%)
    5 / 301 (1.66%)
         occurrences all number
    6
    6
    Fibula fracture
    Additional description: Fibula fracture
         subjects affected / exposed
    0 / 304 (0.00%)
    2 / 301 (0.66%)
         occurrences all number
    0
    2
    Head injury
    Additional description: Head injury
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Joint dislocation
    Additional description: Joint dislocation
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Joint injury
    Additional description: Joint injury
         subjects affected / exposed
    2 / 304 (0.66%)
    0 / 301 (0.00%)
         occurrences all number
    2
    0
    Joint sprain
    Additional description: Joint sprain
         subjects affected / exposed
    2 / 304 (0.66%)
    0 / 301 (0.00%)
         occurrences all number
    2
    0
    Ligament injury
    Additional description: Ligament injury
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Limb injury
    Additional description: Limb injury
         subjects affected / exposed
    0 / 304 (0.00%)
    4 / 301 (1.33%)
         occurrences all number
    0
    4
    Medication error
    Additional description: Medication error
         subjects affected / exposed
    2 / 304 (0.66%)
    0 / 301 (0.00%)
         occurrences all number
    3
    0
    Muscle injury
    Additional description: Muscle injury
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Muscle rupture
    Additional description: Muscle rupture
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Muscle strain
    Additional description: Muscle strain
         subjects affected / exposed
    3 / 304 (0.99%)
    4 / 301 (1.33%)
         occurrences all number
    3
    4
    Neck injury
    Additional description: Neck injury
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Pelvic fracture
    Additional description: Pelvic fracture
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Procedural pain
    Additional description: Procedural pain
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Rib fracture
    Additional description: Rib fracture
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Skin laceration
    Additional description: Skin laceration
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Soft tissue injury
    Additional description: Soft tissue injury
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Spinal column injury
    Additional description: Spinal column injury
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Tendon injury
    Additional description: Tendon injury
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Tendon rupture
    Additional description: Tendon rupture
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Thermal burn
    Additional description: Thermal burn
         subjects affected / exposed
    1 / 304 (0.33%)
    1 / 301 (0.33%)
         occurrences all number
    1
    1
    Tooth fracture
    Additional description: Tooth fracture
         subjects affected / exposed
    2 / 304 (0.66%)
    0 / 301 (0.00%)
         occurrences all number
    2
    0
    Upper limb fracture
    Additional description: Upper limb fracture
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Wound complication
    Additional description: Wound complication
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Wrist fracture
    Additional description: Wrist fracture
         subjects affected / exposed
    0 / 304 (0.00%)
    3 / 301 (1.00%)
         occurrences all number
    0
    3
    Cardiac disorders
    Aortic valve incompetence
    Additional description: Aortic valve incompetence
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Arrhythmia
    Additional description: Arrhythmia
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Atrial fibrillation
    Additional description: Atrial fibrillation
         subjects affected / exposed
    0 / 304 (0.00%)
    2 / 301 (0.66%)
         occurrences all number
    0
    2
    Bradycardia
    Additional description: Bradycardia
         subjects affected / exposed
    2 / 304 (0.66%)
    3 / 301 (1.00%)
         occurrences all number
    2
    3
    Cardiac flutter
    Additional description: Cardiac flutter
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Extrasystoles
    Additional description: Extrasystoles
         subjects affected / exposed
    0 / 304 (0.00%)
    2 / 301 (0.66%)
         occurrences all number
    0
    2
    Myocardial ischaemia
    Additional description: Myocardial ischaemia
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Palpitations
    Additional description: Palpitations
         subjects affected / exposed
    13 / 304 (4.28%)
    13 / 301 (4.32%)
         occurrences all number
    15
    15
    Tachycardia
    Additional description: Tachycardia
         subjects affected / exposed
    1 / 304 (0.33%)
    3 / 301 (1.00%)
         occurrences all number
    1
    14
    Nervous system disorders
    Altered state of consciousness
    Additional description: Altered state of consciousness
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Amnesia
    Additional description: Amnesia
         subjects affected / exposed
    1 / 304 (0.33%)
    1 / 301 (0.33%)
         occurrences all number
    1
    1
    Aphasia
    Additional description: Aphasia
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Aphonia
    Additional description: Aphonia
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Aura
    Additional description: Aura
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Balance disorder
    Additional description: Balance disorder
         subjects affected / exposed
    3 / 304 (0.99%)
    1 / 301 (0.33%)
         occurrences all number
    3
    1
    Burning sensation
    Additional description: Burning sensation
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Cerebral haemorrhage
