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Clinical Trial Results:
A Phase 1/2 Study of Bosutinib (SKI-606) in Philadelphia Chromosome Positive Leukemias

Summary
EudraCT number	2005-004230-40
Trial protocol	DE ES HU AT FI SE GB
Global end of trial date	06 Aug 2015

Results information
Results version number	v1(current)
This version publication date	20 Aug 2016
First version publication date	20 Aug 2016
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

3160A4-200-WW

ISRCTN number

US NCT number

NCT00261846

WHO universal trial number (UTN)

Other trial identifiers

Alias ID: B1871006

Sponsor organisation name

Pfizer, Inc.

Sponsor organisation address

235 E 42nd Street, New York, United States, NY 10017

Public contact

Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com

Scientific contact

Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.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

06 Aug 2015

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

06 Aug 2015

Was the trial ended prematurely?

Yes

Main objective of the trial

This open-label, multicentre, continuous dosing, 2-part safety and efficacy Phase 1/2 study of oral bosutinib once daily in participants with Philadelphia chromosome-positive (Ph+) leukemia primarily defined the maximum tolerated dose (MTD) in participants with chronic phase (CP) chronic myelogenous leukemia (CML) resistant or refractory to imatinib and evaluated the overall pharmacokinetic (PK) parameters in this population. Secondary objectives were to determine the rate of major cytogenetic response (MCyR) in CP CML participants and to obtain data on the ability of bosutinib to inhibit phosphorylation of Crk-like protein (CrkL) and breakpoint cluster region-abelson kinase (Bcr-Abl) at various dose levels of bosutinib.

Protection of trial subjects

This study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Council for Harmonisation Good Clinical Practice Guidelines. In addition, all local regulatory requirements were followed, in particular, those affording greater protection to the safety of trial participants. The final protocol, amendments, and informed consent documentation were reviewed and approved by the Institutional Review Board(s) and/or Independent Ethics Committee(s) at each of the investigational centers participating in the study.

Background therapy

Evidence for comparator

Actual start date of recruitment

18 Jan 2006

Long term follow-up planned

Yes

Long term follow-up rationale

Efficacy, Safety

Long term follow-up duration

2 Years

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Argentina: 20

Country: Number of subjects enrolled

Australia: 9

Country: Number of subjects enrolled

Austria: 2

Country: Number of subjects enrolled

Brazil: 26

Country: Number of subjects enrolled

Canada: 16

Country: Number of subjects enrolled

Chile: 2

Country: Number of subjects enrolled

China: 43

Country: Number of subjects enrolled

Colombia: 4

Country: Number of subjects enrolled

Germany: 40

Country: Number of subjects enrolled

Spain: 10

Country: Number of subjects enrolled

Finland: 7

Country: Number of subjects enrolled

United Kingdom: 9

Country: Number of subjects enrolled

Hong Kong: 6

Country: Number of subjects enrolled

Hungary: 10

Country: Number of subjects enrolled

India: 22

Country: Number of subjects enrolled

Italy: 53

Country: Number of subjects enrolled

Korea, Republic of: 32

Country: Number of subjects enrolled

Mexico: 4

Country: Number of subjects enrolled

Netherlands: 17

Country: Number of subjects enrolled

Norway: 3

Country: Number of subjects enrolled

Peru: 6

Country: Number of subjects enrolled

Russian Federation: 66

Country: Number of subjects enrolled

Singapore: 5

Country: Number of subjects enrolled

South Africa: 9

Country: Number of subjects enrolled

Sweden: 1

Country: Number of subjects enrolled

Taiwan: 2

Country: Number of subjects enrolled

United States: 146

Worldwide total number of subjects

570

EEA total number of subjects

152

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)

451

From 65 to 84 years

117

85 years and over

Subject disposition

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Recruitment details

Screening details

Participants were analyzed based on worst disease stage since diagnosis and previous tyrosine kinase inhibitor usage prior to screening and classified into 1 of 11 cohorts.

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

Bosutinib 400 mg (Part 1)

Arm description

Single oral dose of bosutinib 400 milligram (mg) on Day 1 and then bosutinib 400 mg orally once daily continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in chronic phase second-line chronic myelogenous leukemia (CP2L-CML) Part 2 of the study.

