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    Clinical Trial Results:
    An open label study to evaluate the efficacy, safety and tolerability of RWJ333369 as adjunctive therapy in subjects with partial onset seizure

    Due to a system error, the data reported in v1 is not correct and has been removed from public view.
    Summary
    EudraCT number
    2007-001801-99
    Trial protocol
    HU  
    Global end of trial date
    05 Oct 2010

    Results information
    Results version number
    v2(current)
    This version publication date
    02 Jun 2016
    First version publication date
    02 Aug 2015
    Other versions
    v1 (removed from public view)
    Version creation reason
    • Correction of full data set
    Review of data

    Trial information

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    Trial identification
    Sponsor protocol code
    333369EPY3004
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00991757
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Janssen-Cilag International N.V.
    Sponsor organisation address
    Antwerpseweg 15-17, B-2340 Beerse, Belgium,
    Public contact
    Clinical Registry Group, Clinical Registry Group, +31 71 524 21 66,, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Janssen-Cilag International NV, Janssen-Cilag International NV, +31 71 524 21 66,, ClinicalTrialsEU@its.jnj.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    05 Oct 2010
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Oct 2010
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this open label study is to determine the long-term safety and tolerability of RWJ-333369 as adjunctive treatment of partial onset seizures. Safety evaluation will include worsening of seizures, including rates of status epilepticus.
    Protection of trial subjects
    Safety was evaluated by examining the incidence and severity of adverse events; laboratory safety (hematology, serum chemistry, serum lipid profile and urinalysis); Electrocardiogram, vital signs; physical and neurological examination.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    12 Feb 2007
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 38
    Country: Number of subjects enrolled
    Australia: 16
    Country: Number of subjects enrolled
    Bulgaria: 33
    Country: Number of subjects enrolled
    Canada: 19
    Country: Number of subjects enrolled
    China: 110
    Country: Number of subjects enrolled
    Croatia: 10
    Country: Number of subjects enrolled
    Czech Republic: 33
    Country: Number of subjects enrolled
    Finland: 17
    Country: Number of subjects enrolled
    Germany: 19
    Country: Number of subjects enrolled
    Hong Kong: 13
    Country: Number of subjects enrolled
    Hungary: 25
    Country: Number of subjects enrolled
    India: 137
    Country: Number of subjects enrolled
    Malaysia: 9
    Country: Number of subjects enrolled
    Norway: 11
    Country: Number of subjects enrolled
    Poland: 62
    Country: Number of subjects enrolled
    Korea, Republic of: 62
    Country: Number of subjects enrolled
    Russian Federation: 99
    Country: Number of subjects enrolled
    Sweden: 13
    Country: Number of subjects enrolled
    Taiwan: 48
    Country: Number of subjects enrolled
    Thailand: 37
    Country: Number of subjects enrolled
    Ukraine: 81
    Country: Number of subjects enrolled
    United States: 118
    Worldwide total number of subjects
    1010
    EEA total number of subjects
    223
    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)
    41
    Adults (18-64 years)
    952
    From 65 to 84 years
    17
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was initiated on 12 February 2007 and completed on 5 October 2010 involving subjects from 168 centers in 22 countries.

    Pre-assignment
    Screening details
    Total 1010 subjects entered the study out of these 445 subjects completed the study while 565 subjects withdraw from the study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Carsibamate less than (<) 400 mg
    Arm description
    Carsibamate (CRS) tablet modal dose less than 400 mg given orally per day
    Arm type
    Experimental

    Investigational medicinal product name
    Carsibamate
    Investigational medicinal product code
    Other name
    RWJ-333369
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Carsibamate (CRS) tablet modal dose less than 400 mg given orally per day

    Arm title
    Carisbamate 400-<600mg
    Arm description
    Subjects received Carsibamate modal dose from 400 to less than 600 mg given orally per Day.
    Arm type
    Experimental

    Investigational medicinal product name
    Carsibamate
    Investigational medicinal product code
    Other name
    RWJ-333369
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Carsibamate modal dose from 400 to less than 600 mg given orally per Day.

    Arm title
    Carisbamate 600-800mg
    Arm description
    Subjects received Carsibamate modal dose from 600 to 800 mg given orally per Day.
    Arm type
    Experimental

    Investigational medicinal product name
    Carsibamate
    Investigational medicinal product code
    Other name
    RWJ-333369
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Carsibamate modal dose from 600 to 800 mg given orally per Day.

    Arm title
    Carsibamate >800-1000mg
    Arm description
    Subjects received Carsibamate modal dose more than 800 to 1000 mg given orally per Day.
    Arm type
    Experimental

    Investigational medicinal product name
    Carsibamate
    Investigational medicinal product code
    Other name
    RWJ-333369
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Carsibamate modal dose more than 800 to 1000 mg given orally per Day.