    Additional description: Cerebral haemorrhage
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Clumsiness
    Additional description: Clumsiness
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Coordination abnormal
    Additional description: Coordination abnormal
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Crying
    Additional description: Crying
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Disturbance in attention
    Additional description: Disturbance in attention
         subjects affected / exposed
    1 / 304 (0.33%)
    2 / 301 (0.66%)
         occurrences all number
    1
    2
    Dizziness
    Additional description: Dizziness
         subjects affected / exposed
    73 / 304 (24.01%)
    62 / 301 (20.60%)
         occurrences all number
    98
    80
    Dizziness exertional
    Additional description: Dizziness exertional
         subjects affected / exposed
    0 / 304 (0.00%)
    3 / 301 (1.00%)
         occurrences all number
    0
    3
    Dizziness postural
    Additional description: Dizziness postural
         subjects affected / exposed
    16 / 304 (5.26%)
    12 / 301 (3.99%)
         occurrences all number
    18
    18
    Drug withdrawal headache
    Additional description: Drug withdrawal headache
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Dysaesthesia
    Additional description: Dysaesthesia
         subjects affected / exposed
    1 / 304 (0.33%)
    2 / 301 (0.66%)
         occurrences all number
    1
    2
    Dysgeusia
    Additional description: Dysgeusia
         subjects affected / exposed
    1 / 304 (0.33%)
    1 / 301 (0.33%)
         occurrences all number
    1
    1
    Head discomfort
    Additional description: Head discomfort
         subjects affected / exposed
    0 / 304 (0.00%)
    2 / 301 (0.66%)
         occurrences all number
    0
    2
    Headache
    Additional description: Headache
         subjects affected / exposed
    51 / 304 (16.78%)
    59 / 301 (19.60%)
         occurrences all number
    72
    88
    Hypoaesthesia
    Additional description: Hypoaesthesia
         subjects affected / exposed
    6 / 304 (1.97%)
    5 / 301 (1.66%)
         occurrences all number
    6
    10
    Lethargy
    Additional description: Lethargy
         subjects affected / exposed
    20 / 304 (6.58%)
    22 / 301 (7.31%)
         occurrences all number
    20
    24
    Memory impairment
    Additional description: Memory impairment
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Migraine
    Additional description: Migraine
         subjects affected / exposed
    6 / 304 (1.97%)
    7 / 301 (2.33%)
         occurrences all number
    6
    8
    Migraine with aura
    Additional description: Migraine with aura
         subjects affected / exposed
    1 / 304 (0.33%)
    2 / 301 (0.66%)
         occurrences all number
    1
    2
    Nerve compression
    Additional description: Nerve compression
         subjects affected / exposed
    1 / 304 (0.33%)
    2 / 301 (0.66%)
         occurrences all number
    1
    2
    Neuralgia
    Additional description: Neuralgia
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Paraesthesia
    Additional description: Paraesthesia
         subjects affected / exposed
    17 / 304 (5.59%)
    12 / 301 (3.99%)
         occurrences all number
    19
    13
    Poor quality sleep
    Additional description: Poor quality sleep
         subjects affected / exposed
    0 / 304 (0.00%)
    2 / 301 (0.66%)
         occurrences all number
    0
    3
    Presyncope
    Additional description: Presyncope
         subjects affected / exposed
    1 / 304 (0.33%)
    1 / 301 (0.33%)
         occurrences all number
    3
    1
    Restless legs syndrome
    Additional description: Restless legs syndrome
         subjects affected / exposed
    0 / 304 (0.00%)
    2 / 301 (0.66%)
         occurrences all number
    0
    2
    Sciatica
    Additional description: Sciatica
         subjects affected / exposed
    6 / 304 (1.97%)
    5 / 301 (1.66%)
         occurrences all number
    6
    5
    Sensory disturbance
    Additional description: Sensory disturbance
         subjects affected / exposed
    0 / 304 (0.00%)
    3 / 301 (1.00%)
         occurrences all number
    0
    3
    Somnolence
    Additional description: Somnolence
         subjects affected / exposed
    1 / 304 (0.33%)
    1 / 301 (0.33%)
         occurrences all number
    1
    1
    Speech disorder
    Additional description: Speech disorder
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Syncope
    Additional description: Syncope
         subjects affected / exposed
    5 / 304 (1.64%)
    4 / 301 (1.33%)
         occurrences all number
    5
    4
    Tension headache
    Additional description: Tension headache
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Tremor
    Additional description: Tremor
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    VIIth nerve paralysis
    Additional description: VIIth nerve paralysis
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Anaemia
    Additional description: Anaemia
         subjects affected / exposed
    2 / 304 (0.66%)
    0 / 301 (0.00%)
         occurrences all number
    2
    0
    Ear and labyrinth disorders
    Deafness unilateral
    Additional description: Deafness unilateral
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Ear congestion
    Additional description: Ear congestion
         subjects affected / exposed
    0 / 304 (0.00%)
    2 / 301 (0.66%)
         occurrences all number
    0
    2
    Ear discomfort
    Additional description: Ear discomfort
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Ear disorder
    Additional description: Ear disorder
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Eustachian tube dysfunction