Arm type

Experimental

Investigational medicinal product name

Bosutinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Bosutinib 400 mg administered orally once daily with water and food to potentially improve tolerance and absorption.

Bosutinib 500 mg (Part 1)

Arm description

Single oral dose of bosutinib 500 mg on Day 1 and then bosutinib 500 mg orally once daily continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in chronic phase second-line chronic myelogenous leukemia (CP2L-CML) Part 2 of the study.

Arm type

Experimental

Investigational medicinal product name

Bosutinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Bosutinib 500 mg administered orally once daily with water and food to potentially improve tolerance and absorption.

Bosutinib 600 mg (Part 1)

Arm description

Single oral dose of bosutinib 600 mg on Day 1 and then bosutinib 600 mg orally once daily continuously from Day 3 up to Week 4. Eleven participants who completed treatment in Part 1 were continued in chronic phase second-line chronic myelogenous leukemia (CP2L-CML) Part 2 of the study and 1 participant was continued in advanced phase chronic myelogenous leukemia (AP-CML) Part 2 of the study.

Arm type

Experimental

Investigational medicinal product name

Bosutinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Bosutinib 600 mg administered orally once daily with water and food to potentially improve tolerance and absorption.

Bosutinib 500 mg, CP2L-CML IM-R (Part 2)

Arm description

Bosutinib 500 mg was administered orally once-daily in participants with chronic phase second-line (CP2L) imatinib (IM) resistant/refractory (R) chronic myelogenous leukemia (CML); who had no prior proto-oncogene tyrosine-protein kinase sarcoma (Src), Abelson kinase (Abl), or Src-Abl inhibitor exposure other than IM.

Arm type

Experimental

Investigational medicinal product name

Bosutinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Bosutinib 500 mg administered orally once daily with water and food to potentially improve tolerance and absorption.

Bosutinib 500 mg, CP2L-CML IM-I (Part 2)

Arm description

Bosutinib 500 mg was administered orally once-daily in participants with chronic phase second-line (CP2L) imatinib (IM) intolerant (I) chronic myelogenous leukemia (CML); who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.

Arm type

Experimental

Investigational medicinal product name

Bosutinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Bosutinib 500 mg administered orally once daily with water and food to potentially improve tolerance and absorption.

Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2)

Arm description

Bosutinib 500 mg was administered orally once-daily in participants with chronic phase third-line (CP3L) imatinib (IM) resistant/intolerant (R/I), dasatinib (D) and nilotinib (NI) resistant/intolerant (R/I) or imatinib (IM) resistant/intolerant (R/I) and nilotinib (NI) intolerant (I) chronic myelogenous leukemia (CML).

Arm type

Experimental

Investigational medicinal product name

Bosutinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Bosutinib 500 mg administered orally once daily with water and food to potentially improve tolerance and absorption.

Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2)

Arm description

Bosutinib 500 mg was administered orally once-daily in participants with chronic phase third-line (CP3L) imatinib (IM) resistant/intolerant (R/I) and dasatinib (D) resistant (R) chronic myelogenous leukemia (CML).

Arm type

Experimental

Investigational medicinal product name

Bosutinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Bosutinib 500 mg administered orally once daily with water and food to potentially improve tolerance and absorption.

Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2)

Arm description

Bosutinib 500 mg was administered orally once-daily in participants with chronic phase third-line (CP3L) imatinib (IM) resistant/intolerant (R/I) and dasatinib (D) intolerant (I) chronic myelogenous leukemia (CML).

Arm type

Experimental

Investigational medicinal product name

Bosutinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Bosutinib 500 mg administered orally once daily with water and food to potentially improve tolerance and absorption.

Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2)

Arm description

Bosutinib 500 mg was administered orally once-daily in participants with chronic phase third-line (CP3L) imatinib (IM) resistant/intolerant (R/I) and nilotinib (NI) resistant (R) chronic myelogenous leukemia (CML).

Arm type

Experimental

Investigational medicinal product name

Bosutinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Bosutinib 500 mg administered orally once daily with water and food to potentially improve tolerance and absorption.

