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Clinical Trial Results:
A Pivotal Phase 2 Trial of Ponatinib (AP24534) in Patients with Refractory Chronic Myeloid Leukemia and Ph+ Acute Lymphoblastic Leukemia

Summary
EudraCT number	2010-020414-28
Trial protocol	GB SE DE FR BE NL ES IT
Global end of trial date	17 Jan 2019

Results information
Results version number	v1(current)
This version publication date	02 Feb 2020
First version publication date	02 Feb 2020
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

AP24534-10-201

ISRCTN number

US NCT number

NCT01207440

WHO universal trial number (UTN)

Sponsor organisation name

Takeda

Sponsor organisation address

40 Landsdowne Street, Cambridge, MA, United States, 02139

Public contact

Medical Director, Clinical Science, Takeda, +1 877-825-3327, clinicaltrialregistry@tpna.com

Scientific contact

Medical Director, Clinical Science, Takeda, +1 877-825-3327, clinicaltrialregistry@tpna.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

17 Jan 2019

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

17 Jan 2019

Was the trial ended prematurely?

Main objective of the trial

The objective of this study is to determine the efficacy of ponatinib in participants with chronic myeloid leukemia (CML) in chronic phase (CP), accelerated phase (AP) or blast phase (BP) or with philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) who either are resistant or intolerant to either dasatinib or nilotinib, or have the (T)hreonine-315-(I)soleucine (T315I) mutation.

Protection of trial subjects

All study participants were required to read and sign an Informed Consent Form.

Background therapy

Evidence for comparator

Actual start date of recruitment

30 Sep 2010

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

96 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Spain: 9

Country: Number of subjects enrolled

Sweden: 6

Country: Number of subjects enrolled

United Kingdom: 29

Country: Number of subjects enrolled

United States: 189

Country: Number of subjects enrolled

Australia: 12

Country: Number of subjects enrolled

Belgium: 7

Country: Number of subjects enrolled

Canada: 17

Country: Number of subjects enrolled

France: 55

Country: Number of subjects enrolled

Germany: 37

Country: Number of subjects enrolled

Italy: 39

Country: Number of subjects enrolled

Korea, Republic of: 27

Country: Number of subjects enrolled

Netherlands: 5

Country: Number of subjects enrolled

Singapore: 17

Worldwide total number of subjects

449

EEA total number of subjects

187

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

294

From 65 to 84 years

150

85 years and over

Subject disposition

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Recruitment details

Participants took part in the study at 66 investigative sites in the Australia, Belgium, Canada, France, Germany, Italy, the Netherlands, Republic of Korea, Singapore, Spain, Sweden, the United Kingdom and the United States from 30 September 2010 to 17 January 2019.

Screening details

Participants were assigned to 1 of 6 cohorts: chronic myeloid leukemia (CML) in chronic (CP), accelerated (AP), or blast phase (BP), or with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) who were resistant or intolerant (R-I) to either dasatinib or nilotinib or had (T)hreonine-315-(I)soleucine (T315I) mutation.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Cohort A: CP-CML R-I

Arm description

CP-CML participants R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).

Arm type

Experimental

Investigational medicinal product name

Ponatinib

Investigational medicinal product code

Other name

AP24534 Iclusig

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Ponatinib tablets.

Cohort B: CP-CML with T315I Mutation

Arm description

CP-CML participants who had T315I mutation of breakpoint cluster region-Abelson complex (BCR-ABL) were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).

Arm type

Experimental

Investigational medicinal product name

Ponatinib

Investigational medicinal product code

Other name

AP24534 Iclusig

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Ponatinib tablets.

Cohort C: AP-CML R-I

Arm description

AP-CML R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).

Arm type

Experimental

Investigational medicinal product name

Ponatinib

Investigational medicinal product code

Other name

AP24534 Iclusig

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Ponatinib tablets.

Cohort D: AP-CML with T315I Mutation

Arm description

AP-CML participants who had T315I mutation of BCR-ABL were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).

Arm type

Experimental

Investigational medicinal product name

Ponatinib

Investigational medicinal product code

Other name

AP24534 Iclusig

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Ponatinib tablets.

Cohort E: BP-CML/Ph+ ALL R-I

Arm description

BP-CML or Ph+ ALL R-I to dasatinib or nilotinib or Ph+ ALL R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).

Arm type

Experimental

Investigational medicinal product name

Ponatinib

Investigational medicinal product code

Other name

AP24534 Iclusig

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Ponatinib tablets.

Cohort F: BP-CML or Ph+ ALL with T315I Mutation

Arm description

BP-CML or Ph+ ALL participants who had T315I mutation of BCR-ABL were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).

Arm type

Experimental

Investigational medicinal product name

Ponatinib

Investigational medicinal product code

Other name

AP24534 Iclusig

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Ponatinib tablets.

Unassigned to Cohorts A-F

Arm description

Participants who were not assigned to any of the cohorts and have no T315I mutation at study entry and were not resistant or intolerant to dasatinib or nilotinib, administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).

Arm type

Experimental

Investigational medicinal product name

Ponatinib

Investigational medicinal product code

Other name

AP24534 Iclusig

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Ponatinib tablets.

Number of subjects in period 1	Cohort A: CP-CML R-I	Cohort B: CP-CML with T315I Mutation	Cohort C: AP-CML R-I	Cohort D: AP-CML with T315I Mutation	Cohort E: BP-CML/Ph+ ALL R-I	Cohort F: BP-CML or Ph+ ALL with T315I Mutation	Unassigned to Cohorts A-F
Started	203	64	65	18	48	46	5
Completed	0	0	0	0	0	0	0
Not completed	203	64	65	18	48	46	5
Adverse event, serious fatal	6	3	2	2	7	5	1
Terminated by Sponsor	69	19	12	2	3	-	2
Consent withdrawn by subject	29	4	5	3	2	2	-
Physician decision	6	5	5	-	1	-	-
Non-compliance with Study Drug	3	-	1	-	-	-	-
Adverse event, non-fatal	46	11	7	2	6	6	2
Reason Not Specified	10	10	7	-	4	3	-
Progressive Disease	19	10	19	7	23	27	-
Lost to follow-up	-	-	2	1	-	-	-
Lack of efficacy	13	2	5	1	2	3	-
Protocol deviation	2	-	-	-	-	-	-

Baseline characteristics

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Reporting group title

Cohort A: CP-CML R-I

Reporting group description

Reporting group title

Cohort B: CP-CML with T315I Mutation

Reporting group description

Reporting group title

Cohort C: AP-CML R-I

Reporting group description

Reporting group title

Cohort D: AP-CML with T315I Mutation

Reporting group description

Reporting group title

Cohort E: BP-CML/Ph+ ALL R-I

Reporting group description

Reporting group title

Cohort F: BP-CML or Ph+ ALL with T315I Mutation

Reporting group description

Reporting group title

Unassigned to Cohorts A-F

Reporting group description

Reporting group values	Cohort A: CP-CML R-I	Cohort B: CP-CML with T315I Mutation	Cohort C: AP-CML R-I	Cohort D: AP-CML with T315I Mutation	Cohort E: BP-CML/Ph+ ALL R-I	Cohort F: BP-CML or Ph+ ALL with T315I Mutation	Unassigned to Cohorts A-F	Total
Number of subjects	203	64	65	18	48	46	5	449
Age categorical
Units: Subjects
Age Continuous
Units: years
median (full range (min-max))	61.0 (22 to 94)	52.0 (18 to 87)	60.0 (23 to 82)	54.0 (24 to 78)	54.0 (18 to 74)	56.0 (18 to 80)	63.0 (51 to 71)	-
Sex: Female, Male
Units: Subjects
Female	108	16	40	7	17	20	3	211
Male	95	48	25	11	31	26	2	238
Race/Ethnicity, Customized
Units: Subjects
American Indian/Alaska native	1	0	1	0	0	0	0	2
Asian	17	14	8	3	8	7	2	59
Black/African American	7	4	7	5	1	1	0	25
White	174	42	47	9	39	38	3	352
Unknown	3	3	2	0	0	0	0	8
Other	1	1	0	1	0	0	0	3
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	13	8	6	1	2	12	0	42
Not Hispanic or Latino	190	56	59	17	46	34	5	407
Unknown or Not Reported	0	0	0	0	0	0	0	0
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)
ECOG-PS measured on-therapy assessed participant's performance status on 5 point scale: 0=Fully active/able to carry on all pre-disease activities without restriction; 1=restricted in physically strenuous activity, ambulatory/able to carry out light or sedentary work; 2=ambulatory (>50% of waking hrs), capable of all self care, unable to carry out any work activities; 3=capable of only limited self care, confined to bed/chair >50% of waking hrs; 4=completely disabled, cannot carry on any self care, totally confined to bed/chair; 5=dead.
Units: Subjects
ECOG=0	139	47	33	12	15	16	5	267
ECOG=1	60	17	25	6	20	19	0	147
ECOG=2	4	0	7	0	12	11	0	34
Missing ECOG Data	0	0	0	0	1	0	0	1
Time From Diagnosis to First Dose
Units: years
median (full range (min-max))	7.85 (0.45 to 27.43)	4.78 (1.16 to 19.49)	7.13 (0.33 to 28.47)	6.61 (1.17 to 15.90)	3.96 (0.62 to 27.21)	1.63 (0.46 to 14.14)	4.80 (1.74 to 18.60)	-

End points

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Reporting group title

Cohort A: CP-CML R-I

Reporting group description

Reporting group title

Cohort B: CP-CML with T315I Mutation

Reporting group description

Reporting group title

Cohort C: AP-CML R-I

Reporting group description

Reporting group title

Cohort D: AP-CML with T315I Mutation

Reporting group description

Reporting group title

Cohort E: BP-CML/Ph+ ALL R-I

Reporting group description

Reporting group title

Cohort F: BP-CML or Ph+ ALL with T315I Mutation

Reporting group description

Reporting group title

Unassigned to Cohorts A-F

Reporting group description

Primary: Percentage of CP-CML Participants with Major Cytogenetic Response (MCyR)

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End point title

Percentage of CP-CML Participants with Major Cytogenetic Response (MCyR) ^[1] ^[2]

End point description

MCyR is defined as percentage of participants with complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR). Cytogenetic response is the percentage of Philadelphia chromosome positive (Ph+) metaphases in bone marrow (BM). Response is further defined as MCyR: CCyR or PCyR, where CCyR: no Ph+ cells; PCyR: 1 to 35% Ph+ cells. Treated population included all participants assigned to Cohorts A to F who received at least 1 dose of ponatinib. The data for this outcome measure is applicable for Cohorts A and B only.

End point type

Primary

End point timeframe

Up to 12 months after initiation of study 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: This endpoint was analyzed only in Cohorts C and D.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in Cohorts A and B.

End point values	Cohort A: CP-CML R-I	Cohort B: CP-CML with T315I Mutation
Number of subjects analysed	203	64
Units: percentage of participants
number (confidence interval 95%)	50.7 (43.6 to 57.8)	70.3 (57.6 to 81.1)

No statistical analyses for this end point

Primary: Percentage of AP-CML Participants with Major Hematologic Response (MaHR)

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End point title

Percentage of AP-CML Participants with Major Hematologic Response (MaHR) ^[3] ^[4]

End point description

MaHR is defined as percentage of participants with complete hematologic response (CHR) or no evidence of leukemia(NEL). Response criteria for CHR is reported as white blood cells(WBC)≤institutional upper limit of normal (ULN), absolute neutrophil count (ANC)≥1000/mm^3, platelets≥100,000/mm^3, no blasts or promyelocytes in peripheral blood,BM blasts ≤5%,<5% myelocytes plus metamyelocytes in peripheral blood,basophils in peripheral blood <5%,no extramedullary involvement;Response criteria for NEL is reported as WBC≤institutional ULN,no blasts or promyelocytes in peripheral blood,BM blasts ≤5%,<5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <5%,no extramedullary involvement,at least 1 of the following:(i)20,000/mm^3≤platelets<100,000/mm^3;(ii)500/mm^3≤ANC<1000/mm^3.Treated population included all participants assigned to Cohorts A to F who received at least 1 dose of ponatinib.The data for this outcome measure is applicable for Cohorts C and D only.

End point type

Primary

End point timeframe

Up to 6 months after initiation of study 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: This endpoint was analyzed only in Cohorts C and D.
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in Cohorts c and D.

End point values	Cohort C: AP-CML R-I	Cohort D: AP-CML with T315I Mutation
Number of subjects analysed	65	18
Units: percentage of participants
number (confidence interval 95%)	56.9 (44.0 to 69.2)	55.6 (30.8 to 78.5)

No statistical analyses for this end point

Primary: Percentage of BP-CML/Ph+ ALL Participants with MaHR

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End point title

Percentage of BP-CML/Ph+ ALL Participants with MaHR ^[5] ^[6]

End point description

MaHR is defined as percentage of participants with CHR or NEL. Response criteria for CHR is reported as WBC≤institutional upper limit of normal, ANC≥1000/mm^3, platelets ≥100,000/mm^3, no blasts or promyelocytes in peripheral blood, BM blasts ≤5%, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <5%, no extramedullary involvement; Response criteria for NEL is reported as WBC≤ institutional upper limit of normal, no blasts or promyelocytes in peripheral blood, BM blasts ≤5%, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <5%, no extramedullary involvement, at least 1 of the following: (i) 20,000/mm^3 ≤platelets<100,000/mm^3; (ii) 500/mm^3≤ANC<1000/mm^3. Treated population included all participants assigned to Cohorts A to F who received at least 1 dose of ponatinib. The data for this outcome measure is applicable for Cohorts E and F only.