    Number of subjects in period 1
    Carsibamate less than (<) 400 mg Carisbamate 400-<600mg Carisbamate 600-800mg Carsibamate >800-1000mg
    Started
    37
    521
    450
    2
    Completed
    10
    208
    225
    2
    Not completed
    27
    313
    225
    0
         Protocol deviation
    -
    5
    7
    -
         Other
    10
    70
    86
    -
         Pregnancy
    -
    6
    1
    -
         Adverse event, serious fatal
    -
    2
    5
    -
         Adverse event, non-fatal
    6
    49
    16
    -
         Consent withdrawn by subject
    11
    152
    89
    -
         Lost to follow-up
    -
    29
    21
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Carsibamate less than (<) 400 mg
    Reporting group description
    Carsibamate (CRS) tablet modal dose less than 400 mg given orally per day

    Reporting group title
    Carisbamate 400-<600mg
    Reporting group description
    Subjects received Carsibamate modal dose from 400 to less than 600 mg given orally per Day.

    Reporting group title
    Carisbamate 600-800mg
    Reporting group description
    Subjects received Carsibamate modal dose from 600 to 800 mg given orally per Day.

    Reporting group title
    Carsibamate >800-1000mg
    Reporting group description
    Subjects received Carsibamate modal dose more than 800 to 1000 mg given orally per Day.

    Reporting group values
    Carsibamate less than (<) 400 mg Carisbamate 400-<600mg Carisbamate 600-800mg Carsibamate >800-1000mg Total
    Number of subjects
    37 521 450 2 1010
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    0 0 0 0 0
        Adolescents (12-17 years)
    3 17 21 0 41
        Adults (18-64 years)
    34 495 421 2 952
        From 65 to 84 years
    0 9 8 0 17
        85 years and over
    0 0 0 0 0
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    37.7 ± 11.84 35.4 ± 12.74 35.5 ± 12.9 27 ± 4.24 -
    Title for Gender
    Units: subjects
        Female
    23 276 210 1 510
        Male
    14 245 240 1 500

    End points

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    End points reporting groups
    Reporting group title
    Carsibamate less than (<) 400 mg
    Reporting group description
    Carsibamate (CRS) tablet modal dose less than 400 mg given orally per day

    Reporting group title
    Carisbamate 400-<600mg
    Reporting group description
    Subjects received Carsibamate modal dose from 400 to less than 600 mg given orally per Day.

    Reporting group title
    Carisbamate 600-800mg
    Reporting group description
    Subjects received Carsibamate modal dose from 600 to 800 mg given orally per Day.

    Reporting group title
    Carsibamate >800-1000mg
    Reporting group description
    Subjects received Carsibamate modal dose more than 800 to 1000 mg given orally per Day.

    Subject analysis set title
    Intent-to-treat (ITT) population
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The intent-to treat (ITT) analyses set was defined as subjects who provided seizure diary data for at least 1 visit in the open-label extension.

    Primary: Percentage of Subjects who were Responders

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    End point title
    Percentage of Subjects who were Responders [1]
    End point description
    Responders were defined as subjects who had at least a 50% reduction from baseline in monthly seizure rate.
    End point type
    Primary
    End point timeframe
    Baseline up to End of Treatment
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed
    End point values
    Intent-to-treat (ITT) population
    Number of subjects analysed
    1008 [2]
    Units: Percentage of Subects
        number (not applicable)
    44.5
    Notes
    [2] - ITT Population
    No statistical analyses for this end point

    Primary: Percent Reduction from Baseline to Open-Label Phase in Partial Onset Seizure Frequency

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    End point title
    Percent Reduction from Baseline to Open-Label Phase in Partial Onset Seizure Frequency [3]
    End point description
    Change in Partial Onset Seizure Frequency evaluated as the percent reduction from the pretreatment baseline phase in Partial Onset Seizure Frequency compared with the :Open-Label Extension phase
    End point type
    Primary
    End point timeframe
    Baseline up to End of Treatment
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed
    End point values
    Intent-to-treat (ITT) population
    Number of subjects analysed
    1008 [4]
    Units: Percent change
        median (full range (min-max))
    43.48 (-398.1 to 100)
    Notes
    [4] - ITT Population
    No statistical analyses for this end point

    Primary: Percent Reduction From Baseline to the Last 6 Months of the Open-Label Phase in Partial Onset Seizure Frequency

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    End point title
    Percent Reduction From Baseline to the Last 6 Months of the Open-Label Phase in Partial Onset Seizure Frequency [5]
    End point description
    Change in Partial Onset Seizure Frequency evaluated as the percent reduction from the pretreatment baseline phase in Partial Onset Seizure Frequency compared with the :Open-Label Extension phase
    End point type
    Primary
    End point timeframe
    Baseline upto 6 Months
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed
    End point values
    Intent-to-treat (ITT) population
    Number of subjects analysed
    1008 [6]
    Units: Percent Change
        median (full range (min-max))
    49.15 (-748.3 to 100)
    Notes
    [6] - ITT Population
    No statistical analyses for this end point