AP-CML Total (Part 2)

Arm description

All participants who received bosutinib 500 mg orally once daily in advanced phase (AP) chronic myelogenous leukemia (CML) who were imatinib (IM) resistant/intolerant (R/I) or Multi-TKI (multiple tyrosine kinase inhibitor: imatinib, dasatinib and/or nilotinib) resistant/intolerant (R/I).

Arm type

Experimental

Investigational medicinal product name

Bosutinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Bosutinib 500 mg administered orally once daily with water and food to potentially improve tolerance and absorption.

BP-CML Total (Part 2)

Arm description

All participants who received bosutinib 500 mg orally once daily in blast phase (BP) chronic myelogenous leukemia (CML) who were imatinib (IM) resistant/intolerant (R/I) or Multi-TKI (multiple tyrosine kinase inhibitor: imatinib, dasatinib and/or nilotinib) resistant/intolerant (R/I).

Arm type

Experimental

Investigational medicinal product name

Bosutinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Bosutinib 500 mg administered orally once daily with water and food to potentially improve tolerance and absorption.

Bosutinib 500 mg, Ph+ ALL (Part 2)

Arm description

Bosutinib 500 mg was administered orally once-daily in participants with philadelphia chromosome-positive acute lymphocytic leukemia (Ph+ ALL).

Arm type

Experimental

Investigational medicinal product name

Bosutinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Bosutinib 500 mg administered orally once daily with water and food to potentially improve tolerance and absorption.

Number of subjects in period 1	Bosutinib 400 mg (Part 1)	Bosutinib 500 mg (Part 1)	Bosutinib 600 mg (Part 1)	Bosutinib 500 mg, CP2L-CML IM-R (Part 2)	Bosutinib 500 mg, CP2L-CML IM-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2)	AP-CML Total (Part 2)	BP-CML Total (Part 2)	Bosutinib 500 mg, Ph+ ALL (Part 2)
Started	3	3	12	195	89	5	38	50	26	79	64	24
Completed	0	0	0	60	39	3	16	21	12	30	15	1
Not completed	3	3	12	135	50	2	22	29	14	49	49	23
Adverse event, serious fatal	-	-	-	37	7	1	10	12	3	30	44	22
Consent withdrawn by subject	-	-	-	9	8	1	3	3	-	2	-	-
Extension study	-	-	-	61	27	-	4	9	5	9	1	1
Discontinuation of study by sponsor	-	-	-	1	-	-	-	-	1	-	-	-
Unspecified	-	-	-	15	4	-	1	5	4	4	-	-
Lost to follow-up	-	-	-	12	4	-	4	-	1	4	4	-
Continued in to Part 2	3	3	12	-	-	-	-	-	-	-	-	-

Baseline characteristics

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Reporting group title

Overall Study

Reporting group description

Reporting group values	Overall Study	Total
Number of subjects	570	570
Age, Customized
Units: Participants
<18 years	0	0
Between 18 and 64 years	451	451
Between 65 and 84 years	117	117
>=85 years	2	2
Age continuous
Units: years
arithmetic mean (full range (min-max))	51.6 (18 to 91)	-
Gender, Male/Female
Units: participants
Female	270	270
Male	300	300

End points

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Reporting group title

Bosutinib 400 mg (Part 1)

Reporting group description

Reporting group title

Bosutinib 500 mg (Part 1)

Reporting group description

Reporting group title

Bosutinib 600 mg (Part 1)

Reporting group description

Reporting group title

Bosutinib 500 mg, CP2L-CML IM-R (Part 2)

Reporting group description

Reporting group title

Bosutinib 500 mg, CP2L-CML IM-I (Part 2)

Reporting group description

Reporting group title

Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2)

Reporting group description

Reporting group title

Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2)

Reporting group description

Reporting group title

Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2)

Reporting group description

Reporting group title

Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2)

Reporting group description

Reporting group title

AP-CML Total (Part 2)

Reporting group description

Reporting group title

BP-CML Total (Part 2)

Reporting group description

Reporting group title

Bosutinib 500 mg, Ph+ ALL (Part 2)

Reporting group description

Bosutinib 500 mg was administered orally once-daily in participants with philadelphia chromosome-positive acute lymphocytic leukemia (Ph+ ALL).