End point type

Primary

End point timeframe

Up to 6 months after initiation of study treatment

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: This endpoint was analyzed only in Cohorts E and F.
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in Cohorts E and F.

End point values	Cohort E: BP-CML/Ph+ ALL R-I	Cohort F: BP-CML or Ph+ ALL with T315I Mutation
Number of subjects analysed	48	46
Units: percentage of participants
number (confidence interval 95%)	35.4 (22.2 to 50.5)	32.6 (19.5 to 48.0)

No statistical analyses for this end point

Secondary: Percentage of CP-CML Participants with CHR

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End point title

Percentage of CP-CML Participants with CHR ^[7]

End point description

Response criteria for CHR is reported as WBC≤institutional upper limit of normal, platelets<450,000/mm^3, no blasts or promyelocytes in peripheral blood, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <5%, no extramedullary involvement (including no hepatomegaly or splenomegaly). Treated population included all participants assigned to Cohorts A to F who received at least 1 dose of ponatinib. The data for this outcome measure is applicable for Cohorts A and B only.

End point type

Secondary

End point timeframe

Every 3 cycles up to 39 cycles, followed by every subsequent sixth cycle (Up to approximately 48 months after first dose)

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in Cohorts A and B.

End point values	Cohort A: CP-CML R-I	Cohort B: CP-CML with T315I Mutation
Number of subjects analysed	203	64
Units: percentage of participants
number (confidence interval 95%)	94.6 (90.5 to 97.3)	92.2 (82.7 to 97.4)

No statistical analyses for this end point

Secondary: Percentage of CP-CML Participants with Confirmed MCyR

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End point title

Percentage of CP-CML Participants with Confirmed MCyR ^[8]

End point description

Confirmed MCyR is defined as 2 assessments of CCyR or PCyR at least 28 days apart. For CP participants entering the trial in PCyR, confirmed MCyR is defined as 2 assessments of CCyR at least 28 days apart. Treated population included all participants assigned to Cohorts A to F who received at least 1 dose of ponatinib. The data for this outcome measure is applicable for Cohorts A and B only.

End point type

Secondary

End point timeframe

Every 3 cycles up to 39 cycles, followed by every subsequent sixth cycle (Up to approximately 48 months after first dose)

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in Cohorts A and B.

End point values	Cohort A: CP-CML R-I	Cohort B: CP-CML with T315I Mutation
Number of subjects analysed	203	64
Units: percentage of participants
number (confidence interval 95%)	40.9 (34.1 to 48.0)	62.5 (49.5 to 74.3)

No statistical analyses for this end point

Secondary: Percentage of CP-CML Participants with Major Molecular Response (MMR)

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End point title

Percentage of CP-CML Participants with Major Molecular Response (MMR) ^[9]

End point description

MMR is defined as a ratio of reverse transcribed transcript of BCR-ABL to ABL ≤0.1% on the international scale (equivalent to a 3-log reduction in transcript). Treated population included all participants assigned to Cohorts A to F who received at least 1 dose of ponatinib. The data for this outcome measure is applicable for Cohorts A and B only.

End point type

Secondary

End point timeframe

Every 3 cycles up to 39 cycles, followed by every subsequent sixth cycle (Up to approximately 48 months after first dose)

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in Cohorts A and B.

End point values	Cohort A: CP-CML R-I	Cohort B: CP-CML with T315I Mutation
Number of subjects analysed	203	64
Units: percentage of participants
number (confidence interval 95%)	35.0 (28.4 to 42.0)	57.8 (44.8 to 70.1)

No statistical analyses for this end point

Secondary: Percentage of AP-CML or BP-CML/Ph+ ALL Participants with MCyR

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End point title

Percentage of AP-CML or BP-CML/Ph+ ALL Participants with MCyR ^[10]

End point description

MCyR is defined as percentage of participants with CCyR or PCyR. Cytogenetic response is the percentage of Ph+ metaphases in BM. Response is further defined as MCyR: CCyR or PCyR, where CCyR: no Ph+ cells; PCyR: 1 to 35% Ph+ cells. Treated population included all participants assigned to Cohorts A to F who received at least 1 dose of ponatinib. The data for this outcome measure is applicable for Cohorts C to F only.

End point type

Secondary

End point timeframe

Every 2 cycles up to 26 cycles, followed by every 3 cycles from cycles 27 through 39, and then every subsequent sixth cycle (Up to approximately 48 months after first dose)

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in Cohorts C, D, E and F.

End point values	Cohort C: AP-CML R-I	Cohort D: AP-CML with T315I Mutation	Cohort E: BP-CML/Ph+ ALL R-I	Cohort F: BP-CML or Ph+ ALL with T315I Mutation
Number of subjects analysed	65	18	48	46
Units: percentage of participants
number (confidence interval 95%)	33.8 (22.6 to 46.6)	55.6 (30.8 to 78.5)	27.1 (15.3 to 41.8)	34.8 (21.4 to 50.2)

No statistical analyses for this end point

Secondary: Percentage of AP-CML or BP-CML/Ph+ ALL Participants with Confirmed MCyR

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End point title

Percentage of AP-CML or BP-CML/Ph+ ALL Participants with Confirmed MCyR ^[11]

End point description

Confirmed MCyR is defined as 2 assessments of CCyR or PCyR at least 28 days apart. Treated population included all participants assigned to Cohorts A to F who received at least 1 dose of ponatinib. The data for this outcome measure is applicable for Cohorts C to F only.

End point type

Secondary

End point timeframe

Every 2 cycles up to 26 cycles, followed by every 3 cycles from cycles 27 through 39, and then every subsequent sixth cycle (Up to approximately 48 months after first dose)

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in Cohorts C, D, E and F.

End point values	Cohort C: AP-CML R-I	Cohort D: AP-CML with T315I Mutation	Cohort E: BP-CML/Ph+ ALL R-I	Cohort F: BP-CML or Ph+ ALL with T315I Mutation
Number of subjects analysed	65	18	48	46
Units: percentage of participants
number (confidence interval 95%)	24.6 (14.8 to 36.9)	38.9 (17.3 to 64.3)	20.8 (10.5 to 35.0)	15.2 (6.3 to 28.9)

No statistical analyses for this end point

Secondary: Percentage of AP-CML or BP-CML/Ph+ ALL Participants with MMR

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End point title

Percentage of AP-CML or BP-CML/Ph+ ALL Participants with MMR ^[12]

End point description

End point type

Secondary

End point timeframe

Every 2 cycles up to 26 cycles, followed by every 3 cycles from cycles 27 through 39, and then every subsequent sixth cycle (Up to approximately 48 months after first dose)

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in Cohorts E and F.

End point values	Cohort C: AP-CML R-I	Cohort D: AP-CML with T315I Mutation	Cohort E: BP-CML/Ph+ ALL R-I	Cohort F: BP-CML or Ph+ ALL with T315I Mutation
Number of subjects analysed	65	18	48	46
Units: percentage of participants
number (confidence interval 95%)	18.5 (9.9 to 30.0)	33.3 (13.3 to 59.0)	18.8 (8.9 to 32.6)	4.3 (0.5 to 14.8)

No statistical analyses for this end point

Secondary: Time to Response

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End point title

Time to Response ^[13]

End point description

Time to response is defined as the interval from the first dose of study treatment until the criteria for response are first met, censored at the last assessment of response. Median time to response was estimated using the Kaplan-Meier method. Treated population included all participants assigned to Cohorts A to F who received at least 1 dose of ponatinib. Median time to response was reported for responders only. Participants who did not achieve the specified response were censored at the last response assessment. Number analysed: participants with data available at given time-point.

End point type

Secondary

End point timeframe

Up to approximately 48 months after first dose

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in all Cohorts except the unassigned cohorts.

End point values	Cohort A: CP-CML R-I	Cohort B: CP-CML with T315I Mutation	Cohort C: AP-CML R-I	Cohort D: AP-CML with T315I Mutation	Cohort E: BP-CML/Ph+ ALL R-I	Cohort F: BP-CML or Ph+ ALL with T315I Mutation
Number of subjects analysed	203	64	65	18	48	46
Units: days
median (full range (min-max))
Hematologic Response (n= 192, 59, 37, 10, 17, 15)	13.0 (1 to 417)	10.0 (4 to 1008)	21.0 (12 to 112)	20.5 (14 to 176)	28.0 (14 to 168)	24.0 (11 to 57)
Cytogenetic Response (n= 103, 45, 22, 10, 13, 16)	85.0 (56 to 343)	84.0 (49 to 333)	113.5 (26 to 280)	83.0 (25 to 295)	28.0 (28 to 168)	56.0 (27 to 112)
Molecular Response (n= 71, 37, 12, 6, 9, 2)	173.0 (55 to 1686)	167.0 (81 to 756)	340.5 (55 to 1364)	335.5 (107 to 925)	56.0 (54 to 113)	63.0 (59 to 67)

No statistical analyses for this end point

Secondary: Duration of Response

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End point title

Duration of Response ^[14]

End point description

Duration of Response is defined as the interval between the first assessment at which the criteria for response are met until the criteria for progression are met, censored at the last date at which the criteria for response are met. Duration of response was estimated by the Kaplan-Meier method as the probability of remaining in response. Treated population included all participants assigned to Cohorts A to F who received at least 1 dose of ponatinib. Number analysed is number of participants with data available for analysis at given time-point. 9999 indicates duration of response was not reached for Cohorts A and B due to fewer number of participants with events. 99999 indicates duration of response was not reached due to fewer number of participants with events.

End point type

Secondary

End point timeframe

Up to approximately 48 months after first dose

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in all Cohorts except the unassigned cohorts.

End point values	Cohort A: CP-CML R-I	Cohort B: CP-CML with T315I Mutation	Cohort C: AP-CML R-I	Cohort D: AP-CML with T315I Mutation	Cohort E: BP-CML/Ph+ ALL R-I	Cohort F: BP-CML or Ph+ ALL with T315I Mutation
Number of subjects analysed	203	64	65	18	48	46
Units: days
median (full range (min-max))
Hematologic Response (n= 192, 59, 37, 10, 17, 15)	9999 (9999 to 9999)	9999 (9999 to 9999)	360.0 (35 to 2079)	732.0 (42 to 1334)	196.0 (54 to 1811)	108.0 (54 to 1038)
Cytogenetic Response (n= 103, 45, 22, 10, 13, 16)	9999 (9999 to 9999)	9999 (9999 to 9999)	99999 (99999 to 99999)	728.0 (28 to 1569)	99999 (99999 to 99999)	63.0 (1 to 673)
Molecular Response (n= 71, 37, 12, 6, 9, 2)	9999 (9999 to 9999)	9999 (9999 to 9999)	560.0 (1 to 1666)	222.0 (1 to 783)	99999 (99999 to 99999)	98.0 (1 to 98)

No statistical analyses for this end point

Secondary: Progression-free Survival (PFS)

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End point title

Progression-free Survival (PFS) ^[15]

End point description

PFS is interval from first dose of study drug until criteria for progression or death are met,censored at last response assessment.Progression from CP reported as death,development of AP or BP,loss of CHR (in absence of cytogenetic response),confirmed by development in complete blood counts(CBCs) >=4weeks apart,loss of MCyR,increasing WBC in participant without CHR defined by doubling of WBC to >20K on 2 occasions >=4weeks apart;Progression from AP reported as death,development of confirmed BP,loss of previous major or minor hematologic response over a 2-week period,no decrease from baseline levels in percentage blasts in peripheral blood or BM on all assessments over a 4-week period;Progression from BP or Ph+ ALL reported as death, increasing blasts in peripheral blood or BM over a 4 week period.Treated population:participants assigned to Cohorts A to F who received >=1 dose of ponatinib.999999:PFS was not reached for Cohorts A and B due to fewer number of participants with events.

End point type

Secondary

End point timeframe

Every 12 weeks ± 2 weeks from last dose of study drug or the investigator/participant decision to discontinue treatment, whichever occurred later (Up to approximately 96 months after last dose)

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in all Cohorts except the unassigned cohorts.

End point values	Cohort A: CP-CML R-I	Cohort B: CP-CML with T315I Mutation	Cohort C: AP-CML R-I	Cohort D: AP-CML with T315I Mutation	Cohort E: BP-CML/Ph+ ALL R-I	Cohort F: BP-CML or Ph+ ALL with T315I Mutation
Number of subjects analysed	203	64	65	18	48	46
Units: days
median (confidence interval 95%)	999999 (1285.0 to 999999)	1809.0 (1028.0 to 999999)	432.0 (335.0 to 714.0)	959.0 (186.0 to 1847.0)	111.0 (55.0 to 169.0)	83.0 (55.0 to 150.0)

No statistical analyses for this end point

Secondary: Overall Survival (OS)

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End point title

Overall Survival (OS) ^[16]

End point description

OS is defined as the interval from the first dose of study treatment until death, censored at the last date at which participant was known to be alive. Treated population included all participants assigned to Cohorts A to F who received at least 1 dose of ponatinib. 9999999 indicates median OS has not been reached for Cohort A and B due to fewer number of participants with events. 99999999 indicates uper limit of 95% confidence interval was not estimable due to fewer number of participants with events.

End point type

Secondary

End point timeframe

From the first dose of study treatment until death (Up to 96 months post last dose)

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in all Cohorts except the unassigned cohorts.