    Additional description: Eustachian tube dysfunction
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Tinnitus
    Additional description: Tinnitus
         subjects affected / exposed
    2 / 304 (0.66%)
    4 / 301 (1.33%)
         occurrences all number
    2
    5
    Tympanic membrane perforation
    Additional description: Tympanic membrane perforation
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Vertigo
    Additional description: Vertigo
         subjects affected / exposed
    7 / 304 (2.30%)
    1 / 301 (0.33%)
         occurrences all number
    7
    6
    Vertigo positional
    Additional description: Vertigo positional
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Blepharitis
    Additional description: Blepharitis
         subjects affected / exposed
    3 / 304 (0.99%)
    0 / 301 (0.00%)
         occurrences all number
    4
    0
    Conjunctivitis
    Additional description: Conjunctivitis
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Conjunctival haemorrhage
    Additional description: Conjunctival haemorrhage
         subjects affected / exposed
    1 / 304 (0.33%)
    3 / 301 (1.00%)
         occurrences all number
    1
    3
    Conjunctivitis allergic
    Additional description: Conjunctivitis allergic
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Dry eye
    Additional description: Dry eye
         subjects affected / exposed
    3 / 304 (0.99%)
    2 / 301 (0.66%)
         occurrences all number
    3
    2
    Episcleritis
    Additional description: Episcleritis
         subjects affected / exposed
    0 / 304 (0.00%)
    3 / 301 (1.00%)
         occurrences all number
    0
    3
    Eye disorder
    Additional description: Eye disorder
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Eye irritation
    Additional description: Eye irritation
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Eye pain
    Additional description: Eye pain
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Eye pruritus
    Additional description: Eye pruritus
         subjects affected / exposed
    1 / 304 (0.33%)
    1 / 301 (0.33%)
         occurrences all number
    1
    1
    Eye swelling
    Additional description: Eye swelling
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Eyelid margin crusting
    Additional description: Eyelid margin crusting
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Iritis
    Additional description: Iritis
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Macular degeneration
    Additional description: Macular degeneration
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Ocular hyperaemia
    Additional description: Ocular hyperaemia
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Retinal tear
    Additional description: Retinal tear
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Scleritis
    Additional description: Scleritis
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Vision blurred
    Additional description: Vision blurred
         subjects affected / exposed
    3 / 304 (0.99%)
    2 / 301 (0.66%)
         occurrences all number
    3
    2
    Visual impairment
    Additional description: Visual impairment
         subjects affected / exposed
    5 / 304 (1.64%)
    3 / 301 (1.00%)
         occurrences all number
    5
    3
    Vitreous floaters
    Additional description: Vitreous floaters
         subjects affected / exposed
    0 / 304 (0.00%)
    2 / 301 (0.66%)
         occurrences all number
    0
    2
    Gastrointestinal disorders
    Abdominal discomfort
    Additional description: Abdominal discomfort
         subjects affected / exposed
    10 / 304 (3.29%)
    9 / 301 (2.99%)
         occurrences all number
    12
    9
    Abdominal distension
    Additional description: Abdominal distension
         subjects affected / exposed
    6 / 304 (1.97%)
    5 / 301 (1.66%)
         occurrences all number
    6
    5
    Abdominal pain
    Additional description: Abdominal pain
         subjects affected / exposed
    4 / 304 (1.32%)
    7 / 301 (2.33%)
         occurrences all number
    4
    9
    Abdominal pain lower
    Additional description: Abdominal pain lower
         subjects affected / exposed
    1 / 304 (0.33%)
    4 / 301 (1.33%)
         occurrences all number
    1
    4
    Abdominal pain upper
    Additional description: Abdominal pain upper
         subjects affected / exposed
    4 / 304 (1.32%)
    3 / 301 (1.00%)
         occurrences all number
    4
    3
    Anal fissure
    Additional description: Anal fissure
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Change of bowel habit
    Additional description: Change of bowel habit
         subjects affected / exposed
    2 / 304 (0.66%)
    0 / 301 (0.00%)
         occurrences all number
    2
    0
    Constipation
    Additional description: Constipation
         subjects affected / exposed
    10 / 304 (3.29%)
    3 / 301 (1.00%)
         occurrences all number
    10
    3
    Dental discomfort
    Additional description: Dental discomfort
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Diarrhoea
    Additional description: Diarrhoea
         subjects affected / exposed
    20 / 304 (6.58%)
    13 / 301 (4.32%)
         occurrences all number
    21
    13
    Diverticulum
    Additional description: Diverticulum
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Dry mouth
    Additional description: Dry mouth
         subjects affected / exposed
    4 / 304 (1.32%)
    5 / 301 (1.66%)
         occurrences all number
    4
    5
    Dyspepsia
    Additional description: Dyspepsia
         subjects affected / exposed
    16 / 304 (5.26%)
    3 / 301 (1.00%)
         occurrences all number
    18
    3
    Dysphagia
    Additional description: Dysphagia
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Faeces discoloured