Subject analysis set title

Bosutinib 500 mg, AP-CML IM R/I (Part 2)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Bosutinib 500 mg was administered orally once-daily in participants with advanced phase (AP) imatinib (IM) resistant/intolerant (R/I) chronic myelogenous leukemia (CML); who had no prior proto-oncogene tyrosine-protein kinase sarcoma (Src), abelson kinase (Abl), or Src-Abl inhibitor exposure other than IM.

Subject analysis set title

Bosutinib 500 mg, AP-CML Multi-TKI R/I (Part 2)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Bosutinib 500 mg was administered orally once-daily in participants with advanced phase (AP) Multi-TKI (multiple tyrosine kinase inhibitor: imatinib, dasatinib and/or nilotinib) resistant/intolerant (R/I) chronic myelogenous leukemia (CML).

Subject analysis set title

Bosutinib 500 mg, BP-CML IM R/I (Part 2)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Bosutinib 500 mg was administered orally once-daily in participants with blast phase (BP) imatinib (IM) resistant/intolerant (R/I) chronic myelogenous leukemia (CML).

Subject analysis set title

Bosutinib 500 mg, BP-CML Multi-TKI R/I (Part 2)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Bosutinib 500 mg was administered orally once-daily in participants with blast phase (BP) Multi-TKI (multiple tyrosine kinase inhibitor: imatinib, dasatinib and/or nilotinib) resistant/intolerant (R/I) chronic myelogenous leukemia (CML).

Primary: Number of Participants With Dose Limiting Toxicity (DLT)

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End point title

Number of Participants With Dose Limiting Toxicity (DLT) ^[1] ^[2]

End point description

DLT was defined as any of the following events occurring during the first 28 days of study medication and considered at least possibly-related to study medication: any grade 3 or 4 clinically-relevant non-hematologic toxicity, any clinically-significant grade 2 non-hematologic toxicity that requires 14 days to resolve (to grade 1). Safety population included all participants who received at least 1 dose of study medication.

End point type

Primary

End point timeframe

Part 1 Baseline up to Day 28

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: The planned analysis was descriptive only.
[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: Only data for Part 1 are presented for this endpoint.

End point values	Bosutinib 400 mg (Part 1)	Bosutinib 500 mg (Part 1)	Bosutinib 600 mg (Part 1)
Number of subjects analysed	3	3	12
Units: participants	0	0	1

No statistical analyses for this end point

Primary: Maximum Tolerated Dose (MTD)

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End point title

Maximum Tolerated Dose (MTD) ^[3] ^[4]

End point description

MTD was defined as highest dose level for which no more than 1 participant in a dose cohort experienced DLT. DLT was defined as any of the following events occurring during the first 28 days of study medication and considered at least possibly-related to study medication: any grade 3 or 4 clinically-relevant non-hematologic toxicity, any clinically-significant grade 2 non-hematologic toxicity that requires 14 days to resolve (to grade 1).9999 = not estimable, MTD was not achieved since no more than 1 DLT was observed in any cohort. At the 600mg dose level, 1 DLT and several treatment related grade 2 toxicities were observed, thus, Bosutinib 500 mg was selected as the recommended dose for part 2. Safety population, included all participants who received at least 1 dose of study medication.

End point type

Primary

End point timeframe

Part 1 Baseline up to Day 28

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: The planned analysis was descriptive only.
[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: Only data for Part 1 are presented for this endpoint.

End point values	Bosutinib 400 mg (Part 1)	Bosutinib 500 mg (Part 1)	Bosutinib 600 mg (Part 1)
Number of subjects analysed	3	3	12
Units: mg	9999	9999	9999

No statistical analyses for this end point

Primary: Maximum Observed Plasma Concentration (Cmax) - Part 1

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End point title

Maximum Observed Plasma Concentration (Cmax) - Part 1 ^[5] ^[6]

End point description

Evaluable population included all enrolled participants who received at least 1 dose of study medication and had an adequate baseline efficacy assessment.

End point type

Primary

End point timeframe

0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1

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: The planned analysis was descriptive only.
[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: Only data for Part 1 are presented for this endpoint.