    Primary: Percentage of Subjects who are seizure free from Baseline to Open-Label Phase

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    End point title
    Percentage of Subjects who are seizure free from Baseline to Open-Label Phase [7]
    End point description
    Seizure-free days evaluated as the percent change from the pretreatment baseline phase in average monthly seizure-free days per 28 days compared with the Open-Label Phase phase.
    End point type
    Primary
    End point timeframe
    Baseline upto End of treatment
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed
    End point values
    Intent-to-treat (ITT) population
    Number of subjects analysed
    962 [8]
    Units: Percentage of Subjects
        number (not applicable)
    5.8
    Notes
    [8] - ITT Population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline upto End of treatment
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    12.1
    Reporting groups
    Reporting group title
    Carsibamate <400 mg
    Reporting group description
    Carsibamate (CRS) tablet less than 400 mg given orally per day

    Reporting group title
    Carsibamate 400-<600mg
    Reporting group description
    Carsibamate tablet 400 mg to less than 600 mg given orally per day

    Reporting group title
    Carisbamate 600-800 mg
    Reporting group description
    Carsibamate tablet 600 mg to 800 mg given orally per day

    Reporting group title
    Carsibamate >800-1000mg
    Reporting group description
    Carsibamate tablet greater than 800 mg to 1000 mg given orally per day