End point values	Cohort A: CP-CML R-I	Cohort B: CP-CML with T315I Mutation	Cohort C: AP-CML R-I	Cohort D: AP-CML with T315I Mutation	Cohort E: BP-CML/Ph+ ALL R-I	Cohort F: BP-CML or Ph+ ALL with T315I Mutation
Number of subjects analysed	203	64	65	18	48	46
Units: days
median (confidence interval 95%)	9999999 (9999999 to 9999999)	9999999 (9999999 to 9999999)	1689.0 (969.0 to 99999999)	1847.0 (281.0 to 2143.0)	209.0 (119.0 to 379.0)	200.0 (150.0 to 279.0)

No statistical analyses for this end point

Secondary: Number of Participants with Treatment-Emergent Adverse Event (TEAE) and Serious AE (SAE)

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End point title

Number of Participants with Treatment-Emergent Adverse Event (TEAE) and Serious AE (SAE)

End point description

AE is any untoward medical occurrence in a participant administered medicinal investigational drug.Untoward medical occurrence does not necessarily have to have causal relationship with treatment.SAE is any untoward medical occurrence that results in death;is life-threatening;requires inpatient hospitalization or prolongation of present hospitalization;results in persistent or significant disability/incapacity;is congenital anomaly/birth defect or is medically important event that may not be immediately life-threatening or result in death or hospitalization, but may jeopardize the participant or may require intervention to prevent one of other outcomes listed in definition above,or involves suspected transmission via medicinal product of infectious agent.TEAE:an AE that occurs after administration of first dose and through 30 days after last dose of study drug or until start of subsequent antineoplastic therapy.Safety population:participants who received >=1 dose of ponatinib.

End point type

Secondary

End point timeframe

From first dose up to 30 days after last dose of the study drug (Up to approximately 49 months)

End point values	Cohort A: CP-CML R-I	Cohort B: CP-CML with T315I Mutation	Cohort C: AP-CML R-I	Cohort D: AP-CML with T315I Mutation	Cohort E: BP-CML/Ph+ ALL R-I	Cohort F: BP-CML or Ph+ ALL with T315I Mutation	Unassigned to Cohorts A-F
Number of subjects analysed	203	64	65	18	48	46	5
Units: participants
TEAE	203	64	65	18	48	46	5
SAE	132	39	44	13	41	37	3

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

SAEs and Other AEs: From first dose up to 30 days after last dose of the study drug (Up to approximately 49 months); All-Cause Mortality: Up to approximately 8 years

Adverse event reporting additional description

At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

19.0

Reporting group title

Cohort A: CP-CML R-I

Reporting group description

Reporting group title

Cohort B: CP-CML with T315I Mutation

Reporting group description

Reporting group title

Cohort C: AP-CML R-I

Reporting group description

Reporting group title

Cohort D: AP-CML with T315I Mutation

Reporting group description

Reporting group title

Cohort E: BP-CML/Ph+ ALL R-I

Reporting group description

Reporting group title

Cohort F: BP-CML or Ph+ ALL with T315I Mutation

Reporting group description

Reporting group title

Unassigned AP/CP-CML

Reporting group description

Participants who were not assigned to any of the cohorts and have no T315I mutation at study entry and were not R-I to dasatinib or nilotinib, administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).