    Additional description: Faeces discoloured
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Flatulence
    Additional description: Flatulence
         subjects affected / exposed
    3 / 304 (0.99%)
    0 / 301 (0.00%)
         occurrences all number
    3
    0
    Food poisoning
    Additional description: Food poisoning
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Frequent bowel movements
    Additional description: Frequent bowel movements
         subjects affected / exposed
    2 / 304 (0.66%)
    0 / 301 (0.00%)
         occurrences all number
    2
    0
    Gastrointestinal haemorrhage
    Additional description: Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal motility disorder
    Additional description: Gastrointestinal motility disorder
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Gastrooesophageal reflux disease
    Additional description: Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 304 (0.33%)
    3 / 301 (1.00%)
         occurrences all number
    1
    3
    Gingival pain
    Additional description: Gingival pain
         subjects affected / exposed
    0 / 304 (0.00%)
    3 / 301 (1.00%)
         occurrences all number
    0
    3
    Gingival recession
    Additional description: Gingival recession
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Haematochezia
    Additional description: Haematochezia
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Haemorrhoids
    Additional description: Haemorrhoids
         subjects affected / exposed
    2 / 304 (0.66%)
    0 / 301 (0.00%)
         occurrences all number
    2
    0
    Hiatus hernia
    Additional description: Hiatus hernia
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Irritable bowel syndrome
    Additional description: Irritable bowel syndrome
         subjects affected / exposed
    1 / 304 (0.33%)
    1 / 301 (0.33%)
         occurrences all number
    1
    1
    Lip dry
    Additional description: Lip dry
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Lip swelling
    Additional description: Lip swelling
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Nausea
    Additional description: Nausea
         subjects affected / exposed
    20 / 304 (6.58%)
    14 / 301 (4.65%)
         occurrences all number
    26
    16
    Oral pain
    Additional description: Oral pain
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Proctalgia
    Additional description: Proctalgia
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Rectal haemorrhage
    Additional description: Rectal haemorrhage
         subjects affected / exposed
    6 / 304 (1.97%)
    3 / 301 (1.00%)
         occurrences all number
    7
    3
    Tongue coated
    Additional description: Tongue coated
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Tongue geographic
    Additional description: Tongue geographic
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Tongue ulceration
    Additional description: Tongue ulceration
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Tooth loss
    Additional description: Tooth loss
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Toothache
    Additional description: Toothache
         subjects affected / exposed
    2 / 304 (0.66%)
    2 / 301 (0.66%)
         occurrences all number
    2
    2
    Vomiting
    Additional description: Vomiting
         subjects affected / exposed
    14 / 304 (4.61%)
    9 / 301 (2.99%)
         occurrences all number
    14
    10
    Hepatobiliary disorders
    Biliary dilatation
    Additional description: Biliary dilatation
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Cholelithiasis
    Additional description: Cholelithiasis
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Hepatic steatosis
    Additional description: Hepatic steatosis
         subjects affected / exposed
    1 / 304 (0.33%)
    2 / 301 (0.66%)
         occurrences all number
    1
    2
    Skin and subcutaneous tissue disorders
    Actinic keratosis
    Additional description: Actinic keratosis
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    2
    0
    Alopecia
    Additional description: Alopecia
         subjects affected / exposed
    1 / 304 (0.33%)
    3 / 301 (1.00%)
         occurrences all number
    1
    3
    Blood blister
    Additional description: Blood blister
         subjects affected / exposed
    2 / 304 (0.66%)
    0 / 301 (0.00%)
         occurrences all number
    2
    0
    Dandruff
    Additional description: Dandruff
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Dermal cyst
    Additional description: Dermal cyst
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Dermatitis
    Additional description: Dermatitis
         subjects affected / exposed
    1 / 304 (0.33%)
    1 / 301 (0.33%)
         occurrences all number
    1
    1
    Dry skin
    Additional description: Dry skin
         subjects affected / exposed
    1 / 304 (0.33%)
    2 / 301 (0.66%)
         occurrences all number
    1
    2
    Eczema
    Additional description: Eczema
         subjects affected / exposed
    1 / 304 (0.33%)
    1 / 301 (0.33%)
         occurrences all number
    1
    1
    Hair texture abnormal
    Additional description: Hair texture abnormal
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Heat rash
    Additional description: Heat rash
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Hyperhidrosis
    Additional description: Hyperhidrosis
         subjects affected / exposed
    4 / 304 (1.32%)
    7 / 301 (2.33%)
         occurrences all number
    5
    7
    Increased tendency to bruise
    Additional description: Increased tendency to bruise
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Intertrigo
    Additional description: Intertrigo
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Night sweats