    Serious adverse events
    Carsibamate <400 mg Carsibamate 400-<600mg Carisbamate 600-800 mg Carsibamate >800-1000mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 37 (16.22%)
    74 / 521 (14.20%)
    70 / 450 (15.56%)
    0 / 2 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Aneurysm Arteriovenous
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Arthrodesis
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 521 (0.00%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac Pacemaker Insertion
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cataract Operation
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Elective Surgery
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocervical Curettage
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hospitalisation
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hysterectomy
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    3 / 450 (0.67%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Medical Device Removal
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasal Operation
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neurosurgery
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian Cystectomy
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal Fusion Surgery
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgery
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vagal Nerve Stimulator Removal
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 521 (0.38%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Basal Cell Carcinoma
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 521 (0.00%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast Cancer
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 521 (0.38%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fibroadenoma of Breast
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lip And/Or Oral Cavity Cancer
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Melanocytic Naevus
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-Hodgkin's Lymphoma
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oligodendroglioma
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thyroid Cancer
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine Leiomyoma
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest Pain
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drowning
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Abnormal Behaviour
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute Psychosis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aggression
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Agitation
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 521 (0.00%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Conversion Disorder
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 521 (0.38%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysphoria
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hallucination
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypomania
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Major Depression
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychotic Disorder
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 521 (0.38%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide Attempt
         subjects affected / exposed
    0 / 37 (0.00%)
    3 / 521 (0.58%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign Prostatic Hyperplasia
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metrorrhagia
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 521 (0.38%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian Cyst
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental Exposure
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ankle Fracture
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain Contusion
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral Haemorrhage Traumatic
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clavicle Fracture
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug Toxicity
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Extradural Haematoma
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eyeball Rupture
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Face Injury
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Facial Bones Fracture
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur Fracture
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 521 (0.00%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Head Injury
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 521 (0.38%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip Fracture
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Humerus Fracture
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    2 / 450 (0.44%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower Limb Fracture
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    2 / 450 (0.44%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar Vertebral Fracture
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Open Wound
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Poisoning
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Road Traffic Accident
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin Laceration
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skull Fracture
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thermal Burn
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Traumatic Brain Injury
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    2 / 450 (0.44%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wrist Fracture
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Diagnostic Procedure
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Electroencephalogram
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver Function Test Abnormal
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Myocardial Infarction
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mitral Valve Prolapse
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericardial Effusion
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Odontogenic Cyst
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asphyxia
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia Aspiration
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory Distress
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Balance Disorder
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain Stem Infarction
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral Haematoma
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrosclerosis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular Accident
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coma
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 521 (0.00%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Complex Partial Seizures
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    2 / 450 (0.44%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    2 / 37 (5.41%)
    11 / 521 (2.11%)
    5 / 450 (1.11%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 15
    1 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 37 (2.70%)
    6 / 521 (1.15%)
    5 / 450 (1.11%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 8
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Grand Mal Convulsion