End point values	Bosutinib 400 mg (Part 1)	Bosutinib 500 mg (Part 1)	Bosutinib 600 mg (Part 1)
Number of subjects analysed	3	3	12
Units: nanogram per milliliter (ng/mL)
arithmetic mean (standard deviation)	89.3 ± 50	101 ± 35.6	120 ± 40.2

No statistical analyses for this end point

Primary: Time to Reach Maximum Observed Plasma Concentration (Tmax) - Part 1

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End point title

Time to Reach Maximum Observed Plasma Concentration (Tmax) - Part 1 ^[7] ^[8]

End point description

Evaluable population included all enrolled participants who received at least one dose of study medication and had an adequate baseline efficacy assessment.

End point type

Primary

End point timeframe

0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1

Notes
[7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The planned analysis was descriptive only.
[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: Only data for Part 1 are presented for this endpoint.

End point values	Bosutinib 400 mg (Part 1)	Bosutinib 500 mg (Part 1)	Bosutinib 600 mg (Part 1)
Number of subjects analysed	3	3	12
Units: hours (hrs)
median (full range (min-max))	4 (3.33 to 48.08)	6 (6 to 6)	4 (2.17 to 49.33)

No statistical analyses for this end point

Primary: Plasma Decay Half-Life (t1/2) - Part 1

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End point title

Plasma Decay Half-Life (t1/2) - Part 1 ^[9] ^[10]

End point description

Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.9999 = not estimable, standard deviation was not estimable since only 2 participants were evaluable. Evaluable population included all enrolled participants who received at least 1 dose of study medication and had an adequate baseline efficacy assessment. 'N' (number of participants analyzed) signifies number of participants who were evaluable for this measure.

End point type

Primary

End point timeframe

0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1

Notes
[9] - 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: The planned analysis was descriptive only.
[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: Only data for Part 1 are presented for this endpoint.

End point values	Bosutinib 400 mg (Part 1)	Bosutinib 500 mg (Part 1)	Bosutinib 600 mg (Part 1)
Number of subjects analysed	2	3	8
Units: hrs
arithmetic mean (standard deviation)	22.91 ± 9999	22.46 ± 1.73	22.24 ± 5.03

No statistical analyses for this end point

Primary: Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC(0-48)] - Part 1

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End point title

Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC(0-48)] - Part 1 ^[11] ^[12]

End point description

AUC(0-48)= Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-48). Evaluable population included all enrolled participants who received at least 1 dose of study medication and had an adequate baseline efficacy assessment.

End point type

Primary

End point timeframe

0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1

Notes
[11] - 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: The planned analysis was descriptive only.
[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: Only data for Part 1 are presented for this endpoint.

End point values	Bosutinib 400 mg (Part 1)	Bosutinib 500 mg (Part 1)	Bosutinib 600 mg (Part 1)
Number of subjects analysed	3	3	12
Units: ng*hr/mL
arithmetic mean (standard deviation)	1850 ± 710	2060 ± 483	2340 ± 1140

No statistical analyses for this end point

Primary: Area under the Concentration-Time Curve (AUC) - Part 1

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End point title

Area under the Concentration-Time Curve (AUC) - Part 1 ^[13] ^[14]

End point description

AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption. 9999 = not estimable, standard deviation was not estimable since only 2 participants were evaluable Evaluable population included all enrolled participants who received at least 1 dose of study medication and had an adequate baseline efficacy assessment. 'N' (number of participants analyzed) signifies number of participants who were evaluable for this measure.

End point type

Primary

End point timeframe

0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1

Notes
[13] - 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: The planned analysis was descriptive only.
[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: Only data for Part 1 are presented for this endpoint.

End point values	Bosutinib 400 mg (Part 1)	Bosutinib 500 mg (Part 1)	Bosutinib 600 mg (Part 1)
Number of subjects analysed	2	3	8
Units: ng*hr/mL
arithmetic mean (standard deviation)	2530 ± 9999	2760 ± 687	2420 ± 457

No statistical analyses for this end point

Primary: Apparent Oral Clearance (CL/F) - Part 1

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End point title

Apparent Oral Clearance (CL/F) - Part 1 ^[15] ^[16]

End point description

Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. 9999 = not estimable. Evaluable population included all enrolled participants who received at least 1 dose of study medication and had an adequate baseline efficacy assessment. 'N' (number of participants analyzed) signifies number of participants who were evaluable for this measure.