Serious adverse events	Cohort A: CP-CML R-I	Cohort B: CP-CML with T315I Mutation	Cohort C: AP-CML R-I	Cohort D: AP-CML with T315I Mutation	Cohort E: BP-CML/Ph+ ALL R-I	Cohort F: BP-CML or Ph+ ALL with T315I Mutation	Unassigned AP/CP-CML
Total subjects affected by serious adverse events
subjects affected / exposed	132 / 203 (65.02%)	39 / 64 (60.94%)	44 / 65 (67.69%)	13 / 18 (72.22%)	41 / 48 (85.42%)	37 / 46 (80.43%)	3 / 5 (60.00%)
number of deaths (all causes)	11	5	5	5	20	14	2
number of deaths resulting from adverse events	2	0	0	1	2	1	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasm progression
subjects affected / exposed	6 / 203 (2.96%)	2 / 64 (3.13%)	7 / 65 (10.77%)	4 / 18 (22.22%)	14 / 48 (29.17%)	8 / 46 (17.39%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 6	0 / 2	0 / 7	0 / 4	0 / 14	0 / 8	0 / 0
deaths causally related to treatment / all	0 / 4	0 / 1	0 / 2	0 / 2	0 / 10	0 / 5	0 / 0
Myelodysplastic syndrome
subjects affected / exposed	3 / 203 (1.48%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Malignant melanoma
subjects affected / exposed	2 / 203 (0.99%)	1 / 64 (1.56%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Malignant pleural effusion
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Basal cell carcinoma
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	2 / 65 (3.08%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 3	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blast crisis in myelogenous leukaemia
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	1 / 65 (1.54%)	1 / 18 (5.56%)	1 / 48 (2.08%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
Squamous cell carcinoma of skin
subjects affected / exposed	3 / 203 (1.48%)	0 / 64 (0.00%)	2 / 65 (3.08%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 3	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chloroma
subjects affected / exposed	0 / 203 (0.00%)	1 / 64 (1.56%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colon cancer
subjects affected / exposed	2 / 203 (0.99%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin squamous cell carcinoma metastatic
subjects affected / exposed	2 / 203 (0.99%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Large cell lung cancer recurrent
subjects affected / exposed	0 / 203 (0.00%)	1 / 64 (1.56%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Non-hodgkin's lymphoma
subjects affected / exposed	0 / 203 (0.00%)	1 / 64 (1.56%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vulval cancer
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Central nervous system leukaemia
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	1 / 18 (5.56%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Acute lymphocytic leukaemia recurrent
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatic carcinoma
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neuroendocrine carcinoma metastatic
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bowen's disease
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Hypertension
subjects affected / exposed	11 / 203 (5.42%)	0 / 64 (0.00%)	2 / 65 (3.08%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	8 / 13	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypotension
subjects affected / exposed	2 / 203 (0.99%)	1 / 64 (1.56%)	2 / 65 (3.08%)	0 / 18 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 2	0 / 2	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	4 / 203 (1.97%)	1 / 64 (1.56%)	0 / 65 (0.00%)	0 / 18 (0.00%)	1 / 48 (2.08%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	1 / 4	0 / 1	0 / 0	0 / 0	0 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hot flush
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral ischaemia
subjects affected / exposed	3 / 203 (1.48%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Extremity necrosis
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypertensive crisis
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Embolism venous
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thrombophlebitis superficial
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral arterial occlusive disease
subjects affected / exposed	10 / 203 (4.93%)	4 / 64 (6.25%)	1 / 65 (1.54%)	1 / 18 (5.56%)	1 / 48 (2.08%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	8 / 10	4 / 5	0 / 1	1 / 2	1 / 2	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral artery stenosis
subjects affected / exposed	4 / 203 (1.97%)	3 / 64 (4.69%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 5 (20.00%)
occurrences causally related to treatment / all	3 / 6	2 / 3	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral artery occlusion
subjects affected / exposed	4 / 203 (1.97%)	1 / 64 (1.56%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	3 / 6	1 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral vascular disorder
subjects affected / exposed	2 / 203 (0.99%)	1 / 64 (1.56%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	2 / 2	1 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dry gangrene
subjects affected / exposed	1 / 203 (0.49%)	1 / 64 (1.56%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aortic arteriosclerosis
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Temporal arteritis
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Varicose vein
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vasculitis
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Coeliac artery occlusion
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Embolism arterial
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intermittent claudication
subjects affected / exposed	2 / 203 (0.99%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	5 / 203 (2.46%)	3 / 64 (4.69%)	5 / 65 (7.69%)	2 / 18 (11.11%)	2 / 48 (4.17%)	2 / 46 (4.35%)	1 / 5 (20.00%)
occurrences causally related to treatment / all	1 / 5	2 / 3	0 / 5	0 / 2	1 / 2	1 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Non-cardiac chest pain
subjects affected / exposed	4 / 203 (1.97%)	1 / 64 (1.56%)	2 / 65 (3.08%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 4	1 / 1	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Asthenia
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	1 / 65 (1.54%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chest pain
subjects affected / exposed	2 / 203 (0.99%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chills
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	2 / 48 (4.17%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pain
subjects affected / exposed	1 / 203 (0.49%)	1 / 64 (1.56%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0	0 / 0	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Systemic inflammatory response syndrome
subjects affected / exposed	0 / 203 (0.00%)	2 / 64 (3.13%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 3	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Implant site pain
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Impaired healing
subjects affected / exposed	2 / 203 (0.99%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gait disturbance
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular stent occlusion
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fatigue
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Multiple organ dysfunction syndrome
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	1 / 48 (2.08%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
Immune system disorders
Hypersensitivity
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Graft versus host disease in skin
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anaphylactic reaction
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anaphylactoid reaction
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Drug hypersensitivity
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Social circumstances
Immobile
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Prostatic obstruction
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Prostatitis
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhagic ovarian cyst
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ovarian cyst
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	2 / 203 (0.99%)	3 / 64 (4.69%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 5 (20.00%)
occurrences causally related to treatment / all	2 / 3	2 / 3	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	3 / 203 (1.48%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	3 / 48 (6.25%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0	0 / 1	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Epistaxis
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	2 / 203 (0.99%)	1 / 64 (1.56%)	1 / 65 (1.54%)	0 / 18 (0.00%)	1 / 48 (2.08%)	1 / 46 (2.17%)	1 / 5 (20.00%)
occurrences causally related to treatment / all	1 / 2	0 / 1	0 / 1	0 / 0	1 / 1	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	2 / 65 (3.08%)	0 / 18 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	2 / 46 (4.35%)	1 / 5 (20.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea exertional
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleuritic pain
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary hypertension
subjects affected / exposed	2 / 203 (0.99%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung disorder
subjects affected / exposed	0 / 203 (0.00%)	1 / 64 (1.56%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Confusional state
subjects affected / exposed	3 / 203 (1.48%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mental status changes
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	2 / 46 (4.35%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Delirium
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Product issues
Device dislocation
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Lipase increased
subjects affected / exposed	4 / 203 (1.97%)	3 / 64 (4.69%)	1 / 65 (1.54%)	0 / 18 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	4 / 4	3 / 3	1 / 1	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Platelet count decreased
subjects affected / exposed	2 / 203 (0.99%)	0 / 64 (0.00%)	2 / 65 (3.08%)	0 / 18 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	2 / 6	0 / 0	2 / 2	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Alanine aminotransferase increased
subjects affected / exposed	3 / 203 (1.48%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neutrophil count decreased
subjects affected / exposed	2 / 203 (0.99%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood alkaline phosphatase increased
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ejection fraction decreased
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	2 / 48 (4.17%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	2 / 2	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gamma-glutamyltransferase increased
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	2 / 65 (3.08%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood bilirubin increased
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urine analysis abnormal
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic enzyme increased
subjects affected / exposed	0 / 203 (0.00%)	1 / 64 (1.56%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
International normalised ratio increased
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Liver function test increased
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood potassium increased
subjects affected / exposed	0 / 203 (0.00%)	1 / 64 (1.56%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemoglobin decreased
subjects affected / exposed	0 / 203 (0.00%)	1 / 64 (1.56%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
JC polyomavirus test positive
subjects affected / exposed	0 / 203 (0.00%)	1 / 64 (1.56%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Subarachnoid haemorrhage
subjects affected / exposed	0 / 203 (0.00%)	1 / 64 (1.56%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Concussion
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peripancreatic fluid collection
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Procedural vomiting
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	1 / 65 (1.54%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	2 / 203 (0.99%)	0 / 64 (0.00%)	2 / 65 (3.08%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural haematoma
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural haemorrhage
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Procedural pain
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Traumatic intracranial haemorrhage
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Pneumonitis chemical
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral artery restenosis
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Head injury
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal column injury
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Wound dehiscence
subjects affected / exposed	0 / 203 (0.00%)	1 / 64 (1.56%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Wrist fracture
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	11 / 203 (5.42%)	4 / 64 (6.25%)	0 / 65 (0.00%)	0 / 18 (0.00%)	3 / 48 (6.25%)	2 / 46 (4.35%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	9 / 21	0 / 4	0 / 0	0 / 0	1 / 3	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	5 / 203 (2.46%)	3 / 64 (4.69%)	1 / 65 (1.54%)	0 / 18 (0.00%)	1 / 48 (2.08%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	4 / 5	2 / 4	1 / 2	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Coronary artery disease
subjects affected / exposed	4 / 203 (1.97%)	6 / 64 (9.38%)	1 / 65 (1.54%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	2 / 4	5 / 7	1 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	2 / 203 (0.99%)	1 / 64 (1.56%)	1 / 65 (1.54%)	2 / 18 (11.11%)	2 / 48 (4.17%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	1 / 5	1 / 2	1 / 1	1 / 2	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	10 / 203 (4.93%)	4 / 64 (6.25%)	0 / 65 (0.00%)	0 / 18 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	8 / 13	3 / 5	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	2 / 203 (0.99%)	1 / 64 (1.56%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
Coronary artery stenosis
subjects affected / exposed	2 / 203 (0.99%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrial tachycardia
subjects affected / exposed	0 / 203 (0.00%)	1 / 64 (1.56%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pericardial effusion
subjects affected / exposed	3 / 203 (1.48%)	1 / 64 (1.56%)	1 / 65 (1.54%)	0 / 18 (0.00%)	1 / 48 (2.08%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	3 / 3	1 / 1	1 / 1	0 / 0	1 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sinus tachycardia
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute coronary syndrome
subjects affected / exposed	3 / 203 (1.48%)	3 / 64 (4.69%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 5 (20.00%)
occurrences causally related to treatment / all	3 / 3	3 / 3	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiopulmonary failure
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Cardiac failure
subjects affected / exposed	0 / 203 (0.00%)	1 / 64 (1.56%)	0 / 65 (0.00%)	1 / 18 (5.56%)	3 / 48 (6.25%)	0 / 46 (0.00%)	1 / 5 (20.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1	1 / 3	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrial flutter
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrioventricular block complete
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac tamponade
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiogenic shock
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pericarditis
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Right ventricular failure
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tachycardia
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Coronary artery occlusion
subjects affected / exposed	2 / 203 (0.99%)	1 / 64 (1.56%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	2 / 2	1 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute left ventricular failure
subjects affected / exposed	0 / 203 (0.00%)	1 / 64 (1.56%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Angina unstable
subjects affected / exposed	0 / 203 (0.00%)	1 / 64 (1.56%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aortic valve stenosis
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arrhythmia supraventricular
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arteriosclerosis coronary artery
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arteriospasm coronary
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bradycardia
subjects affected / exposed	0 / 203 (0.00%)	1 / 64 (1.56%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac Discomfort
subjects affected / exposed	0 / 203 (0.00%)	1 / 64 (1.56%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure acute
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardio-respiratory arrest
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Congestive cardiomyopathy
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dressler's syndrome
subjects affected / exposed	0 / 203 (0.00%)	1 / 64 (1.56%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemic cardiomyopathy
subjects affected / exposed	0 / 203 (0.00%)	1 / 64 (1.56%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Left ventricular dysfunction
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mitral valve incompetence
subjects affected / exposed	0 / 203 (0.00%)	1 / 64 (1.56%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sinus node dysfunction
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ventricular tachycardia
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure chronic
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bundle branch block right
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Left ventricular failure
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	3 / 203 (1.48%)	4 / 64 (6.25%)	2 / 65 (3.08%)	0 / 18 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	1 / 3	3 / 5	0 / 2	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebrovascular accident
subjects affected / exposed	5 / 203 (2.46%)	4 / 64 (6.25%)	1 / 65 (1.54%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	2 / 7	1 / 4	1 / 1	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	2 / 203 (0.99%)	0 / 64 (0.00%)	0 / 65 (0.00%)	1 / 18 (5.56%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	2 / 203 (0.99%)	2 / 64 (3.13%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	1 / 4	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ataxia
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral artery stenosis
subjects affected / exposed	0 / 203 (0.00%)	2 / 64 (3.13%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 3	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral infarction
subjects affected / exposed	5 / 203 (2.46%)	3 / 64 (4.69%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	4 / 5	3 / 4	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhagic cerebral infarction