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    2 / 450 (0.44%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage Intracranial
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 521 (0.00%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Loss of Consciousness
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Memory Impairment
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Parkinsonism
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Partial Seizures
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postictal State
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 521 (0.38%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychomotor Hyperactivity
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Speech Disorder
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Status Epilepticus
         subjects affected / exposed
    0 / 37 (0.00%)
    7 / 521 (1.34%)
    3 / 450 (0.67%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 7
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Temporal Lobe Epilepsy
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient Ischaemic Attack
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Blindness
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vertigo
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Hernia
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric Ulcer
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal Haemorrhage
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal Hernia
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis Acute
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    2 / 450 (0.44%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Periproctitis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Salivary Gland Calculus
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small Intestinal Obstruction
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus Ureteric
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Incontinence
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal Failure Acute
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal Impairment
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary Retention
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gallbladder Non-Functioning
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash Generalised
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Scar
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back Pain
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone Pain
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 521 (0.00%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervical Spinal Stenosis
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Groin Pain
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral Disc Disorder
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar Spinal Stenosis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal Chest Pain
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neck Pain
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in Extremity
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal Osteoarthritis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 521 (0.00%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear Infection
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis Viral
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian Infection
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic Inflammatory Disease
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 521 (0.00%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Plasmodium Falciparum Infection
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 521 (0.00%)
    2 / 450 (0.44%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia Primary Atypical
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis Acute
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Typhoid Fever
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 521 (0.00%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    Carsibamate <400 mg Carsibamate 400-<600mg Carisbamate 600-800 mg Carsibamate >800-1000mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    32 / 37 (86.49%)
    290 / 521 (55.66%)
    314 / 450 (69.78%)
    2 / 2 (100.00%)
    Vascular disorders
    Hot Flush
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    3
    0
    0
    Hypertension
         subjects affected / exposed
    1 / 37 (2.70%)
    8 / 521 (1.54%)
    15 / 450 (3.33%)
    0 / 2 (0.00%)
         occurrences all number
    15
    26
    34
    0
    Hypotension
         subjects affected / exposed
    1 / 37 (2.70%)
    3 / 521 (0.58%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences all number
    3
    10
    1
    0
    Immune system disorders
    Seasonal Allergy
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 521 (0.19%)
    4 / 450 (0.89%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    6
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 37 (5.41%)
    16 / 521 (3.07%)
    19 / 450 (4.22%)
    0 / 2 (0.00%)
         occurrences all number
    4
    25
    21
    0
    Chest Discomfort
         subjects affected / exposed
    1 / 37 (2.70%)
    5 / 521 (0.96%)
    5 / 450 (1.11%)
    0 / 2 (0.00%)
         occurrences all number
    1
    8
    5
    0
    Chest Pain
         subjects affected / exposed
    2 / 37 (5.41%)
    5 / 521 (0.96%)
    7 / 450 (1.56%)
    0 / 2 (0.00%)
         occurrences all number
    32
    5
    11
    0
    Chills
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 521 (0.19%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Fatigue
         subjects affected / exposed
    8 / 37 (21.62%)
    25 / 521 (4.80%)
    31 / 450 (6.89%)
    0 / 2 (0.00%)
         occurrences all number
    10
    30
    45
    0
    Feeling Cold
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 521 (0.00%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gait Disturbance
         subjects affected / exposed
    0 / 37 (0.00%)
    3 / 521 (0.58%)
    5 / 450 (1.11%)
    0 / 2 (0.00%)
         occurrences all number
    0
    3
    7
    0
    Irritability
         subjects affected / exposed
    3 / 37 (8.11%)
    16 / 521 (3.07%)
    10 / 450 (2.22%)
    0 / 2 (0.00%)
         occurrences all number
    4
    31
    11
    0
    Oedema Peripheral
         subjects affected / exposed
    1 / 37 (2.70%)
    3 / 521 (0.58%)
    4 / 450 (0.89%)
    0 / 2 (0.00%)
         occurrences all number
    1
    3
    5
    0
    Pyrexia
         subjects affected / exposed
    4 / 37 (10.81%)
    17 / 521 (3.26%)
    26 / 450 (5.78%)
    0 / 2 (0.00%)
         occurrences all number
    4
    24
    29
    0
    Sense of Oppression
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 521 (0.00%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 521 (0.19%)
    3 / 450 (0.67%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    3
    0
    Anxiety
         subjects affected / exposed
    3 / 37 (8.11%)
    9 / 521 (1.73%)
    15 / 450 (3.33%)
    0 / 2 (0.00%)
         occurrences all number
    4
    9
    20
    0
    Depression
         subjects affected / exposed
    1 / 37 (2.70%)
    10 / 521 (1.92%)
    16 / 450 (3.56%)
    0 / 2 (0.00%)
         occurrences all number
    1
    11
    19
    0
    Disturbance in Social Behaviour