End point type

Primary

End point timeframe

0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1

Notes
[15] - 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: The planned analysis was descriptive only.
[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: Only data for Part 1 are presented for this endpoint.

End point values	Bosutinib 400 mg (Part 1)	Bosutinib 500 mg (Part 1)	Bosutinib 600 mg (Part 1)
Number of subjects analysed	2	3	8
Units: liter per hour (L/hr)
arithmetic mean (standard deviation)	177 ± 9999	189 ± 47.5	258 ± 61.2

No statistical analyses for this end point

Primary: Apparent Volume of Distribution (Vz/F) - Part 1

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End point title

Apparent Volume of Distribution (Vz/F) - Part 1 ^[17] ^[18]

End point description

Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed. Evaluable population included all enrolled participants who received at least 1 dose of study medication and had an adequate baseline efficacy assessment. 'N' (number of participants analyzed) signifies number of participants who were evaluable for this measure.

End point type

Primary

End point timeframe

0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1

Notes
[17] - 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: The planned analysis was descriptive only.
[18] - 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: Only data for Part 1 are presented for this endpoint.

End point values	Bosutinib 400 mg (Part 1)	Bosutinib 500 mg (Part 1)	Bosutinib 600 mg (Part 1)
Number of subjects analysed	3	3	8
Units: liter
arithmetic mean (standard deviation)	6050 ± 3550	6080 ± 1230	8540 ± 3820

No statistical analyses for this end point

Primary: Maximum Observed Plasma Concentration at Steady State (Cmax,ss) - Part 1

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End point title

Maximum Observed Plasma Concentration at Steady State (Cmax,ss) - Part 1 ^[19] ^[20]

End point description

Maximum plasma concentration over 24 hours at steady state (ss), on Day 15. Evaluable population included all enrolled participants who received at least 1 dose of study medication and had an adequate baseline efficacy assessment. 'N' (number of participants analyzed) signifies number of participants who were evaluable for this measure.

End point type

Primary

End point timeframe

0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 15

Notes
[19] - 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: The planned analysis was descriptive only..
[20] - 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: Only data for Part 1 are presented for this endpoint.

End point values	Bosutinib 400 mg (Part 1)	Bosutinib 500 mg (Part 1)	Bosutinib 600 mg (Part 1)
Number of subjects analysed	3	3	10
Units: ng/mL
arithmetic mean (standard deviation)	146 ± 20	200 ± 11.9	208 ± 73.3

No statistical analyses for this end point

Primary: Time to Reach Maximum Observed Plasma Concentration at Steady State (Tmax,ss) - Part 1

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End point title

Time to Reach Maximum Observed Plasma Concentration at Steady State (Tmax,ss) - Part 1 ^[21] ^[22]

End point description

Time to reach maximum observed plasma concentration over 24 hours at steady state (ss), on Day 15. Evaluable population included all enrolled participants who received at least 1 dose of study medication and had an adequate baseline efficacy assessment.

End point type

Primary

End point timeframe

0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 15

Notes
[21] - 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: The planned analysis was descriptive only.
[22] - 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: Only data for Part 1 are presented for this endpoint.

End point values	Bosutinib 400 mg (Part 1)	Bosutinib 500 mg (Part 1)	Bosutinib 600 mg (Part 1)
Number of subjects analysed	3	3	12
Units: hrs
median (full range (min-max))	4.05 (3.08 to 6.08)	6.05 (4 to 8)	6 (2.83 to 11.08)

No statistical analyses for this end point

Primary: Plasma Decay Half-Life at Steady State (t1/2,ss) - Part 1

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End point title

Plasma Decay Half-Life at Steady State (t1/2,ss) - Part 1 ^[23] ^[24]

End point description

Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. Plasma decay half-life over 24 hours at steady state (ss), on Day 15 was calculated. Evaluable population included all enrolled participants who received at least 1 dose of study medication and had an adequate baseline efficacy assessment. 'N' (number of participants analyzed) signifies number of participants who were evaluable for this measure.

End point type

Primary

End point timeframe

0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 15

Notes
[23] - 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: The planned analysis was descriptive only.
[24] - 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: Only data for Part 1 are presented for this endpoint.