    Additional description: Night sweats
         subjects affected / exposed
    0 / 304 (0.00%)
    2 / 301 (0.66%)
         occurrences all number
    0
    2
    Pain of skin
    Additional description: Pain of skin
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    2
    0
    Papule
    Additional description: Papule
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Pemphigus
    Additional description: Pemphigus
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    2
    0
    Petechiae
    Additional description: Petechiae
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Pruritus
    Additional description: Pruritus
         subjects affected / exposed
    6 / 304 (1.97%)
    11 / 301 (3.65%)
         occurrences all number
    6
    11
    Pruritus generalised
    Additional description: Pruritus generalised
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Psoriasis
    Additional description: Psoriasis
         subjects affected / exposed
    2 / 304 (0.66%)
    0 / 301 (0.00%)
         occurrences all number
    2
    0
    Rash
    Additional description: Rash
         subjects affected / exposed
    12 / 304 (3.95%)
    16 / 301 (5.32%)
         occurrences all number
    12
    22
    Rash erythematous
    Additional description: Rash erythematous
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Rash generalised
    Additional description: Rash generalised
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Rash macular
    Additional description: Rash macular
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Rash papular
    Additional description: Rash papular
         subjects affected / exposed
    2 / 304 (0.66%)
    0 / 301 (0.00%)
         occurrences all number
    2
    0
    Rash pruritic
    Additional description: Rash pruritic
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Rosacea
    Additional description: Rosacea
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Skin burning sensation
    Additional description: Skin burning sensation
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Skin discolouration
    Additional description: Skin discolouration
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    5
    Skin disorder
    Additional description: Skin disorder
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Skin irritation
    Additional description: Skin irritation
         subjects affected / exposed
    1 / 304 (0.33%)
    1 / 301 (0.33%)
         occurrences all number
    1
    2
    Skin lesion
    Additional description: Skin lesion
         subjects affected / exposed
    1 / 304 (0.33%)
    2 / 301 (0.66%)
         occurrences all number
    1
    2
    Skin plaque
    Additional description: Skin plaque
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Skin sensitisation
    Additional description: Skin sensitisation
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Stasis dermatitis
    Additional description: Stasis dermatitis
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Swelling face
    Additional description: Swelling face
         subjects affected / exposed
    2 / 304 (0.66%)
    1 / 301 (0.33%)
         occurrences all number
    2
    1
    Urticaria
    Additional description: Urticaria
         subjects affected / exposed
    0 / 304 (0.00%)
    2 / 301 (0.66%)
         occurrences all number
    0
    2
    Renal and urinary disorders
    Bladder discomfort
    Additional description: Bladder discomfort
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Dysuria
    Additional description: Dysuria
         subjects affected / exposed
    1 / 304 (0.33%)
    3 / 301 (1.00%)
         occurrences all number
    1
    4
    Glycosuria
    Additional description: Glycosuria
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Haematuria
    Additional description: Haematuria
         subjects affected / exposed
    1 / 304 (0.33%)
    2 / 301 (0.66%)
         occurrences all number
    1
    2
    Micturition urgency
    Additional description: Micturition urgency
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Nephrolithiasis
    Additional description: Nephrolithiasis
         subjects affected / exposed
    1 / 304 (0.33%)
    1 / 301 (0.33%)
         occurrences all number
    1
    1
    Nocturia
    Additional description: Nocturia
         subjects affected / exposed
    6 / 304 (1.97%)
    1 / 301 (0.33%)
         occurrences all number
    6
    1
    Oliguria
    Additional description: Oliguria
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Pollakiuria
    Additional description: Pollakiuria
         subjects affected / exposed
    10 / 304 (3.29%)
    12 / 301 (3.99%)
         occurrences all number
    11
    12
    Polyuria
    Additional description: Polyuria
         subjects affected / exposed
    1 / 304 (0.33%)
    2 / 301 (0.66%)
         occurrences all number
    1
    2
    Proteinuria
    Additional description: Proteinuria
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Urge incontinence
    Additional description: Urge incontinence
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Urinary hesitation
    Additional description: Urinary hesitation
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Urinary tract disorder
    Additional description: Urinary tract disorder
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Urine abnormality
    Additional description: Urine abnormality
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Urine flow decreased
    Additional description: Urine flow decreased
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Urine odour abnormal
    Additional description: Urine odour abnormal
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Endocrine disorders
    Hypothyroidism
    Additional description: Hypothyroidism