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 521 (0.00%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dysphoria
         subjects affected / exposed
    0 / 37 (0.00%)
    7 / 521 (1.34%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    7
    0
    0
    Insomnia
         subjects affected / exposed
    4 / 37 (10.81%)
    26 / 521 (4.99%)
    26 / 450 (5.78%)
    0 / 2 (0.00%)
         occurrences all number
    6
    42
    29
    0
    Libido Decreased
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Nervousness
         subjects affected / exposed
    0 / 37 (0.00%)
    7 / 521 (1.34%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences all number
    0
    8
    1
    0
    Stress
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 521 (0.00%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Suicidal Ideation
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 521 (0.19%)
    5 / 450 (1.11%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    5
    0
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    1 / 37 (2.70%)
    3 / 521 (0.58%)
    2 / 450 (0.44%)
    0 / 2 (0.00%)
         occurrences all number
    1
    29
    7
    0
    Hypomenorrhoea
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 521 (0.00%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    2 / 37 (5.41%)
    10 / 521 (1.92%)
    13 / 450 (2.89%)
    0 / 2 (0.00%)
         occurrences all number
    3
    11
    19
    0
    Excoriation
         subjects affected / exposed
    1 / 37 (2.70%)
    5 / 521 (0.96%)
    8 / 450 (1.78%)
    0 / 2 (0.00%)
         occurrences all number
    1
    5
    9
    0
    Fall
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    7 / 450 (1.56%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    10
    0
    Head Injury
         subjects affected / exposed
    0 / 37 (0.00%)
    6 / 521 (1.15%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences all number
    0
    7
    6
    0
    Joint Injury
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 521 (0.19%)
    4 / 450 (0.89%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    4
    0
    Laceration
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 521 (0.38%)
    12 / 450 (2.67%)
    0 / 2 (0.00%)
         occurrences all number
    0
    2
    16
    0
    Ligament Sprain
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 521 (0.00%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Skin Laceration
         subjects affected / exposed
    1 / 37 (2.70%)
    4 / 521 (0.77%)
    16 / 450 (3.56%)
    0 / 2 (0.00%)
         occurrences all number
    1
    8
    19
    0
    Thermal Burn
         subjects affected / exposed
    0 / 37 (0.00%)
    5 / 521 (0.96%)
    6 / 450 (1.33%)
    0 / 2 (0.00%)
         occurrences all number
    0
    5
    6
    0
    Wound
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 521 (0.19%)
    2 / 450 (0.44%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    2
    0
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    0 / 37 (0.00%)
    8 / 521 (1.54%)
    7 / 450 (1.56%)
    0 / 2 (0.00%)
         occurrences all number
    0
    9
    7
    0
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    0 / 37 (0.00%)
    4 / 521 (0.77%)
    6 / 450 (1.33%)
    0 / 2 (0.00%)
         occurrences all number
    0
    5
    6
    0
    Blood Pressure Increased
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 521 (0.19%)
    4 / 450 (0.89%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    9
    0
    Weight Decreased
         subjects affected / exposed
    0 / 37 (0.00%)
    7 / 521 (1.34%)
    12 / 450 (2.67%)
    0 / 2 (0.00%)
         occurrences all number
    0
    11
    12
    0
    Weight Increased
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 521 (0.38%)
    5 / 450 (1.11%)
    0 / 2 (0.00%)
         occurrences all number
    0
    2
    5
    0
    Cardiac disorders
    Cardiac Discomfort
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 521 (0.00%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Palpitations
         subjects affected / exposed
    0 / 37 (0.00%)
    6 / 521 (1.15%)
    3 / 450 (0.67%)
    0 / 2 (0.00%)
         occurrences all number
    0
    6
    4
    0
    Respiratory, thoracic and mediastinal disorders
    Bronchitis Chronic
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 521 (0.00%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Cough
         subjects affected / exposed
    0 / 37 (0.00%)
    7 / 521 (1.34%)
    10 / 450 (2.22%)
    0 / 2 (0.00%)
         occurrences all number
    0
    7
    10
    0
    Dyspnoea
         subjects affected / exposed
    1 / 37 (2.70%)
    2 / 521 (0.38%)
    4 / 450 (0.89%)
    0 / 2 (0.00%)
         occurrences all number
    1
    2
    4
    0
    Epistaxis
         subjects affected / exposed
    1 / 37 (2.70%)
    2 / 521 (0.38%)
    4 / 450 (0.89%)
    0 / 2 (0.00%)
         occurrences all number
    1
    2
    7
    0
    Hyperventilation
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Nasal Congestion
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 521 (0.19%)
    2 / 450 (0.44%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    2
    0
    Rhinitis Allergic
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 521 (0.00%)
    0 / 450 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    1
    0
    0
    1
    Oropharyngeal Pain
         subjects affected / exposed
    2 / 37 (5.41%)
    6 / 521 (1.15%)
    8 / 450 (1.78%)
    0 / 2 (0.00%)
         occurrences all number
    3
    6
    9
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 37 (2.70%)
    3 / 521 (0.58%)
    2 / 450 (0.44%)
    0 / 2 (0.00%)
         occurrences all number
    1
    3
    2
    0
    Sinus Congestion
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 521 (0.00%)
    2 / 450 (0.44%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 37 (2.70%)
    7 / 521 (1.34%)
    3 / 450 (0.67%)
    0 / 2 (0.00%)
         occurrences all number
    1
    10
    3
    0
    Nervous system disorders
    Ageusia
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 521 (0.00%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Agnosia
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 521 (0.00%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Amnesia
         subjects affected / exposed
    1 / 37 (2.70%)
    5 / 521 (0.96%)
    3 / 450 (0.67%)
    0 / 2 (0.00%)
         occurrences all number
    1
    5
    8
    0
    Ataxia
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 521 (0.38%)
    9 / 450 (2.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    2
    12
    0
    Balance Disorder
         subjects affected / exposed
    0 / 37 (0.00%)
    6 / 521 (1.15%)
    9 / 450 (2.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    7
    12
    0
    Convulsion
         subjects affected / exposed
    5 / 37 (13.51%)
    19 / 521 (3.65%)
    33 / 450 (7.33%)
    1 / 2 (50.00%)
         occurrences all number
    5
    24
    44
    1
    Dizziness
         subjects affected / exposed
    11 / 37 (29.73%)
    57 / 521 (10.94%)
    87 / 450 (19.33%)
    2 / 2 (100.00%)
         occurrences all number
    26
    118
    312
    2
    Disturbance in Attention
         subjects affected / exposed
    0 / 37 (0.00%)
    10 / 521 (1.92%)
    7 / 450 (1.56%)
    0 / 2 (0.00%)
         occurrences all number
    0
    11