subjects affected / exposed	0 / 203 (0.00%)	1 / 64 (1.56%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhagic transformation stroke
subjects affected / exposed	0 / 203 (0.00%)	1 / 64 (1.56%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
IVth nerve paralysis
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal cord compression
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebellar infarction
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral haemorrhage
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral ischaemia
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Dizziness
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 4	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Migraine
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Somnolence
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 5 (20.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	3 / 203 (1.48%)	1 / 64 (1.56%)	2 / 65 (3.08%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 1	1 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhage intracranial
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Brain oedema
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Loss of consciousness
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Paraesthesia
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Status epilepticus
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dementia
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Facial Paralysis
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
IIIrd nerve paralysis
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neuropathy peripheral
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Carotid artery stenosis
subjects affected / exposed	5 / 203 (2.46%)	1 / 64 (1.56%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	2 / 5	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrovascular disorder
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Encephalopathy
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypoaesthesia
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intracranial aneurysm
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lacunar infarction
subjects affected / exposed	0 / 203 (0.00%)	1 / 64 (1.56%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Memory impairment
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sciatica
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Carotid artery occlusion
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	7 / 203 (3.45%)	0 / 64 (0.00%)	4 / 65 (6.15%)	0 / 18 (0.00%)	2 / 48 (4.17%)	2 / 46 (4.35%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	2 / 9	0 / 0	1 / 4	0 / 0	1 / 3	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	1 / 65 (1.54%)	1 / 18 (5.56%)	5 / 48 (10.42%)	5 / 46 (10.87%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 2	1 / 1	1 / 6	1 / 6	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	1 / 65 (1.54%)	1 / 18 (5.56%)	2 / 48 (4.17%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1	1 / 1	1 / 2	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Splenic infarction
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperviscosity syndrome
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Hyperleukocytosis
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lymphadenopathy
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	1 / 48 (2.08%)	2 / 46 (4.35%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	1 / 203 (0.49%)	1 / 64 (1.56%)	4 / 65 (6.15%)	0 / 18 (0.00%)	2 / 48 (4.17%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 4	0 / 0	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo positional
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vertigo
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Retinal vein occlusion
subjects affected / exposed	2 / 203 (0.99%)	1 / 64 (1.56%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cataract
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cystoid macular oedema
subjects affected / exposed	0 / 203 (0.00%)	1 / 64 (1.56%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Retinal artery occlusion
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Retinal vein thrombosis
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ulcerative keratitis
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vision blurred
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Macular fibrosis
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Pancreatitis
subjects affected / exposed	10 / 203 (4.93%)	4 / 64 (6.25%)	3 / 65 (4.62%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	9 / 10	4 / 5	3 / 4	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	7 / 203 (3.45%)	1 / 64 (1.56%)	4 / 65 (6.15%)	1 / 18 (5.56%)	4 / 48 (8.33%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	6 / 9	1 / 1	0 / 4	0 / 1	1 / 5	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	3 / 203 (1.48%)	1 / 64 (1.56%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	3 / 3	0 / 1	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	1 / 203 (0.49%)	1 / 64 (1.56%)	1 / 65 (1.54%)	1 / 18 (5.56%)	1 / 48 (2.08%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 1	1 / 1	0 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	2 / 203 (0.99%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 203 (0.00%)	1 / 64 (1.56%)	1 / 65 (1.54%)	0 / 18 (0.00%)	2 / 48 (4.17%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	2 / 203 (0.99%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	1 / 4	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hiatus hernia
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ileus
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oesophagitis
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhoidal haemorrhage
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 5 (20.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ascites
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rectal haemorrhage
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 5 (20.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Retroperitoneal haematoma
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	2 / 65 (3.08%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	2 / 46 (4.35%)	1 / 5 (20.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
Abdominal distension
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute abdomen
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastric haemorrhage
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastritis haemorrhagic
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
Stomatitis
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Appendicitis Noninfective
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colitis Ischaemic
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Faecaloma
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 5 (20.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fistula of small intestine
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastric ulcer haemorrhage
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Large intestinal obstruction
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	0 / 203 (0.00%)	1 / 64 (1.56%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peritoneal haemorrhage
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mesenteric arterial occlusion
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	2 / 203 (0.99%)	1 / 64 (1.56%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	5 / 203 (2.46%)	1 / 64 (1.56%)	2 / 65 (3.08%)	0 / 18 (0.00%)	2 / 48 (4.17%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 10	0 / 1	0 / 2	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Bile duct stone
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholangitis
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	2 / 203 (0.99%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	1 / 203 (0.49%)	1 / 64 (1.56%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Portal vein thrombosis
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Non-alcoholic steatohepatitis
subjects affected / exposed	0 / 203 (0.00%)	1 / 64 (1.56%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Venoocclusive liver disease
subjects affected / exposed	0 / 203 (0.00%)	1 / 64 (1.56%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Biliary dilatation
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gallbladder obstruction
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperbilirubinaemia
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Angioedema
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Erythema
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Erythema multiforme
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperkeratosis
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin ulcer
subjects affected / exposed	2 / 203 (0.99%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute febrile neutrophilic dermatosis
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dermatitis exfoliative generalised
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin swelling
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diabetic foot
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mucocutaneous haemorrhage
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rash erythematous
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rash maculo-papular
subjects affected / exposed	0 / 203 (0.00%)	1 / 64 (1.56%)	0 / 65 (0.00%)	0 / 18 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Renal failure
subjects affected / exposed	2 / 203 (0.99%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute kidney injury
subjects affected / exposed	2 / 203 (0.99%)	2 / 64 (3.13%)	2 / 65 (3.08%)	0 / 18 (0.00%)	3 / 48 (6.25%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 3	1 / 2	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal artery stenosis
subjects affected / exposed	2 / 203 (0.99%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haematuria
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 5 (20.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 5 (20.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dysuria
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Thyroid mass
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 203 (0.00%)	1 / 64 (1.56%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Back pain
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Flank pain
subjects affected / exposed	2 / 203 (0.99%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myalgia
subjects affected / exposed	0 / 203 (0.00%)	1 / 64 (1.56%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal osteoarthritis
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lumbar spinal stenosis
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bone pain
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	2 / 48 (4.17%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal pain
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal column stenosis
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	2 / 203 (0.99%)	0 / 64 (0.00%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral disc protrusion
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Pneumonia
subjects affected / exposed	10 / 203 (4.93%)	5 / 64 (7.81%)	8 / 65 (12.31%)	1 / 18 (5.56%)	4 / 48 (8.33%)	5 / 46 (10.87%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	2 / 13	0 / 8	1 / 9	0 / 1	0 / 6	1 / 6	0 / 0
deaths causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	4 / 203 (1.97%)	1 / 64 (1.56%)	2 / 65 (3.08%)	1 / 18 (5.56%)	2 / 48 (4.17%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	2 / 4	0 / 1	0 / 2	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	2 / 203 (0.99%)	1 / 64 (1.56%)	2 / 65 (3.08%)	1 / 18 (5.56%)	2 / 48 (4.17%)	2 / 46 (4.35%)	1 / 5 (20.00%)
occurrences causally related to treatment / all	1 / 2	0 / 2	0 / 2	0 / 1	1 / 2	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1	0 / 0
Upper respiratory tract infection
subjects affected / exposed	2 / 203 (0.99%)	1 / 64 (1.56%)	0 / 65 (0.00%)	0 / 18 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	1 / 2	1 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	5 / 203 (2.46%)	2 / 64 (3.13%)	0 / 65 (0.00%)	1 / 18 (5.56%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 7	0 / 2	0 / 0	1 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bacterial infection
subjects affected / exposed	0 / 203 (0.00%)	1 / 64 (1.56%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	2 / 203 (0.99%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Herpes oesophagitis
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteomyelitis
subjects affected / exposed	2 / 203 (0.99%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory syncytial virus infection
subjects affected / exposed	0 / 203 (0.00%)	1 / 64 (1.56%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Wound infection
subjects affected / exposed	0 / 203 (0.00%)	1 / 64 (1.56%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	1 / 65 (1.54%)	1 / 18 (5.56%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	1 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	2 / 65 (3.08%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Breast cellulitis
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	3 / 203 (1.48%)	0 / 64 (0.00%)	2 / 65 (3.08%)	0 / 18 (0.00%)	2 / 48 (4.17%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 2	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infection
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	2 / 65 (3.08%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Localised infection
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung infection
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pharyngitis streptococcal
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia fungal
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
Pulmonary tuberculosis
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	2 / 46 (4.35%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 2	0 / 0
Splenic abscess
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Klebsiella sepsis
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	2 / 46 (4.35%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Catheter site cellulitis
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	2 / 48 (4.17%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haematoma infection
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Otitis externa
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia respiratory syncytial viral
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural infection
subjects affected / exposed	2 / 203 (0.99%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal sepsis
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arthritis bacterial
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arthritis viral
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis infective
subjects affected / exposed	0 / 203 (0.00%)	1 / 64 (1.56%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Clostridium difficile infection
subjects affected / exposed	0 / 203 (0.00%)	1 / 64 (1.56%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Genital infection bacterial
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Otitis media chronic
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peritonitis
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia mycoplasmal
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis acute
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Systemic infection
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Viral infection
subjects affected / exposed	0 / 203 (0.00%)	1 / 64 (1.56%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Wound infection staphylococcal
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia staphylococcal
subjects affected / exposed	0 / 203 (0.00%)	1 / 64 (1.56%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gangrene
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis norovirus
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Kidney infection
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal candidiasis
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atypical pneumonia
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Device related sepsis
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infectious colitis
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Pneumonia influenzal
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Postoperative wound infection
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Staphylococcal bacteraemia
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumocystis jirovecii pneumonia
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Hyponatraemia
subjects affected / exposed	4 / 203 (1.97%)	1 / 64 (1.56%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	2 / 5	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	4 / 203 (1.97%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	2 / 48 (4.17%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	1 / 5	0 / 0	0 / 1	0 / 0	0 / 2	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Diabetes mellitus
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Electrolyte imbalance
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tumour lysis syndrome
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	1 / 18 (5.56%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Failure to thrive
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fluid overload
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fluid retention
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperuricaemia
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypercalcaemia
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	0 / 203 (0.00%)	1 / 64 (1.56%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Cohort A: CP-CML R-I	Cohort B: CP-CML with T315I Mutation	Cohort C: AP-CML R-I	Cohort D: AP-CML with T315I Mutation	Cohort E: BP-CML/Ph+ ALL R-I	Cohort F: BP-CML or Ph+ ALL with T315I Mutation	Unassigned AP/CP-CML
Total subjects affected by non serious adverse events
subjects affected / exposed	203 / 203 (100.00%)	64 / 64 (100.00%)	65 / 65 (100.00%)	18 / 18 (100.00%)	48 / 48 (100.00%)	46 / 46 (100.00%)	5 / 5 (100.00%)
Vascular disorders
Flushing
subjects affected / exposed	8 / 203 (3.94%)	2 / 64 (3.13%)	4 / 65 (6.15%)	0 / 18 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	11	2	4	0	1	0	0
Haemorrhage
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	0	0	0	0	0	1
Hot flush
subjects affected / exposed	12 / 203 (5.91%)	1 / 64 (1.56%)	4 / 65 (6.15%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 5 (20.00%)
occurrences all number	13	1	4	0	0	0	1
Hypertension
subjects affected / exposed	68 / 203 (33.50%)	21 / 64 (32.81%)	13 / 65 (20.00%)	8 / 18 (44.44%)	13 / 48 (27.08%)	8 / 46 (17.39%)	2 / 5 (40.00%)
occurrences all number	92	25	13	10	14	8	2
Hypotension
subjects affected / exposed	6 / 203 (2.96%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	3 / 48 (6.25%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences all number	6	0	1	0	4	1	0