         subjects affected / exposed
    1 / 304 (0.33%)
    1 / 301 (0.33%)
         occurrences all number
    1
    1
    Musculoskeletal and connective tissue disorders
    Ankylosing spondylitis
    Additional description: Ankylosing spondylitis
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Arthralgia
    Additional description: Arthralgia
         subjects affected / exposed
    17 / 304 (5.59%)
    19 / 301 (6.31%)
         occurrences all number
    17
    27
    Arthritis
    Additional description: Arthritis
         subjects affected / exposed
    4 / 304 (1.32%)
    0 / 301 (0.00%)
         occurrences all number
    4
    0
    Arthropathy
    Additional description: Arthropathy
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Back disorder
    Additional description: Back disorder
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Back pain
    Additional description: Back pain
         subjects affected / exposed
    14 / 304 (4.61%)
    21 / 301 (6.98%)
         occurrences all number
    15
    23
    Bunion
    Additional description: Bunion
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Costochondritis
    Additional description: Costochondritis
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Dupuytren's contracture
    Additional description: Dupuytren's contracture
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Fibromyalgia
    Additional description: Fibromyalgia
         subjects affected / exposed
    1 / 304 (0.33%)
    1 / 301 (0.33%)
         occurrences all number
    1
    2
    Flank pain
    Additional description: Flank pain
         subjects affected / exposed
    1 / 304 (0.33%)
    2 / 301 (0.66%)
         occurrences all number
    2
    3
    Groin pain
    Additional description: Groin pain
         subjects affected / exposed
    2 / 304 (0.66%)
    0 / 301 (0.00%)
         occurrences all number
    2
    0
    Joint crepitation
    Additional description: Joint crepitation
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Joint stiffness
    Additional description: Joint stiffness
         subjects affected / exposed
    0 / 304 (0.00%)
    2 / 301 (0.66%)
         occurrences all number
    0
    2
    Joint swelling
    Additional description: Joint swelling
         subjects affected / exposed
    14 / 304 (4.61%)
    11 / 301 (3.65%)
         occurrences all number
    15
    16
    Limb discomfort
    Additional description: Limb discomfort
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Lumbar spinal stenosis
    Additional description: Lumbar spinal stenosis
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Muscle fatigue
    Additional description: Muscle fatigue
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Muscle spasms
    Additional description: Muscle spasms
         subjects affected / exposed
    15 / 304 (4.93%)
    11 / 301 (3.65%)
         occurrences all number
    18
    15
    Muscle tightness
    Additional description: Muscle tightness
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Muscular weakness
    Additional description: Muscular weakness
         subjects affected / exposed
    1 / 304 (0.33%)
    1 / 301 (0.33%)
         occurrences all number
    1
    1
    Musculoskeletal chest pain
    Additional description: Musculoskeletal chest pain
         subjects affected / exposed
    1 / 304 (0.33%)
    4 / 301 (1.33%)
         occurrences all number
    1
    4
    Musculoskeletal pain
    Additional description: Musculoskeletal pain
         subjects affected / exposed
    3 / 304 (0.99%)
    14 / 301 (4.65%)
         occurrences all number
    3
    17
    Musculoskeletal stiffness
    Additional description: Musculoskeletal stiffness
         subjects affected / exposed
    3 / 304 (0.99%)
    1 / 301 (0.33%)
         occurrences all number
    3
    1
    Myalgia
    Additional description: Myalgia
         subjects affected / exposed
    3 / 304 (0.99%)
    5 / 301 (1.66%)
         occurrences all number
    3
    5
    Neck pain
    Additional description: Neck pain
         subjects affected / exposed
    6 / 304 (1.97%)
    6 / 301 (1.99%)
         occurrences all number
    6
    6
    Osteoarthritis
    Additional description: Osteoarthritis
         subjects affected / exposed
    0 / 304 (0.00%)
    2 / 301 (0.66%)
         occurrences all number
    0
    2
    Osteoporosis
    Additional description: Osteoporosis
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Pain in extremity
    Additional description: Pain in extremity
         subjects affected / exposed
    21 / 304 (6.91%)
    14 / 301 (4.65%)
         occurrences all number
    25
    16
    Pain in jaw
    Additional description: Pain in jaw
         subjects affected / exposed
    1 / 304 (0.33%)
    1 / 301 (0.33%)
         occurrences all number
    1
    1
    Periarthritis
    Additional description: Periarthritis
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Pubic pain
    Additional description: Pubic pain
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Rotator cuff syndrome
    Additional description: Rotator cuff syndrome
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Sensation of heaviness
    Additional description: Sensation of heaviness
         subjects affected / exposed
    0 / 304 (0.00%)
    3 / 301 (1.00%)
         occurrences all number
    0
    3
    Spinal osteoarthritis
    Additional description: Spinal osteoarthritis
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Synovial cyst
    Additional description: Synovial cyst
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Tendonitis
    Additional description: Tendonitis
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Trigger finger
    Additional description: Trigger finger
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Infections and infestations