    8
    0
    Facial Palsy
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 521 (0.00%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Head Discomfort
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 521 (0.00%)
    2 / 450 (0.44%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Headache
         subjects affected / exposed
    10 / 37 (27.03%)
    91 / 521 (17.47%)
    83 / 450 (18.44%)
    0 / 2 (0.00%)
         occurrences all number
    48
    646
    514
    0
    Hypoaesthesia
         subjects affected / exposed
    0 / 37 (0.00%)
    5 / 521 (0.96%)
    5 / 450 (1.11%)
    0 / 2 (0.00%)
         occurrences all number
    0
    7
    6
    0
    Hypotonia
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 521 (0.00%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Lethargy
         subjects affected / exposed
    1 / 37 (2.70%)
    3 / 521 (0.58%)
    3 / 450 (0.67%)
    0 / 2 (0.00%)
         occurrences all number
    1
    4
    3
    0
    Memory Impairment
         subjects affected / exposed
    0 / 37 (0.00%)
    8 / 521 (1.54%)
    11 / 450 (2.44%)
    0 / 2 (0.00%)
         occurrences all number
    0
    8
    13
    0
    Migraine
         subjects affected / exposed
    1 / 37 (2.70%)
    4 / 521 (0.77%)
    9 / 450 (2.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    5
    19
    0
    Nystagmus
         subjects affected / exposed
    0 / 37 (0.00%)
    4 / 521 (0.77%)
    5 / 450 (1.11%)
    0 / 2 (0.00%)
         occurrences all number
    0
    4
    9
    0
    Paraesthesia
         subjects affected / exposed
    1 / 37 (2.70%)
    7 / 521 (1.34%)
    7 / 450 (1.56%)
    0 / 2 (0.00%)
         occurrences all number
    1
    10
    8
    0
    Poor Quality Sleep
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Postictal State
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Sedation
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 521 (0.00%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Simple Partial Seizures
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 521 (0.00%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Somnolence
         subjects affected / exposed
    0 / 37 (0.00%)
    24 / 521 (4.61%)
    37 / 450 (8.22%)
    0 / 2 (0.00%)
         occurrences all number
    0
    26
    47
    0
    Tension Headache
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 521 (0.19%)
    2 / 450 (0.44%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    3
    0
    Tremor
         subjects affected / exposed
    0 / 37 (0.00%)
    8 / 521 (1.54%)
    12 / 450 (2.67%)
    0 / 2 (0.00%)
         occurrences all number
    0
    8
    26
    0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 521 (0.19%)
    3 / 450 (0.67%)
    0 / 2 (0.00%)
         occurrences all number
    2
    1
    3
    0
    Diplopia
         subjects affected / exposed
    0 / 37 (0.00%)
    5 / 521 (0.96%)
    16 / 450 (3.56%)
    0 / 2 (0.00%)
         occurrences all number
    0
    6
    46
    0
    Eye Movement Disorder
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 521 (0.00%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Lacrimation Increased
         subjects affected / exposed
    1 / 37 (2.70%)
    2 / 521 (0.38%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Vision Blurred
         subjects affected / exposed
    3 / 37 (8.11%)
    9 / 521 (1.73%)
    20 / 450 (4.44%)
    0 / 2 (0.00%)
         occurrences all number
    9
    11
    33
    0
    Visual Acuity Reduced
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    5 / 450 (1.11%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    5
    0
    Visual Impairment
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 521 (0.19%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Ear and labyrinth disorders
    Ear Pain
         subjects affected / exposed
    1 / 37 (2.70%)
    2 / 521 (0.38%)
    3 / 450 (0.67%)
    0 / 2 (0.00%)
         occurrences all number
    2
    2
    4
    0
    Vertigo
         subjects affected / exposed
    0 / 37 (0.00%)
    10 / 521 (1.92%)
    11 / 450 (2.44%)
    0 / 2 (0.00%)
         occurrences all number
    0
    17
    30
    0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    2 / 37 (5.41%)
    6 / 521 (1.15%)
    9 / 450 (2.00%)
    0 / 2 (0.00%)
         occurrences all number
    5
    59
    10
    0
    Abdominal Pain Lower
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 521 (0.19%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Abdominal Pain Upper
         subjects affected / exposed
    4 / 37 (10.81%)
    11 / 521 (2.11%)
    13 / 450 (2.89%)
    0 / 2 (0.00%)
         occurrences all number
    4
    22
    17
    0
    Aphthous Stomatitis
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 521 (0.19%)
    2 / 450 (0.44%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    7
    0
    Constipation
         subjects affected / exposed
    3 / 37 (8.11%)
    14 / 521 (2.69%)
    12 / 450 (2.67%)
    0 / 2 (0.00%)
         occurrences all number
    3
    15
    15
    0
    Diarrhoea
         subjects affected / exposed
    3 / 37 (8.11%)
    20 / 521 (3.84%)
    23 / 450 (5.11%)
    0 / 2 (0.00%)
         occurrences all number
    6
    26
    32
    0
    Duodenitis
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 521 (0.00%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dyspepsia
         subjects affected / exposed
    1 / 37 (2.70%)
    9 / 521 (1.73%)
    20 / 450 (4.44%)
    1 / 2 (50.00%)
         occurrences all number
    1
    14
    35
    1
    Gastric Ulcer
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Gastritis
         subjects affected / exposed
    1 / 37 (2.70%)
    9 / 521 (1.73%)
    4 / 450 (0.89%)
    1 / 2 (50.00%)
         occurrences all number
    1
    10
    4
    1
    Gastrooesophageal Reflux Disease
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    6 / 450 (1.33%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    7
    0
    Nausea
         subjects affected / exposed
    5 / 37 (13.51%)
    26 / 521 (4.99%)
    27 / 450 (6.00%)
    0 / 2 (0.00%)
         occurrences all number
    6
    34
    40
    0
    Periodontitis
         subjects affected / exposed
    1 / 37 (2.70%)
    2 / 521 (0.38%)
    2 / 450 (0.44%)
    0 / 2 (0.00%)
         occurrences all number
    1
    2
    2
    0
    Rectal Haemorrhage
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 521 (0.00%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Toothache
         subjects affected / exposed
    1 / 37 (2.70%)
    5 / 521 (0.96%)
    5 / 450 (1.11%)
    0 / 2 (0.00%)
         occurrences all number
    1
    8
    5
    0
    Vomiting
         subjects affected / exposed
    4 / 37 (10.81%)
    26 / 521 (4.99%)
    21 / 450 (4.67%)
    0 / 2 (0.00%)
         occurrences all number
    10
    29
    34
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    5 / 450 (1.11%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    5
    0
    Polyuria
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 521 (0.19%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Urinary Tract Pain
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 521 (0.00%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 37 (0.00%)
    8 / 521 (1.54%)
    6 / 450 (1.33%)
    0 / 2 (0.00%)
         occurrences all number
    0