Peripheral ischaemia
subjects affected / exposed	0 / 203 (0.00%)	2 / 64 (3.13%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	2	0	1	0	0	0
Peripheral venous disease
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0	0	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	40 / 203 (19.70%)	8 / 64 (12.50%)	5 / 65 (7.69%)	4 / 18 (22.22%)	3 / 48 (6.25%)	8 / 46 (17.39%)	0 / 5 (0.00%)
occurrences all number	50	10	5	5	3	13	0
Chest pain
subjects affected / exposed	13 / 203 (6.40%)	4 / 64 (6.25%)	1 / 65 (1.54%)	1 / 18 (5.56%)	1 / 48 (2.08%)	0 / 46 (0.00%)	1 / 5 (20.00%)
occurrences all number	17	4	1	1	1	0	1
Chills
subjects affected / exposed	16 / 203 (7.88%)	4 / 64 (6.25%)	6 / 65 (9.23%)	4 / 18 (22.22%)	7 / 48 (14.58%)	2 / 46 (4.35%)	1 / 5 (20.00%)
occurrences all number	20	4	7	4	7	2	1
Fatigue
subjects affected / exposed	60 / 203 (29.56%)	21 / 64 (32.81%)	22 / 65 (33.85%)	8 / 18 (44.44%)	16 / 48 (33.33%)	9 / 46 (19.57%)	1 / 5 (20.00%)
occurrences all number	77	29	28	9	18	10	1
Feeling hot
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	1 / 18 (5.56%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	1	0	0
General physical health deterioration
subjects affected / exposed	1 / 203 (0.49%)	2 / 64 (3.13%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 5 (20.00%)
occurrences all number	1	2	0	0	0	0	1
Hernia
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Influenza like illness
subjects affected / exposed	10 / 203 (4.93%)	3 / 64 (4.69%)	4 / 65 (6.15%)	0 / 18 (0.00%)	1 / 48 (2.08%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences all number	13	5	6	0	2	1	0
Localised oedema
subjects affected / exposed	1 / 203 (0.49%)	1 / 64 (1.56%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	1	0	1	0	0	0
Non-cardiac chest pain
subjects affected / exposed	13 / 203 (6.40%)	6 / 64 (9.38%)	3 / 65 (4.62%)	0 / 18 (0.00%)	2 / 48 (4.17%)	2 / 46 (4.35%)	0 / 5 (0.00%)
occurrences all number	13	6	3	0	3	2	0
Oedema peripheral
subjects affected / exposed	36 / 203 (17.73%)	8 / 64 (12.50%)	9 / 65 (13.85%)	5 / 18 (27.78%)	12 / 48 (25.00%)	5 / 46 (10.87%)	1 / 5 (20.00%)
occurrences all number	48	15	9	7	12	5	1
Pain
subjects affected / exposed	19 / 203 (9.36%)	7 / 64 (10.94%)	8 / 65 (12.31%)	3 / 18 (16.67%)	8 / 48 (16.67%)	3 / 46 (6.52%)	0 / 5 (0.00%)
occurrences all number	23	10	8	3	9	3	0
Performance status decreased
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	0	0	0	0	0	1
Peripheral swelling
subjects affected / exposed	5 / 203 (2.46%)	4 / 64 (6.25%)	5 / 65 (7.69%)	2 / 18 (11.11%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences all number	6	5	5	2	0	1	0
Pyrexia
subjects affected / exposed	52 / 203 (25.62%)	13 / 64 (20.31%)	20 / 65 (30.77%)	11 / 18 (61.11%)	16 / 48 (33.33%)	12 / 46 (26.09%)	0 / 5 (0.00%)
occurrences all number	77	14	31	16	18	26	0
Immune system disorders
Seasonal allergy
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	1 / 18 (5.56%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	1	0	0
Social circumstances
Activities of daily living impaired
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	0	0	0	0	0	1
Reproductive system and breast disorders
Breast mass
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Erectile dysfunction
subjects affected / exposed	9 / 203 (4.43%)	6 / 64 (9.38%)	4 / 65 (6.15%)	4 / 18 (22.22%)	1 / 48 (2.08%)	0 / 46 (0.00%)	1 / 5 (20.00%)
occurrences all number	9	6	4	5	1	0	1
Testicular pain
subjects affected / exposed	0 / 203 (0.00%)	1 / 64 (1.56%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	1	0	0	0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 5 (20.00%)
occurrences all number	1	0	0	0	0	0	1
Catarrh
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 5 (20.00%)
occurrences all number	1	0	0	0	0	0	1
Cough
subjects affected / exposed	36 / 203 (17.73%)	11 / 64 (17.19%)	15 / 65 (23.08%)	3 / 18 (16.67%)	8 / 48 (16.67%)	6 / 46 (13.04%)	1 / 5 (20.00%)
occurrences all number	47	15	21	5	8	6	1
Dysphonia
subjects affected / exposed	14 / 203 (6.90%)	5 / 64 (7.81%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences all number	17	5	1	0	0	1	0
Dyspnoea
subjects affected / exposed	30 / 203 (14.78%)	14 / 64 (21.88%)	12 / 65 (18.46%)	4 / 18 (22.22%)	11 / 48 (22.92%)	3 / 46 (6.52%)	1 / 5 (20.00%)
occurrences all number	37	16	13	5	13	3	2
Epistaxis
subjects affected / exposed	16 / 203 (7.88%)	3 / 64 (4.69%)	6 / 65 (9.23%)	1 / 18 (5.56%)	5 / 48 (10.42%)	3 / 46 (6.52%)	0 / 5 (0.00%)
occurrences all number	22	3	7	1	6	3	0
Nasal congestion
subjects affected / exposed	2 / 203 (0.99%)	1 / 64 (1.56%)	2 / 65 (3.08%)	1 / 18 (5.56%)	4 / 48 (8.33%)	2 / 46 (4.35%)	0 / 5 (0.00%)
occurrences all number	2	1	2	1	4	2	0
Oropharyngeal pain
subjects affected / exposed	12 / 203 (5.91%)	6 / 64 (9.38%)	4 / 65 (6.15%)	3 / 18 (16.67%)	8 / 48 (16.67%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences all number	15	6	4	5	9	3	0
Pharyngeal erythema
subjects affected / exposed	2 / 203 (0.99%)	0 / 64 (0.00%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	2	9	9	1	0	0	0
Pleural effusion
subjects affected / exposed	10 / 203 (4.93%)	2 / 64 (3.13%)	7 / 65 (10.77%)	2 / 18 (11.11%)	8 / 48 (16.67%)	4 / 46 (8.70%)	1 / 5 (20.00%)
occurrences all number	10	2	8	2	8	4	2
Productive cough
subjects affected / exposed	6 / 203 (2.96%)	2 / 64 (3.13%)	2 / 65 (3.08%)	1 / 18 (5.56%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences all number	7	4	2	1	0	1	0
Sleep apnoea syndrome
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	1 / 65 (1.54%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	1	1	0	0	0
Psychiatric disorders
Anxiety
subjects affected / exposed	10 / 203 (4.93%)	3 / 64 (4.69%)	11 / 65 (16.92%)	4 / 18 (22.22%)	4 / 48 (8.33%)	3 / 46 (6.52%)	0 / 5 (0.00%)
occurrences all number	10	3	14	4	4	3	0
Confusional state
subjects affected / exposed	4 / 203 (1.97%)	1 / 64 (1.56%)	1 / 65 (1.54%)	2 / 18 (11.11%)	2 / 48 (4.17%)	3 / 46 (6.52%)	0 / 5 (0.00%)
occurrences all number	5	1	1	2	2	3	0
Depression
subjects affected / exposed	13 / 203 (6.40%)	2 / 64 (3.13%)	5 / 65 (7.69%)	0 / 18 (0.00%)	3 / 48 (6.25%)	1 / 46 (2.17%)	1 / 5 (20.00%)
occurrences all number	14	2	5	0	3	1	2
Hallucination
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	0	1	0	0	0	1
Hallucination, visual
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	0	0	0	0	0	1
Insomnia
subjects affected / exposed	25 / 203 (12.32%)	5 / 64 (7.81%)	10 / 65 (15.38%)	1 / 18 (5.56%)	10 / 48 (20.83%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences all number	27	5	10	3	10	1	0
Libido decreased
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	39 / 203 (19.21%)	12 / 64 (18.75%)	15 / 65 (23.08%)	4 / 18 (22.22%)	7 / 48 (14.58%)	5 / 46 (10.87%)	0 / 5 (0.00%)
occurrences all number	63	27	21	6	9	6	0
Amylase increased
subjects affected / exposed	19 / 203 (9.36%)	2 / 64 (3.13%)	6 / 65 (9.23%)	1 / 18 (5.56%)	4 / 48 (8.33%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences all number	24	2	12	1	6	1	0
Aspartate aminotransferase increased
subjects affected / exposed	31 / 203 (15.27%)	11 / 64 (17.19%)	11 / 65 (16.92%)	5 / 18 (27.78%)	7 / 48 (14.58%)	6 / 46 (13.04%)	0 / 5 (0.00%)
occurrences all number	46	20	12	5	8	6	0
Blood alkaline phosphatase increased
subjects affected / exposed	20 / 203 (9.85%)	5 / 64 (7.81%)	9 / 65 (13.85%)	0 / 18 (0.00%)	3 / 48 (6.25%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	24	5	9	0	3	0	0
Blood bilirubin increased
subjects affected / exposed	2 / 203 (0.99%)	1 / 64 (1.56%)	4 / 65 (6.15%)	1 / 18 (5.56%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences all number	2	1	7	1	0	1	0
Blood cholesterol increased
subjects affected / exposed	9 / 203 (4.43%)	3 / 64 (4.69%)	1 / 65 (1.54%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 5 (20.00%)
occurrences all number	11	3	1	1	0	0	1
Blood creatinine increased
subjects affected / exposed	8 / 203 (3.94%)	4 / 64 (6.25%)	5 / 65 (7.69%)	0 / 18 (0.00%)	5 / 48 (10.42%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences all number	8	6	8	0	5	1	0
Blood glucose increased
subjects affected / exposed	1 / 203 (0.49%)	2 / 64 (3.13%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 5 (20.00%)
occurrences all number	1	2	0	0	0	0	1
Blood phosphorus decreased
subjects affected / exposed	1 / 203 (0.49%)	1 / 64 (1.56%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	4	1	0	1	0	0	0
Blood triglycerides increased
subjects affected / exposed	6 / 203 (2.96%)	2 / 64 (3.13%)	1 / 65 (1.54%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	9	2	1	4	0	0	0
Gamma-glutamyltransferase increased
subjects affected / exposed	16 / 203 (7.88%)	5 / 64 (7.81%)	5 / 65 (7.69%)	3 / 18 (16.67%)	2 / 48 (4.17%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	23	5	6	3	3	0	0
Haemoglobin decreased
subjects affected / exposed	2 / 203 (0.99%)	1 / 64 (1.56%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	2	1	0	1	0	0	0
Lipase increased
subjects affected / exposed	56 / 203 (27.59%)	15 / 64 (23.44%)	10 / 65 (15.38%)	2 / 18 (11.11%)	8 / 48 (16.67%)	3 / 46 (6.52%)	0 / 5 (0.00%)
occurrences all number	79	21	29	2	11	4	0
N-terminal prohormone brain natriuretic peptide increased
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Neutrophil count decreased
subjects affected / exposed	8 / 203 (3.94%)	2 / 64 (3.13%)	0 / 65 (0.00%)	3 / 18 (16.67%)	5 / 48 (10.42%)	2 / 46 (4.35%)	0 / 5 (0.00%)
occurrences all number	9	2	0	4	5	3	0
Platelet count decreased
subjects affected / exposed	15 / 203 (7.39%)	3 / 64 (4.69%)	6 / 65 (9.23%)	1 / 18 (5.56%)	2 / 48 (4.17%)	3 / 46 (6.52%)	0 / 5 (0.00%)
occurrences all number	61	3	9	1	3	3	0
Platelet count increased
subjects affected / exposed	3 / 203 (1.48%)	1 / 64 (1.56%)	1 / 65 (1.54%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	3	1	1	1	0	0	0
Weight decreased
subjects affected / exposed	23 / 203 (11.33%)	5 / 64 (7.81%)	7 / 65 (10.77%)	0 / 18 (0.00%)	5 / 48 (10.42%)	2 / 46 (4.35%)	1 / 5 (20.00%)
occurrences all number	25	6	8	0	5	2	1
White blood cell count decreased
subjects affected / exposed	4 / 203 (1.97%)	1 / 64 (1.56%)	2 / 65 (3.08%)	1 / 18 (5.56%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences all number	6	1	2	1	0	1	0
Injury, poisoning and procedural complications
Arthropod bite
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	3	0	0	0
Fall
subjects affected / exposed	9 / 203 (4.43%)	1 / 64 (1.56%)	1 / 65 (1.54%)	0 / 18 (0.00%)	3 / 48 (6.25%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	10	1	4	0	3	0	0
Hand fracture
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Head injury
subjects affected / exposed	1 / 203 (0.49%)	1 / 64 (1.56%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	1	0	1	0	0	0
Laceration
subjects affected / exposed	3 / 203 (1.48%)	1 / 64 (1.56%)	1 / 65 (1.54%)	1 / 18 (5.56%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	3	1	2	1	1	0	0
Ligament sprain
subjects affected / exposed	4 / 203 (1.97%)	1 / 64 (1.56%)	1 / 65 (1.54%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	4	1	1	1	0	0	0
Procedural pain
subjects affected / exposed	5 / 203 (2.46%)	2 / 64 (3.13%)	2 / 65 (3.08%)	2 / 18 (11.11%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	5	2	2	2	1	0	0
Skin injury
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Subcutaneous haematoma
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	1 / 18 (5.56%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	1	0	0
Tendon rupture
subjects affected / exposed	0 / 203 (0.00%)	1 / 64 (1.56%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	1	0	0	0
Transfusion reaction
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	1 / 65 (1.54%)	1 / 18 (5.56%)	2 / 48 (4.17%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences all number	1	0	1	1	2	1	0
Transfusion related complication
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Cardiac disorders
Angina pectoris
subjects affected / exposed	9 / 203 (4.43%)	4 / 64 (6.25%)	3 / 65 (4.62%)	0 / 18 (0.00%)	3 / 48 (6.25%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	13	5	3	0	6	0	0
Atrial fibrillation
subjects affected / exposed	10 / 203 (4.93%)	3 / 64 (4.69%)	1 / 65 (1.54%)	0 / 18 (0.00%)	2 / 48 (4.17%)	4 / 46 (8.70%)	1 / 5 (20.00%)
occurrences all number	15	4	1	0	2	5	1
Cardiac failure
subjects affected / exposed	1 / 203 (0.49%)	1 / 64 (1.56%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 5 (20.00%)
occurrences all number	1	2	1	0	0	0	1
Cardiomyopathy
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	3 / 48 (6.25%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	0	0	3	0	0
Palpitations
subjects affected / exposed	6 / 203 (2.96%)	1 / 64 (1.56%)	2 / 65 (3.08%)	1 / 18 (5.56%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	7	1	2	1	1	0	0
Pericardial effusion
subjects affected / exposed	5 / 203 (2.46%)	1 / 64 (1.56%)	2 / 65 (3.08%)	0 / 18 (0.00%)	3 / 48 (6.25%)	2 / 46 (4.35%)	0 / 5 (0.00%)
occurrences all number	5	1	2	0	3	2	0
Tachycardia
subjects affected / exposed	3 / 203 (1.48%)	1 / 64 (1.56%)	1 / 65 (1.54%)	0 / 18 (0.00%)	2 / 48 (4.17%)	4 / 46 (8.70%)	0 / 5 (0.00%)
occurrences all number	3	1	2	0	2	4	0
Nervous system disorders
Aphasia
subjects affected / exposed	0 / 203 (0.00%)	1 / 64 (1.56%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	1	0	0	0
Ataxia
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	1 / 65 (1.54%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	1	1	0	0	0
Burning sensation
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	3	0	0	1	0	0	0
Depressed level of consciousness
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Dizziness
subjects affected / exposed	34 / 203 (16.75%)	12 / 64 (18.75%)	7 / 65 (10.77%)	2 / 18 (11.11%)	4 / 48 (8.33%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	37	13	7	2	4	0	0
Dysgeusia
subjects affected / exposed	3 / 203 (1.48%)	6 / 64 (9.38%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences all number	3	6	0	0	0	1	0
Facial paralysis
subjects affected / exposed	3 / 203 (1.48%)	0 / 64 (0.00%)	1 / 65 (1.54%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	4	0	2	1	0	0	0
Headache
subjects affected / exposed	87 / 203 (42.86%)	27 / 64 (42.19%)	18 / 65 (27.69%)	7 / 18 (38.89%)	15 / 48 (31.25%)	12 / 46 (26.09%)	1 / 5 (20.00%)
occurrences all number	136	37	26	14	19	16	2
Hypoaesthesia
subjects affected / exposed	11 / 203 (5.42%)	2 / 64 (3.13%)	1 / 65 (1.54%)	0 / 18 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	13	2	1	0	1	0	0
Migraine
subjects affected / exposed	6 / 203 (2.96%)	0 / 64 (0.00%)	1 / 65 (1.54%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	6	0	1	1	0	0	0
Neuropathy peripheral
subjects affected / exposed	15 / 203 (7.39%)	1 / 64 (1.56%)	2 / 65 (3.08%)	0 / 18 (0.00%)	1 / 48 (2.08%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences all number	16	1	2	0	1	1	0
Paraesthesia
subjects affected / exposed	15 / 203 (7.39%)	5 / 64 (7.81%)	1 / 65 (1.54%)	1 / 18 (5.56%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences all number	18	6	1	1	0	1	0
Radiculopathy
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Sciatica
subjects affected / exposed	11 / 203 (5.42%)	0 / 64 (0.00%)	4 / 65 (6.15%)	0 / 18 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	1 / 5 (20.00%)
occurrences all number	12	0	4	0	1	0	1
Somnolence
subjects affected / exposed	0 / 203 (0.00%)	1 / 64 (1.56%)	0 / 65 (0.00%)	0 / 18 (0.00%)	1 / 48 (2.08%)	1 / 46 (2.17%)	1 / 5 (20.00%)
occurrences all number	0	1	0	0	1	1	1
Vith nerve disorder
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	39 / 203 (19.21%)	7 / 64 (10.94%)	20 / 65 (30.77%)	7 / 18 (38.89%)	14 / 48 (29.17%)	11 / 46 (23.91%)	1 / 5 (20.00%)
occurrences all number	48	7	41	11	24	17	2
Febrile neutropenia
subjects affected / exposed	1 / 203 (0.49%)	1 / 64 (1.56%)	2 / 65 (3.08%)	0 / 18 (0.00%)	3 / 48 (6.25%)	3 / 46 (6.52%)	0 / 5 (0.00%)
occurrences all number	1	1	2	0	3	6	0
Hypochromasia
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	1 / 18 (5.56%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	0	2	1	0	0
Leukopenia
subjects affected / exposed	7 / 203 (3.45%)	0 / 64 (0.00%)	5 / 65 (7.69%)	2 / 18 (11.11%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	7	0	6	2	0	0	0
Lymphadenopathy
subjects affected / exposed	6 / 203 (2.96%)	0 / 64 (0.00%)	2 / 65 (3.08%)	0 / 18 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	1 / 5 (20.00%)
occurrences all number	9	0	2	0	0	1	1
Neutropenia
subjects affected / exposed	42 / 203 (20.69%)	6 / 64 (9.38%)	24 / 65 (36.92%)	4 / 18 (22.22%)	13 / 48 (27.08%)	7 / 46 (15.22%)	0 / 5 (0.00%)
occurrences all number	133	7	54	5	14	7	0
Thrombocytopenia
subjects affected / exposed	90 / 203 (44.33%)	18 / 64 (28.13%)	32 / 65 (49.23%)	4 / 18 (22.22%)	16 / 48 (33.33%)	7 / 46 (15.22%)	1 / 5 (20.00%)
occurrences all number	235	33	97	5	17	10	2
Ear and labyrinth disorders
Tinnitus
subjects affected / exposed	8 / 203 (3.94%)	1 / 64 (1.56%)	1 / 65 (1.54%)	1 / 18 (5.56%)	1 / 48 (2.08%)	0 / 46 (0.00%)	1 / 5 (20.00%)
occurrences all number	9	1	1	1	1	0	1
Vertigo
subjects affected / exposed	8 / 203 (3.94%)	1 / 64 (1.56%)	3 / 65 (4.62%)	1 / 18 (5.56%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	8	1	3	2	1	0	0
Eye disorders
Blepharitis
subjects affected / exposed	3 / 203 (1.48%)	1 / 64 (1.56%)	2 / 65 (3.08%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 5 (20.00%)
occurrences all number	5	1	2	0	0	0	1
Cataract
subjects affected / exposed	7 / 203 (3.45%)	1 / 64 (1.56%)	1 / 65 (1.54%)	1 / 18 (5.56%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	7	1	2	1	1	0	0
Conjunctival hyperaemia
subjects affected / exposed	2 / 203 (0.99%)	0 / 64 (0.00%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	3	0	0	1	0	0	0
Dry eye
subjects affected / exposed	16 / 203 (7.88%)	5 / 64 (7.81%)	4 / 65 (6.15%)	2 / 18 (11.11%)	4 / 48 (8.33%)	3 / 46 (6.52%)	1 / 5 (20.00%)
occurrences all number	17	5	5	2	4	3	2
Eye pain
subjects affected / exposed	8 / 203 (3.94%)	4 / 64 (6.25%)	2 / 65 (3.08%)	0 / 18 (0.00%)	3 / 48 (6.25%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	9	5	2	0	3	0	0
Eyelid disorder
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Eyelid oedema
subjects affected / exposed	3 / 203 (1.48%)	1 / 64 (1.56%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	3	1	0	1	0	0	0
Vision blurred
subjects affected / exposed	13 / 203 (6.40%)	6 / 64 (9.38%)	3 / 65 (4.62%)	1 / 18 (5.56%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	13	6	3	1	1	0	0
Visual acuity reduced
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 5 (20.00%)
occurrences all number	1	0	1	0	0	0	1
Visual impairment
subjects affected / exposed	3 / 203 (1.48%)	1 / 64 (1.56%)	1 / 65 (1.54%)	0 / 18 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	1 / 5 (20.00%)
occurrences all number	3	1	1	0	1	0	1
Vitreous floaters
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	1 / 65 (1.54%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	1	1	0	0	0
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	8 / 203 (3.94%)	3 / 64 (4.69%)	3 / 65 (4.62%)	0 / 18 (0.00%)	1 / 48 (2.08%)	1 / 46 (2.17%)	1 / 5 (20.00%)
occurrences all number	8	4	18	0	1	1	1
Abdominal distension
subjects affected / exposed	12 / 203 (5.91%)	7 / 64 (10.94%)	4 / 65 (6.15%)	1 / 18 (5.56%)	3 / 48 (6.25%)	1 / 46 (2.17%)	1 / 5 (20.00%)