    Acute sinusitis
    Additional description: Acute sinusitis
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Alveolar osteitis
    Additional description: Alveolar osteitis
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Bacterial infection
    Additional description: Bacterial infection
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Bronchitis
    Additional description: Bronchitis
         subjects affected / exposed
    0 / 304 (0.00%)
    2 / 301 (0.66%)
         occurrences all number
    0
    2
    Candidiasis
    Additional description: Candidiasis
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Cellulitis
    Additional description: Cellulitis
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Cystitis
    Additional description: Cystitis
         subjects affected / exposed
    0 / 304 (0.00%)
    2 / 301 (0.66%)
         occurrences all number
    0
    2
    Dermatitis infected
    Additional description: Dermatitis infected
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Diverticulitis
    Additional description: Diverticulitis
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Ear infection
    Additional description: Ear infection
         subjects affected / exposed
    2 / 304 (0.66%)
    3 / 301 (1.00%)
         occurrences all number
    2
    4
    Eye infection
    Additional description: Eye infection
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Fungal infection
    Additional description: Fungal infection
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Furuncle
    Additional description: Furuncle
         subjects affected / exposed
    1 / 304 (0.33%)
    1 / 301 (0.33%)
         occurrences all number
    1
    1
    Gastroenteritis
    Additional description: Gastroenteritis
         subjects affected / exposed
    0 / 304 (0.00%)
    2 / 301 (0.66%)
         occurrences all number
    0
    2
    Gastroenteritis viral
    Additional description: Gastroenteritis viral
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    2
    Gastrointestinal viral infection
    Additional description: Gastrointestinal viral infection
         subjects affected / exposed
    2 / 304 (0.66%)
    1 / 301 (0.33%)
         occurrences all number
    2
    1
    Gingival abscess
    Additional description: Gingival abscess
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Gingival infection
    Additional description: Gingival infection
         subjects affected / exposed
    1 / 304 (0.33%)
    1 / 301 (0.33%)
         occurrences all number
    1
    1
    Herpes zoster
    Additional description: Herpes zoster
         subjects affected / exposed
    1 / 304 (0.33%)
    2 / 301 (0.66%)
         occurrences all number
    1
    4
    Infected bites
    Additional description: Infected bites
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Influenza
    Additional description: Influenza
         subjects affected / exposed
    10 / 304 (3.29%)
    9 / 301 (2.99%)
         occurrences all number
    10
    9
    Labyrinthitis
    Additional description: Labyrinthitis
         subjects affected / exposed
    4 / 304 (1.32%)
    1 / 301 (0.33%)
         occurrences all number
    4
    1
    Laryngitis
    Additional description: Laryngitis
         subjects affected / exposed
    1 / 304 (0.33%)
    4 / 301 (1.33%)
         occurrences all number
    1
    4
    Localised infection
    Additional description: Localised infection
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Lower respiratory tract infection
    Additional description: Lower respiratory tract infection
         subjects affected / exposed
    9 / 304 (2.96%)
    11 / 301 (3.65%)
         occurrences all number
    10
    12
    Lyme disease
    Additional description: Lyme disease
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Mastoiditis
    Additional description: Mastoiditis
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Myringitis
    Additional description: Myringitis
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Nail infection
    Additional description: Nail infection
         subjects affected / exposed
    1 / 304 (0.33%)
    1 / 301 (0.33%)
         occurrences all number
    1
    1
    Nasopharyngitis
    Additional description: Nasopharyngitis
         subjects affected / exposed
    48 / 304 (15.79%)
    39 / 301 (12.96%)
         occurrences all number
    61
    51
    Oral candidiasis
    Additional description: Oral candidiasis
         subjects affected / exposed
    2 / 304 (0.66%)
    1 / 301 (0.33%)
         occurrences all number
    2
    1
    Oral infection
    Additional description: Oral infection
         subjects affected / exposed
    1 / 304 (0.33%)
    1 / 301 (0.33%)
         occurrences all number
    1
    1
    Otitis externa
    Additional description: Otitis externa
         subjects affected / exposed
    0 / 304 (0.00%)
    2 / 301 (0.66%)
         occurrences all number
    0
    2
    Otitis media
    Additional description: Otitis media
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Pharyngitis
    Additional description: Pharyngitis
         subjects affected / exposed
    4 / 304 (1.32%)
    4 / 301 (1.33%)
         occurrences all number
    4
    5
    Pilonidal cyst
    Additional description: Pilonidal cyst
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Prostate infection
    Additional description: Prostate infection
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Respiratory tract infection
    Additional description: Respiratory tract infection
         subjects affected / exposed
    1 / 304 (0.33%)
    1 / 301 (0.33%)
         occurrences all number
    1
    1
    Rhinitis
    Additional description: Rhinitis
         subjects affected / exposed
    8 / 304 (2.63%)
    8 / 301 (2.66%)
         occurrences all number