End point values	Bosutinib 400 mg (Part 1)	Bosutinib 500 mg (Part 1)	Bosutinib 600 mg (Part 1)
Number of subjects analysed	3	3	7
Units: hrs
arithmetic mean (standard deviation)	45.96 ± 32.3	21.71 ± 4.64	25.87 ± 24.85

No statistical analyses for this end point

Primary: Area under the Concentration-Time Curve at Steady State (AUCss) - Part 1

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End point title

Area under the Concentration-Time Curve at Steady State (AUCss) - Part 1 ^[25] ^[26]

End point description

AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption. AUC over 24 hours at steady state (ss), on Day 15 was calculated. Evaluable population included all enrolled participants who received at least 1 dose of study medication and had an adequate baseline efficacy assessment. 'N' (number of participants analyzed) signifies number of participants who were evaluable for this measure.

End point type

Primary

End point timeframe

0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 15

Notes
[25] - 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: The planned analysis was descriptive only.
[26] - 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: Only data for Part 1 are presented for this endpoint.

End point values	Bosutinib 400 mg (Part 1)	Bosutinib 500 mg (Part 1)	Bosutinib 600 mg (Part 1)
Number of subjects analysed	3	3	9
Units: ng*hr/mL
arithmetic mean (standard deviation)	2720 ± 442	3650 ± 425	3630 ± 1270

No statistical analyses for this end point

Primary: Apparent Oral Clearance at Steady State (CL/F,ss) - Part 1

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End point title

Apparent Oral Clearance at Steady State (CL/F,ss) - Part 1 ^[27] ^[28]

End point description

Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. Apparent oral clearance over 24 hours at steady state (ss), on Day 15 was calculated. Evaluable population included all enrolled participants who received at least 1 dose of study medication and had an adequate baseline efficacy assessment. 'N' (number of participants analyzed) signifies number of participants who were evaluable for this measure.

End point type

Primary

End point timeframe

0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 15

Notes
[27] - 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: The planned analysis was descriptive only.
[28] - 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: Only data for Part 1 are presented for this endpoint.

End point values	Bosutinib 400 mg (Part 1)	Bosutinib 500 mg (Part 1)	Bosutinib 600 mg (Part 1)
Number of subjects analysed	3	3	9
Units: L/hr
arithmetic mean (standard deviation)	150 ± 23.2	138 ± 16.6	185 ± 66.2

No statistical analyses for this end point

Primary: Accumulation Ratio (R)

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End point title

Accumulation Ratio (R) ^[29] ^[30]

End point description

R=accumulation ratio (AUCss on Day 15/AUC0-24 on Day 1) Evaluable population included all enrolled participants who received at least 1 dose of study medication and had an adequate baseline efficacy assessment. 'N' (number of participants analyzed) signifies number of participants who were evaluable for this measure.

End point type

Primary

End point timeframe

0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 1 and Day 15

Notes
[29] - 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: The planned analysis was descriptive only.
[30] - 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: Only data for Part 1 are presented for this endpoint.

End point values	Bosutinib 400 mg (Part 1)	Bosutinib 500 mg (Part 1)	Bosutinib 600 mg (Part 1)
Number of subjects analysed	3	3	9
Units: ratio
arithmetic mean (standard deviation)	3.1 ± 1.4	2.8 ± 0.8	2.5 ± 0.9

No statistical analyses for this end point

Primary: Percentage of Participants With MCyR at Week 24 in Chronic Phase Second-line Imatinib Resistant CML Population - Part 2

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End point title

Percentage of Participants With MCyR at Week 24 in Chronic Phase Second-line Imatinib Resistant CML Population - Part 2 ^[31] ^[32]

End point description

CyR is based on the prevalence of Ph+ cells. Major cytogenetic response was categorized as either CCyR or partial CyR (PCyR). CCyR was achieved when there was 0 percent (%) Ph+ cells from at least 20 metaphases from conventional bone marrow cytogenetics or less than (<) 1% positive cells from at least 200 cells analyzed from fluorescent in situ hybridization (FISH). PCyR was achieved when 1 to 35% Ph+ cells were present. Cytogenetic evaluable population included all enrolled participants who received at least one dose of study medication and had an adequate baseline cytogenetic assessment.

End point type

Primary

End point timeframe

Week 24

Notes
[31] - 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: The planned analysis was descriptive only.
[32] - 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: Only data for Part 2 are presented for this endpoint.