occurrences all number	13	8	6	1	4	1	2
Abdominal pain
subjects affected / exposed	75 / 203 (36.95%)	21 / 64 (32.81%)	20 / 65 (30.77%)	7 / 18 (38.89%)	7 / 48 (14.58%)	10 / 46 (21.74%)	2 / 5 (40.00%)
occurrences all number	127	30	30	12	7	12	2
Abdominal pain upper
subjects affected / exposed	40 / 203 (19.70%)	10 / 64 (15.63%)	11 / 65 (16.92%)	2 / 18 (11.11%)	6 / 48 (12.50%)	8 / 46 (17.39%)	2 / 5 (40.00%)
occurrences all number	58	18	19	2	6	9	3
Ascites
subjects affected / exposed	0 / 203 (0.00%)	1 / 64 (1.56%)	0 / 65 (0.00%)	1 / 18 (5.56%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	1	1	0	0
Constipation
subjects affected / exposed	89 / 203 (43.84%)	21 / 64 (32.81%)	16 / 65 (24.62%)	7 / 18 (38.89%)	21 / 48 (43.75%)	13 / 46 (28.26%)	3 / 5 (60.00%)
occurrences all number	131	36	30	11	26	15	4
Dental necrosis
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Diarrhoea
subjects affected / exposed	43 / 203 (21.18%)	10 / 64 (15.63%)	17 / 65 (26.15%)	7 / 18 (38.89%)	15 / 48 (31.25%)	4 / 46 (8.70%)	0 / 5 (0.00%)
occurrences all number	59	18	29	10	16	4	0
Dry mouth
subjects affected / exposed	20 / 203 (9.85%)	6 / 64 (9.38%)	4 / 65 (6.15%)	0 / 18 (0.00%)	4 / 48 (8.33%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences all number	21	6	4	0	4	1	0
Dyspepsia
subjects affected / exposed	12 / 203 (5.91%)	6 / 64 (9.38%)	4 / 65 (6.15%)	0 / 18 (0.00%)	2 / 48 (4.17%)	2 / 46 (4.35%)	0 / 5 (0.00%)
occurrences all number	16	6	5	0	2	2	0
Dysphagia
subjects affected / exposed	3 / 203 (1.48%)	1 / 64 (1.56%)	2 / 65 (3.08%)	0 / 18 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	1 / 5 (20.00%)
occurrences all number	3	1	2	0	2	0	1
Gastrooesophageal reflux disease
subjects affected / exposed	10 / 203 (4.93%)	8 / 64 (12.50%)	2 / 65 (3.08%)	0 / 18 (0.00%)	2 / 48 (4.17%)	0 / 46 (0.00%)	1 / 5 (20.00%)
occurrences all number	11	10	2	0	4	0	1
Gingival bleeding
subjects affected / exposed	3 / 203 (1.48%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	2 / 48 (4.17%)	2 / 46 (4.35%)	1 / 5 (20.00%)
occurrences all number	9	0	1	0	2	2	2
Haemorrhoids
subjects affected / exposed	4 / 203 (1.97%)	1 / 64 (1.56%)	1 / 65 (1.54%)	1 / 18 (5.56%)	2 / 48 (4.17%)	2 / 46 (4.35%)	0 / 5 (0.00%)
occurrences all number	5	1	1	1	2	2	0
Mouth haemorrhage
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	2 / 46 (4.35%)	0 / 5 (0.00%)
occurrences all number	2	0	0	1	0	3	0
Nausea
subjects affected / exposed	53 / 203 (26.11%)	24 / 64 (37.50%)	22 / 65 (33.85%)	5 / 18 (27.78%)	16 / 48 (33.33%)	12 / 46 (26.09%)	1 / 5 (20.00%)
occurrences all number	63	33	33	7	17	14	2
Odynophagia
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	2 / 18 (11.11%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences all number	1	0	0	2	0	1	0
Rectal haemorrhage
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	1 / 5 (20.00%)
occurrences all number	0	0	1	0	0	1	1
Stomatitis
subjects affected / exposed	11 / 203 (5.42%)	2 / 64 (3.13%)	4 / 65 (6.15%)	1 / 18 (5.56%)	2 / 48 (4.17%)	3 / 46 (6.52%)	0 / 5 (0.00%)
occurrences all number	11	2	4	1	2	3	0
Toothache
subjects affected / exposed	13 / 203 (6.40%)	0 / 64 (0.00%)	3 / 65 (4.62%)	0 / 18 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences all number	14	0	4	0	0	1	0
Vomiting
subjects affected / exposed	38 / 203 (18.72%)	12 / 64 (18.75%)	17 / 65 (26.15%)	6 / 18 (33.33%)	14 / 48 (29.17%)	11 / 46 (23.91%)	0 / 5 (0.00%)
occurrences all number	53	20	22	6	27	14	0
Hepatobiliary disorders
Cholelithiasis
subjects affected / exposed	3 / 203 (1.48%)	1 / 64 (1.56%)	2 / 65 (3.08%)	1 / 18 (5.56%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	3	1	2	1	1	0	0
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	19 / 203 (9.36%)	4 / 64 (6.25%)	5 / 65 (7.69%)	4 / 18 (22.22%)	4 / 48 (8.33%)	3 / 46 (6.52%)	0 / 5 (0.00%)
occurrences all number	20	4	5	4	4	3	0
Dry skin
subjects affected / exposed	84 / 203 (41.38%)	28 / 64 (43.75%)	21 / 65 (32.31%)	4 / 18 (22.22%)	15 / 48 (31.25%)	9 / 46 (19.57%)	4 / 5 (80.00%)
occurrences all number	107	38	27	6	16	9	6
Ecchymosis
subjects affected / exposed	2 / 203 (0.99%)	1 / 64 (1.56%)	4 / 65 (6.15%)	0 / 18 (0.00%)	1 / 48 (2.08%)	1 / 46 (2.17%)	1 / 5 (20.00%)
occurrences all number	2	1	5	0	1	1	1
Erythema
subjects affected / exposed	22 / 203 (10.84%)	6 / 64 (9.38%)	6 / 65 (9.23%)	1 / 18 (5.56%)	3 / 48 (6.25%)	4 / 46 (8.70%)	0 / 5 (0.00%)
occurrences all number	32	6	7	1	3	4	0
Exfoliative rash
subjects affected / exposed	7 / 203 (3.45%)	2 / 64 (3.13%)	4 / 65 (6.15%)	0 / 18 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	2 / 5 (40.00%)
occurrences all number	8	2	4	0	0	1	2
Generalised erythema
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 5 (20.00%)
occurrences all number	1	0	0	1	0	0	3
Hyperhidrosis
subjects affected / exposed	17 / 203 (8.37%)	7 / 64 (10.94%)	4 / 65 (6.15%)	1 / 18 (5.56%)	1 / 48 (2.08%)	3 / 46 (6.52%)	1 / 5 (20.00%)
occurrences all number	21	9	4	1	1	3	1
Hyperkeratosis
subjects affected / exposed	4 / 203 (1.97%)	0 / 64 (0.00%)	3 / 65 (4.62%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 5 (20.00%)
occurrences all number	4	0	3	1	0	0	1
Night sweats
subjects affected / exposed	15 / 203 (7.39%)	10 / 64 (15.63%)	4 / 65 (6.15%)	1 / 18 (5.56%)	2 / 48 (4.17%)	2 / 46 (4.35%)	0 / 5 (0.00%)
occurrences all number	24	10	4	3	2	2	0
Photosensitivity reaction
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Pruritus
subjects affected / exposed	29 / 203 (14.29%)	6 / 64 (9.38%)	6 / 65 (9.23%)	1 / 18 (5.56%)	2 / 48 (4.17%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences all number	33	6	7	1	2	1	0
Rash
subjects affected / exposed	28 / 203 (13.79%)	3 / 64 (4.69%)	10 / 65 (15.38%)	3 / 18 (16.67%)	2 / 48 (4.17%)	3 / 46 (6.52%)	0 / 5 (0.00%)
occurrences all number	38	4	14	3	2	3	0
Rash erythematous
subjects affected / exposed	39 / 203 (19.21%)	21 / 64 (32.81%)	9 / 65 (13.85%)	2 / 18 (11.11%)	11 / 48 (22.92%)	8 / 46 (17.39%)	0 / 5 (0.00%)
occurrences all number	53	27	14	4	14	9	0
Rash generalised
subjects affected / exposed	0 / 203 (0.00%)	1 / 64 (1.56%)	1 / 65 (1.54%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	2	1	1	0	0	0
Rash macular
subjects affected / exposed	9 / 203 (4.43%)	4 / 64 (6.25%)	0 / 65 (0.00%)	1 / 18 (5.56%)	2 / 48 (4.17%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	13	5	0	1	2	0	0
Rash maculo-papular
subjects affected / exposed	21 / 203 (10.34%)	11 / 64 (17.19%)	4 / 65 (6.15%)	1 / 18 (5.56%)	3 / 48 (6.25%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	27	13	5	1	4	0	0
Rash papular
subjects affected / exposed	14 / 203 (6.90%)	4 / 64 (6.25%)	5 / 65 (7.69%)	1 / 18 (5.56%)	3 / 48 (6.25%)	1 / 46 (2.17%)	2 / 5 (40.00%)
occurrences all number	17	7	6	1	3	1	2
Rash pruritic
subjects affected / exposed	21 / 203 (10.34%)	6 / 64 (9.38%)	5 / 65 (7.69%)	3 / 18 (16.67%)	2 / 48 (4.17%)	1 / 46 (2.17%)	1 / 5 (20.00%)
occurrences all number	25	7	7	4	2	1	1
Skin disorder
subjects affected / exposed	1 / 203 (0.49%)	1 / 64 (1.56%)	0 / 65 (0.00%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 5 (20.00%)
occurrences all number	1	1	0	0	0	0	1
Skin exfoliation
subjects affected / exposed	12 / 203 (5.91%)	6 / 64 (9.38%)	2 / 65 (3.08%)	1 / 18 (5.56%)	0 / 48 (0.00%)	2 / 46 (4.35%)	1 / 5 (20.00%)
occurrences all number	13	7	2	1	0	2	1
Skin lesion
subjects affected / exposed	4 / 203 (1.97%)	1 / 64 (1.56%)	3 / 65 (4.62%)	1 / 18 (5.56%)	0 / 48 (0.00%)	2 / 46 (4.35%)	0 / 5 (0.00%)
occurrences all number	4	1	3	1	0	2	0
Urticaria
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	1 / 65 (1.54%)	1 / 18 (5.56%)	2 / 48 (4.17%)	2 / 46 (4.35%)	0 / 5 (0.00%)
occurrences all number	0	0	1	1	2	2	0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	3 / 203 (1.48%)	1 / 64 (1.56%)	1 / 65 (1.54%)	0 / 18 (0.00%)	3 / 48 (6.25%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	5	1	1	0	4	0	0
Chronic kidney disease
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Dysuria
subjects affected / exposed	6 / 203 (2.96%)	2 / 64 (3.13%)	3 / 65 (4.62%)	2 / 18 (11.11%)	3 / 48 (6.25%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences all number	6	2	3	2	3	1	0
Haematuria
subjects affected / exposed	2 / 203 (0.99%)	0 / 64 (0.00%)	2 / 65 (3.08%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 5 (20.00%)
occurrences all number	2	0	2	0	0	0	1
Hypertonic bladder
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	0	4	0	0	0
Pollakiuria
subjects affected / exposed	7 / 203 (3.45%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	3 / 48 (6.25%)	0 / 46 (0.00%)	1 / 5 (20.00%)
occurrences all number	9	0	1	0	3	0	1
Renal colic
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	2	0	0	0
Urinary incontinence
subjects affected / exposed	4 / 203 (1.97%)	1 / 64 (1.56%)	2 / 65 (3.08%)	1 / 18 (5.56%)	1 / 48 (2.08%)	1 / 46 (2.17%)	1 / 5 (20.00%)
occurrences all number	4	1	2	1	1	1	1
Urinary retention
subjects affected / exposed	4 / 203 (1.97%)	1 / 64 (1.56%)	3 / 65 (4.62%)	1 / 18 (5.56%)	0 / 48 (0.00%)	2 / 46 (4.35%)	0 / 5 (0.00%)
occurrences all number	4	1	3	1	0	2	0
Endocrine disorders
Adrenal insufficiency
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0	1	0
Hypothyroidism
subjects affected / exposed	7 / 203 (3.45%)	2 / 64 (3.13%)	4 / 65 (6.15%)	0 / 18 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	7	2	4	0	1	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	72 / 203 (35.47%)	18 / 64 (28.13%)	22 / 65 (33.85%)	6 / 18 (33.33%)	10 / 48 (20.83%)	6 / 46 (13.04%)	1 / 5 (20.00%)
occurrences all number	90	22	30	7	11	6	2
Back pain
subjects affected / exposed	50 / 203 (24.63%)	8 / 64 (12.50%)	10 / 65 (15.38%)	3 / 18 (16.67%)	8 / 48 (16.67%)	7 / 46 (15.22%)	1 / 5 (20.00%)
occurrences all number	58	11	11	3	9	7	3
Bone pain
subjects affected / exposed	32 / 203 (15.76%)	6 / 64 (9.38%)	8 / 65 (12.31%)	3 / 18 (16.67%)	8 / 48 (16.67%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences all number	35	6	9	3	8	1	0
Flank pain
subjects affected / exposed	2 / 203 (0.99%)	0 / 64 (0.00%)	3 / 65 (4.62%)	1 / 18 (5.56%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	2	0	3	1	1	0	0
Limb discomfort
subjects affected / exposed	1 / 203 (0.49%)	2 / 64 (3.13%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	3	0	1	0	0	0
Muscle spasms
subjects affected / exposed	32 / 203 (15.76%)	6 / 64 (9.38%)	4 / 65 (6.15%)	1 / 18 (5.56%)	3 / 48 (6.25%)	4 / 46 (8.70%)	2 / 5 (40.00%)
occurrences all number	42	6	5	2	3	4	2
Muscular weakness
subjects affected / exposed	4 / 203 (1.97%)	1 / 64 (1.56%)	2 / 65 (3.08%)	0 / 18 (0.00%)	3 / 48 (6.25%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	4	1	2	0	3	0	0
Musculoskeletal pain
subjects affected / exposed	22 / 203 (10.84%)	5 / 64 (7.81%)	4 / 65 (6.15%)	2 / 18 (11.11%)	3 / 48 (6.25%)	3 / 46 (6.52%)	2 / 5 (40.00%)
occurrences all number	23	7	5	2	3	3	3
Myalgia
subjects affected / exposed	47 / 203 (23.15%)	18 / 64 (28.13%)	14 / 65 (21.54%)	4 / 18 (22.22%)	10 / 48 (20.83%)	3 / 46 (6.52%)	0 / 5 (0.00%)
occurrences all number	56	23	17	4	12	3	0
Neck pain
subjects affected / exposed	13 / 203 (6.40%)	1 / 64 (1.56%)	3 / 65 (4.62%)	0 / 18 (0.00%)	2 / 48 (4.17%)	2 / 46 (4.35%)	0 / 5 (0.00%)
occurrences all number	16	1	5	0	2	2	0
Osteoarthritis
subjects affected / exposed	6 / 203 (2.96%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	1 / 5 (20.00%)
occurrences all number	7	0	0	0	2	0	1
Pain in extremity
subjects affected / exposed	56 / 203 (27.59%)	9 / 64 (14.06%)	11 / 65 (16.92%)	5 / 18 (27.78%)	6 / 48 (12.50%)	6 / 46 (13.04%)	1 / 5 (20.00%)
occurrences all number	83	12	12	6	6	7	1
Limb mass
subjects affected / exposed	3 / 203 (1.48%)	0 / 64 (0.00%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	3	0	0	1	0	0	0
Infections and infestations
Bacteraemia
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	1 / 65 (1.54%)	0 / 18 (0.00%)	3 / 48 (6.25%)	2 / 46 (4.35%)	0 / 5 (0.00%)
occurrences all number	0	0	1	0	3	3	0
Breast cellulitis
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	0	2	0	0	0
Bronchitis
subjects affected / exposed	19 / 203 (9.36%)	5 / 64 (7.81%)	3 / 65 (4.62%)	0 / 18 (0.00%)	1 / 48 (2.08%)	1 / 46 (2.17%)	1 / 5 (20.00%)
occurrences all number	30	6	3	0	1	1	1
Cellulitis
subjects affected / exposed	6 / 203 (2.96%)	1 / 64 (1.56%)	4 / 65 (6.15%)	1 / 18 (5.56%)	4 / 48 (8.33%)	2 / 46 (4.35%)	0 / 5 (0.00%)
occurrences all number	8	1	5	1	4	2	0
Conjunctivitis
subjects affected / exposed	9 / 203 (4.43%)	2 / 64 (3.13%)	2 / 65 (3.08%)	2 / 18 (11.11%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 5 (20.00%)
occurrences all number	10	2	3	2	0	0	2
Cystitis
subjects affected / exposed	5 / 203 (2.46%)	0 / 64 (0.00%)	1 / 65 (1.54%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	8	0	1	2	0	0	0
Ear infection
subjects affected / exposed	1 / 203 (0.49%)	1 / 64 (1.56%)	2 / 65 (3.08%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	1	2	1	0	0	0
Folliculitis
subjects affected / exposed	8 / 203 (3.94%)	6 / 64 (9.38%)	3 / 65 (4.62%)	1 / 18 (5.56%)	1 / 48 (2.08%)	2 / 46 (4.35%)	1 / 5 (20.00%)
occurrences all number	12	6	4	1	1	2	2
Fungaemia
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Gastroenteritis
subjects affected / exposed	6 / 203 (2.96%)	1 / 64 (1.56%)	2 / 65 (3.08%)	1 / 18 (5.56%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences all number	7	1	3	1	0	1	0
Infection
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	1	0	0	0
Influenza
subjects affected / exposed	11 / 203 (5.42%)	1 / 64 (1.56%)	2 / 65 (3.08%)	0 / 18 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	12	1	2	0	1	0	0
Lower respiratory tract infection
subjects affected / exposed	4 / 203 (1.97%)	1 / 64 (1.56%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences all number	6	1	0	1	0	1	0
Mastitis
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Mastoiditis
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Nail infection
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Nasopharyngitis
subjects affected / exposed	26 / 203 (12.81%)	7 / 64 (10.94%)	9 / 65 (13.85%)	5 / 18 (27.78%)	1 / 48 (2.08%)	2 / 46 (4.35%)	1 / 5 (20.00%)
occurrences all number	37	8	12	6	1	2	2
Oral candidiasis
subjects affected / exposed	4 / 203 (1.97%)	1 / 64 (1.56%)	1 / 65 (1.54%)	1 / 18 (5.56%)	3 / 48 (6.25%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences all number	4	1	1	1	3	1	0
Otitis externa
subjects affected / exposed	0 / 203 (0.00%)	2 / 64 (3.13%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	2	0	1	0	0	0
Otitis media acute
subjects affected / exposed	0 / 203 (0.00%)	1 / 64 (1.56%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	1	0	0	0
Periodontitis
subjects affected / exposed	0 / 203 (0.00%)	1 / 64 (1.56%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	1	0	0	0
Pharyngitis
subjects affected / exposed	2 / 203 (0.99%)	1 / 64 (1.56%)	0 / 65 (0.00%)	2 / 18 (11.11%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	2	1	0	2	0	0	0
Pneumonia
subjects affected / exposed	7 / 203 (3.45%)	1 / 64 (1.56%)	2 / 65 (3.08%)	1 / 18 (5.56%)	4 / 48 (8.33%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences all number	10	1	3	1	4	1	0
Respiratory tract infection
subjects affected / exposed	2 / 203 (0.99%)	0 / 64 (0.00%)	1 / 65 (1.54%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	2	0	1	1	0	0	0
Sinusitis
subjects affected / exposed	17 / 203 (8.37%)	7 / 64 (10.94%)	3 / 65 (4.62%)	0 / 18 (0.00%)	1 / 48 (2.08%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences all number	23	11	4	0	1	1	0
Tonsillitis
subjects affected / exposed	4 / 203 (1.97%)	0 / 64 (0.00%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	4	0	0	1	0	0	0
Tooth abscess
subjects affected / exposed	1 / 203 (0.49%)	0 / 64 (0.00%)	2 / 65 (3.08%)	1 / 18 (5.56%)	1 / 48 (2.08%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences all number	1	0	3	1	1	1	0
Tooth infection
subjects affected / exposed	6 / 203 (2.96%)	0 / 64 (0.00%)	4 / 65 (6.15%)	0 / 18 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 5 (20.00%)
occurrences all number	7	0	4	0	0	0	1
Upper respiratory tract infection
subjects affected / exposed	16 / 203 (7.88%)	18 / 64 (28.13%)	9 / 65 (13.85%)	2 / 18 (11.11%)	6 / 48 (12.50%)	2 / 46 (4.35%)	1 / 5 (20.00%)
occurrences all number	24	23	13	2	10	2	1
Urinary tract infection
subjects affected / exposed	18 / 203 (8.87%)	5 / 64 (7.81%)	9 / 65 (13.85%)	3 / 18 (16.67%)	2 / 48 (4.17%)	1 / 46 (2.17%)	2 / 5 (40.00%)
occurrences all number	38	5	11	5	3	1	4
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	28 / 203 (13.79%)	7 / 64 (10.94%)	10 / 65 (15.38%)	2 / 18 (11.11%)	7 / 48 (14.58%)	8 / 46 (17.39%)	0 / 5 (0.00%)
occurrences all number	29	9	12	2	7	8	0
Dehydration
subjects affected / exposed	6 / 203 (2.96%)	4 / 64 (6.25%)	1 / 65 (1.54%)	1 / 18 (5.56%)	3 / 48 (6.25%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	7	5	1	1	3	0	0
Gout
subjects affected / exposed	3 / 203 (1.48%)	5 / 64 (7.81%)	1 / 65 (1.54%)	1 / 18 (5.56%)	3 / 48 (6.25%)	0 / 46 (0.00%)	1 / 5 (20.00%)
occurrences all number	3	5	1	1	4	0	2
Hyperamylasaemia
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	1 / 18 (5.56%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Hypercholesterolaemia
subjects affected / exposed	6 / 203 (2.96%)	4 / 64 (6.25%)	2 / 65 (3.08%)	0 / 18 (0.00%)	2 / 48 (4.17%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	6	4	3	0	2	0	0
Hyperglycaemia
subjects affected / exposed	8 / 203 (3.94%)	7 / 64 (10.94%)	9 / 65 (13.85%)	0 / 18 (0.00%)	3 / 48 (6.25%)	2 / 46 (4.35%)	0 / 5 (0.00%)
occurrences all number	11	7	10	0	3	2	0
Hyperkalaemia
subjects affected / exposed	6 / 203 (2.96%)	3 / 64 (4.69%)	1 / 65 (1.54%)	2 / 18 (11.11%)	5 / 48 (10.42%)	3 / 46 (6.52%)	0 / 5 (0.00%)
occurrences all number	6	3	1	2	6	3	0
Hyperuricaemia
subjects affected / exposed	16 / 203 (7.88%)	3 / 64 (4.69%)	3 / 65 (4.62%)	2 / 18 (11.11%)	5 / 48 (10.42%)	1 / 46 (2.17%)	1 / 5 (20.00%)
occurrences all number	21	3	4	2	5	1	1
Hypocalcaemia
subjects affected / exposed	7 / 203 (3.45%)	1 / 64 (1.56%)	8 / 65 (12.31%)	1 / 18 (5.56%)	5 / 48 (10.42%)	4 / 46 (8.70%)	0 / 5 (0.00%)
occurrences all number	7	2	10	1	5	4	0
Hypokalaemia
subjects affected / exposed	12 / 203 (5.91%)	4 / 64 (6.25%)	3 / 65 (4.62%)	2 / 18 (11.11%)	11 / 48 (22.92%)	4 / 46 (8.70%)	1 / 5 (20.00%)
occurrences all number	17	5	4	2	13	4	1
Hypomagnesaemia
subjects affected / exposed	2 / 203 (0.99%)	2 / 64 (3.13%)	3 / 65 (4.62%)	0 / 18 (0.00%)	3 / 48 (6.25%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences all number	3	2	4	0	3	1	0
Hyponatraemia
subjects affected / exposed	10 / 203 (4.93%)	2 / 64 (3.13%)	3 / 65 (4.62%)	2 / 18 (11.11%)	2 / 48 (4.17%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences all number	12	4	4	3	2	1	0
Hypophosphataemia
subjects affected / exposed	10 / 203 (4.93%)	3 / 64 (4.69%)	3 / 65 (4.62%)	1 / 18 (5.56%)	5 / 48 (10.42%)	1 / 46 (2.17%)	0 / 5 (0.00%)
occurrences all number	18	6	6	1	5	1	0
Iron overload
subjects affected / exposed	0 / 203 (0.00%)	0 / 64 (0.00%)	0 / 65 (0.00%)	0 / 18 (0.00%)	3 / 48 (6.25%)	0 / 46 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	0	0	3	0	0
Type 2 diabetes mellitus
subjects affected / exposed	1 / 203 (0.49%)	2 / 64 (3.13%)	2 / 65 (3.08%)	0 / 18 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	1 / 5 (20.00%)
occurrences all number	1	2	2	0	0	1	1