    8
    10
    Sialoadenitis
    Additional description: Sialoadenitis
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Sinusitis
    Additional description: Sinusitis
         subjects affected / exposed
    3 / 304 (0.99%)
    5 / 301 (1.66%)
         occurrences all number
    3
    5
    Skin infection
    Additional description: Skin infection
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Subcutaneous abscess
    Additional description: Subcutaneous abscess
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Tinea pedis
    Additional description: Tinea pedis
         subjects affected / exposed
    2 / 304 (0.66%)
    0 / 301 (0.00%)
         occurrences all number
    2
    0
    Tooth abscess
    Additional description: Tooth abscess
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Tooth infection
    Additional description: Tooth infection
         subjects affected / exposed
    3 / 304 (0.99%)
    3 / 301 (1.00%)
         occurrences all number
    4
    3
    Upper respiratory tract infection
    Additional description: Upper respiratory tract infection
         subjects affected / exposed
    13 / 304 (4.28%)
    13 / 301 (4.32%)
         occurrences all number
    17
    21
    Urinary tract infection
    Additional description: Urinary tract infection
         subjects affected / exposed
    8 / 304 (2.63%)
    7 / 301 (2.33%)
         occurrences all number
    13
    8
    Viral infection
    Additional description: Viral infection
         subjects affected / exposed
    11 / 304 (3.62%)
    4 / 301 (1.33%)
         occurrences all number
    12
    4
    Viral pharyngitis
    Additional description: Viral pharyngitis
         subjects affected / exposed
    1 / 304 (0.33%)
    1 / 301 (0.33%)
         occurrences all number
    1
    1
    Viral upper respiratory tract infection
    Additional description: Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 304 (0.00%)
    2 / 301 (0.66%)
         occurrences all number
    0
    2
    Vulvovaginal candidiasis
    Additional description: Vulvovaginal candidiasis
         subjects affected / exposed
    2 / 304 (0.66%)
    0 / 301 (0.00%)
         occurrences all number
    2
    0
    Metabolism and nutrition disorders
    Decreased appetite
    Additional description: Decreased appetite
         subjects affected / exposed
    3 / 304 (0.99%)
    2 / 301 (0.66%)
         occurrences all number
    3
    2
    Dehydration
    Additional description: Dehydration
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Diabetes mellitus inadequate control
    Additional description: Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 304 (0.33%)
    2 / 301 (0.66%)
         occurrences all number
    1
    2
    Fluid retention
    Additional description: Fluid retention
         subjects affected / exposed
    2 / 304 (0.66%)
    0 / 301 (0.00%)
         occurrences all number
    2
    0
    Glucose tolerance impaired
    Additional description: Glucose tolerance impaired
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Gout
    Additional description: Gout
         subjects affected / exposed
    3 / 304 (0.99%)
    2 / 301 (0.66%)
         occurrences all number
    3
    3
    Hypercalcaemia
    Additional description: Hypercalcaemia
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Hypercholesterolaemia
    Additional description: Hypercholesterolaemia
         subjects affected / exposed
    1 / 304 (0.33%)
    1 / 301 (0.33%)
         occurrences all number
    1
    1
    Hyperglycaemia
    Additional description: Hyperglycaemia
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Hypocalcaemia
    Additional description: Hypocalcaemia
         subjects affected / exposed
    1 / 304 (0.33%)
    1 / 301 (0.33%)
         occurrences all number
    1
    1
    Hypokalaemia
    Additional description: Hypokalaemia
         subjects affected / exposed
    1 / 304 (0.33%)
    1 / 301 (0.33%)
         occurrences all number
    1
    1
    Hypokalaemic syndrome
    Additional description: Hypokalaemic syndrome
         subjects affected / exposed
    0 / 304 (0.00%)
    4 / 301 (1.33%)
         occurrences all number
    0
    4
    Hyponatraemia
    Additional description: Hyponatraemia
         subjects affected / exposed
    2 / 304 (0.66%)
    0 / 301 (0.00%)
         occurrences all number
    2
    0
    Hyponatraemic syndrome
    Additional description: Hyponatraemic syndrome
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Metabolic syndrome
    Additional description: Metabolic syndrome
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Type 2 diabetes mellitus
    Additional description: Type 2 diabetes mellitus
         subjects affected / exposed
    2 / 304 (0.66%)
    1 / 301 (0.33%)
         occurrences all number
    2
    1
    Vitamin D deficiency
    Additional description: Vitamin D deficiency
         subjects affected / exposed
    1 / 304 (0.33%)
    2 / 301 (0.66%)
         occurrences all number
    1
    2

    More information

    Close Top of page

    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Apr 2010
    Protocol amended to include addition of cardiac MRI scans.
    02 Aug 2010
    Protocol amended to update exclusion criteria and add clarifications on concomitant medications, Doxazosin dosing and patient withdrawal criteria.
    10 Jan 2011
    Protocol amended to update recruitment limiting inclusion and exclusion criteria
    30 Nov 2011
    Protocol amended to permit use of open-label (non-blinded) IMP
    26 Apr 2013
    Protocol amended to allow the use of generics and remove recruitment-limiting exclusion criteria.

    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
    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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