    8
    7
    0
    Decubitus Ulcer
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 521 (0.00%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dermal Cyst
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 521 (0.00%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Eczema
         subjects affected / exposed
    0 / 37 (0.00%)
    7 / 521 (1.34%)
    5 / 450 (1.11%)
    0 / 2 (0.00%)
         occurrences all number
    0
    7
    5
    0
    Hypoaesthesia Facial
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 521 (0.00%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Rash
         subjects affected / exposed
    0 / 37 (0.00%)
    9 / 521 (1.73%)
    14 / 450 (3.11%)
    0 / 2 (0.00%)
         occurrences all number
    0
    11
    17
    0
    Pruritus
         subjects affected / exposed
    2 / 37 (5.41%)
    3 / 521 (0.58%)
    8 / 450 (1.78%)
    0 / 2 (0.00%)
         occurrences all number
    3
    3
    8
    0
    Urticaria
         subjects affected / exposed
    0 / 37 (0.00%)
    3 / 521 (0.58%)
    5 / 450 (1.11%)
    0 / 2 (0.00%)
         occurrences all number
    0
    3
    5
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 37 (2.70%)
    6 / 521 (1.15%)
    15 / 450 (3.33%)
    0 / 2 (0.00%)
         occurrences all number
    3
    10
    17
    0
    Back Pain
         subjects affected / exposed
    2 / 37 (5.41%)
    17 / 521 (3.26%)
    22 / 450 (4.89%)
    0 / 2 (0.00%)
         occurrences all number
    2
    21
    38
    0
    Bone Pain
         subjects affected / exposed
    1 / 37 (2.70%)
    2 / 521 (0.38%)
    2 / 450 (0.44%)
    0 / 2 (0.00%)
         occurrences all number
    1
    35
    2
    0
    Flank Pain
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Muscle Spasms
         subjects affected / exposed
    1 / 37 (2.70%)
    2 / 521 (0.38%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Musculoskeletal Pain
         subjects affected / exposed
    3 / 37 (8.11%)
    4 / 521 (0.77%)
    8 / 450 (1.78%)
    0 / 2 (0.00%)
         occurrences all number
    3
    7
    8
    0
    Musculoskeletal Stiffness
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 521 (0.00%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Myalgia
         subjects affected / exposed
    0 / 37 (0.00%)
    10 / 521 (1.92%)
    11 / 450 (2.44%)
    0 / 2 (0.00%)
         occurrences all number
    0
    15
    14
    0
    Neck Pain
         subjects affected / exposed
    2 / 37 (5.41%)
    2 / 521 (0.38%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences all number
    2
    2
    1
    0
    Pain in Extremity
         subjects affected / exposed
    2 / 37 (5.41%)
    6 / 521 (1.15%)
    13 / 450 (2.89%)
    0 / 2 (0.00%)
         occurrences all number
    2
    6
    13
    0
    Tenosynovitis
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 521 (0.00%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Metabolism and nutrition disorders
    Appetite Disorder
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 521 (0.19%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Decreased Appetite
         subjects affected / exposed
    3 / 37 (8.11%)
    20 / 521 (3.84%)
    14 / 450 (3.11%)
    0 / 2 (0.00%)
         occurrences all number
    4
    25
    15
    0
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    5 / 450 (1.11%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    6
    0
    Hyponatraemia
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 521 (0.19%)
    2 / 450 (0.44%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    2
    0
    Polydipsia
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 521 (0.00%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 37 (5.41%)
    2 / 521 (0.38%)
    9 / 450 (2.00%)
    0 / 2 (0.00%)
         occurrences all number
    3
    4
    12
    0
    Candidiasis
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 521 (0.00%)
    0 / 450 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Ear Infection
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 521 (0.19%)
    7 / 450 (1.56%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    8
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 521 (0.38%)
    6 / 450 (1.33%)
    0 / 2 (0.00%)
         occurrences all number
    0
    2
    8
    0
    Gastroenteritis Viral
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 521 (0.19%)
    4 / 450 (0.89%)
    0 / 2 (0.00%)
         occurrences all number
    2
    2
    4
    0
    Influenza
         subjects affected / exposed
    4 / 37 (10.81%)
    9 / 521 (1.73%)
    19 / 450 (4.22%)
    0 / 2 (0.00%)
         occurrences all number
    4
    10
    26
    0
    Laryngitis
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 521 (0.19%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    7 / 37 (18.92%)
    37 / 521 (7.10%)
    46 / 450 (10.22%)
    1 / 2 (50.00%)
         occurrences all number
    10
    60
    84
    5
    Pharyngitis
         subjects affected / exposed
    0 / 37 (0.00%)
    9 / 521 (1.73%)
    12 / 450 (2.67%)
    1 / 2 (50.00%)
         occurrences all number
    0
    9
    14
    2
    Sinusitis
         subjects affected / exposed
    1 / 37 (2.70%)
    3 / 521 (0.58%)
    7 / 450 (1.56%)
    0 / 2 (0.00%)
         occurrences all number
    3
    3
    9
    0
    Tonsillitis
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 521 (0.00%)
    1 / 450 (0.22%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    1 / 37 (2.70%)
    21 / 521 (4.03%)
    60 / 450 (13.33%)
    0 / 2 (0.00%)
         occurrences all number
    1
    30
    102
    0
    Urinary Tract Infection
         subjects affected / exposed
    1 / 37 (2.70%)
    10 / 521 (1.92%)
    19 / 450 (4.22%)
    0 / 2 (0.00%)
         occurrences all number
    2
    13
    21
    0
    Viral Infection
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 521 (0.00%)
    8 / 450 (1.78%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    10
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Feb 2007
    Decreased the required stable duration of concomitant antiepileptic drug (AED) dosage to be for at least 1 month prior to enrollment; increased monitoring frequency for the occurrence of withdrawal symptoms, and updated the time and events schedule to reflect changes in study procedures
    04 Sep 2007
    It clarified the endpoint for registration in the United States and the Rest of the World, evaluation and measurement of QTc interval using Fridericia’s correction (QTcF), and added additional cardiac-related outcomes
    02 Nov 2007
    It included appropriate corrections to maintain consistency between the synopsis and report body and updates according to amendment INT-2
    08 Sep 2008
    It included increase in the maximum allowed dose in the open-label extension phase from 800 mg per day to 1200 mg per day, replacement of RWJ-333369 by carisbamate to promote name recognition in sections on open-label extension, and added rationales for permitting slow study drug tapering schedule and dosage strengths of the tablets available in the open-label extension phase
    14 Oct 2009
    It included additional withdrawal criteria regarding potential symptoms of Drug Rash with Eosinophilia and Systemic Signs

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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