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Were there any global substantial amendments to the protocol? Yes

27 Oct 2010

The purposes of Protocol Amendment 1 were to: • Mandate examination of 20 metaphases for participant inclusion. • Clarify number of days within which prior treatments were allowed prior to first dose of ponatinib considering the phase of disease. • Update schedule of events and corresponding footnotes for EOT assessments. • Provide clarification on use of dose modification guidelines for AEs attributable to study drug. • Update guidance on dose modification for pancreatitis attributable to study drug in accordance with NCI CTCAE v4. • Include guidance on dose modification for QT prolongation (corrected by Fridericia formula; QTcF) attributable to study drug in accordance with NCI CTCAE v4. • Provide recommendation for ECG monitoring when a participant was taking concomitant medications known to prolong QTc interval. • Update Attachment A – response criteria.

08 Apr 2011

The purposes of Protocol Amendment 2 were to: • Increase overall sample size of the study to allow for over-enrollment in the R/I cohorts to ensure full participant enrollment in the T315I cohorts. • Incorporate details from an administrative letter that was prepared and submitted to investigative sites in March 2011 to clarify concomitant use and administration of hydroxyurea and anagrelide.

24 May 2012

The purposes of Protocol Amendment 3 were to: • Extend the duration of treatment beyond the original plan of 2 years. • Decrease the number of study assessments after the initial 2 years of treatment. • To make other clarifications based on regulatory updates, new information.

27 Mar 2013

The purposes of Protocol Amendment 4 were to: • Adverse Events of Special Interest (AESIs) were added and defined. The list of AESIs was developed based on a growing understanding of the drug’s safety profile gathered from ongoing ponatinib clinical studies and experience from the expanded access program. AESIs are reported to the sponsor in the same manner as SAEs, regardless of whether they meet the regulatory definition of seriousness. • Language on drug-drug interactions was updated to reflect results of drug-drug interaction studies. • The dose modification table for ponatinib was aligned with other studies. • The bone marrow (BM) assessment schedule was modified to allow greater participant convenience in later cycles, while maintaining close assessment of clinical benefit. • Treatment administration was updated to reflect the fact that food does not affect the PK profile of ponatinib.

03 Apr 2015

The purposes of Protocol Amendment 5 were to: • Provide recommendations to investigators for ponatinib dose reduction based on response, to minimize the risk of AEs with ponatinib while maintaining response. These dose reduction recommendations were implemented via direct communication to investigators. • Provide updated information on the management of adverse drug reactions, including vascular occlusion, neuropathy, cardiac failure, and other events. The updated information included both the nature of the risks and recommendations for management of these events. • Provide an updated section on AESIs, updating the list of events considered AESIs and clarifying investigator’s reporting responsibilities. • Provide information on multivariate analyses performed on AP24534-10-201 study data, which sought to explore the impact of dose intensity and several prognostic and predictive factors on clinical responses, AEs, and laboratory changes. • Provide updated guidelines for ponatinib dose modification for management of AEs attributable to study drug. • Revise the criteria for study discontinuation to include MI, stroke, or urgent revascularization, unless the benefit of study drug was believed to outweigh the risk, as determined by the investigator. • Provide guidance to the investigator on optimization of management of HTN and diabetes to decrease the risk of VOEs for participants taking ponatinib. • Add the definition of overdose and how to handle overdoses per standard reporting guidelines. • Provide an update of the ponatinib development program.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: A Pivotal Phase 2 Trial of Ponatinib (AP24534) in Patients with Refractory Chronic Myeloid Leukemia and Ph+ Acute Lymphoblastic Leukemia

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of CP-CML Participants with Major Cytogenetic Response (MCyR)

Primary: Percentage of CP-CML Participants with Major Cytogenetic Response (MCyR)

Primary: Percentage of AP-CML Participants with Major Hematologic Response (MaHR)

Primary: Percentage of AP-CML Participants with Major Hematologic Response (MaHR)

Primary: Percentage of BP-CML/Ph+ ALL Participants with MaHR

Primary: Percentage of BP-CML/Ph+ ALL Participants with MaHR

Secondary: Percentage of CP-CML Participants with CHR

Secondary: Percentage of CP-CML Participants with CHR

Secondary: Percentage of CP-CML Participants with Confirmed MCyR

Secondary: Percentage of CP-CML Participants with Confirmed MCyR

Secondary: Percentage of CP-CML Participants with Major Molecular Response (MMR)

Secondary: Percentage of CP-CML Participants with Major Molecular Response (MMR)

Secondary: Percentage of AP-CML or BP-CML/Ph+ ALL Participants with MCyR

Secondary: Percentage of AP-CML or BP-CML/Ph+ ALL Participants with MCyR

Secondary: Percentage of AP-CML or BP-CML/Ph+ ALL Participants with Confirmed MCyR

Secondary: Percentage of AP-CML or BP-CML/Ph+ ALL Participants with Confirmed MCyR

Secondary: Percentage of AP-CML or BP-CML/Ph+ ALL Participants with MMR

Secondary: Percentage of AP-CML or BP-CML/Ph+ ALL Participants with MMR

Secondary: Time to Response

Secondary: Time to Response

Secondary: Duration of Response

Secondary: Duration of Response

Secondary: Progression-free Survival (PFS)

Secondary: Progression-free Survival (PFS)

Secondary: Overall Survival (OS)

Secondary: Overall Survival (OS)

Secondary: Number of Participants with Treatment-Emergent Adverse Event (TEAE) and Serious AE (SAE)

Secondary: Number of Participants with Treatment-Emergent Adverse Event (TEAE) and Serious AE (SAE)

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A Pivotal Phase 2 Trial of Ponatinib (AP24534) in Patients with Refractory Chronic Myeloid Leukemia and Ph+ Acute Lymphoblastic Leukemia