End point values	Bosutinib 500 mg, CP2L-CML IM-R (Part 2)
Number of subjects analysed	182
Units: percentage of participants
number (confidence interval 95%)	35.7 (28.8 to 43.1)

No statistical analyses for this end point

Secondary: Percentage of Participants With Major Cytogenetic Response (MCyR) - Part 1

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End point title

Percentage of Participants With Major Cytogenetic Response (MCyR) - Part 1 ^[33]

End point description

Cytogenetic response (CyR) is based on the prevalence of Philadelphia positive (Ph+) cells. Major cytogenetic response was categorized as either complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR). CCyR was achieved when there was 0% Ph+ cells from at least 20 metaphases from conventional bone marrow cytogenetics or <1% positive cells from at least 200 cells analyzed from FISH. PCyR was achieved when 1 to 35% Ph+ cells were present. Cytogenetic evaluable population included all enrolled participants who received at least 1 dose of study medication and had an adequate baseline cytogenetic assessment.

End point type

Secondary

End point timeframe

Week 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks thereafter

Notes
[33] - 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: Only data for Part 1 are presented for this endpoint.

End point values	Bosutinib 400 mg (Part 1)	Bosutinib 500 mg (Part 1)	Bosutinib 600 mg (Part 1)
Number of subjects analysed	3	3	12
Units: percentage of participants
number (confidence interval 95%)	66.7 (9.4 to 99.2)	33.3 (0.8 to 90.6)	50 (21.1 to 78.9)

No statistical analyses for this end point

Secondary: Phosphorylation Inhibition of Breakpoint Cluster Region-Abelson Kinase (bcr-Abl) - Part 1

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End point title

Phosphorylation Inhibition of Breakpoint Cluster Region-Abelson Kinase (bcr-Abl) - Part 1 ^[34]

End point description

bcr-Abl is a protein resulting from the transcription of the Philadelphia chromosome following 9:22 chromosomal translocation, and phosphorylation inhibition of which correlates with inhibition of tumor cell growth. Data was not summarized since inadequate data included the issue that molecular transcript analyses could not be performed, because of potential sample quality issues due to time required to transport the specimens from the few investigational sites to the central laboratory.

End point type

Secondary

End point timeframe

Baseline, Week 4, 8, 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks

Notes
[34] - 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: Only data for Part 1 are presented for this endpoint.

End point values	Bosutinib 400 mg (Part 1)	Bosutinib 500 mg (Part 1)	Bosutinib 600 mg (Part 1)
Number of subjects analysed	0 ^[35]	0 ^[36]	0 ^[37]
Units: moles per 100 cells (mol/100 cells)
number (confidence interval 95%)	( to )	( to )	( to )

Notes
[35] - Data not summarized, molecular transcript analyses not performed due to poor sample quality.
[36] - Data not summarized, molecular transcript analyses not performed due to poor sample quality.
[37] - Data not summarized, molecular transcript analyses not performed due to poor sample quality.

No statistical analyses for this end point

Secondary: Phosphorylation Inhibition of Crk Like (CrkL) Protein at Baseline - Part 1

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End point title

Phosphorylation Inhibition of Crk Like (CrkL) Protein at Baseline - Part 1 ^[38]

End point description

CrkL is a protein, phosphorylation of which has been shown to correlate with CML cell growth; and conversely of their phosphorylation correlates with inhibition of tumor cell growth. Phosphorylation of CrkL was monitored in whole blood cells, as well as in the cluster of differentiation 3 (CD3+) (T cell), CD19+ (B cell) and CD34+ (blast cell) compartments by using fluorescent activated cell sorter (FACS) flow cytometry. Evaluable population included all enrolled participants who received at least 1 dose of study medication and had an adequate baseline efficacy assessment. 'N' (number of participants analyzed) signifies number of participants who were evaluable for this measure.

End point type

Secondary

End point timeframe

0 (pre-dose) on Day 1 (Baseline)

Notes
[38] - 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: Only data for Part 1 are presented for this endpoint.

End point values	Bosutinib 400 mg (Part 1)	Bosutinib 500 mg (Part 1)	Bosutinib 600 mg (Part 1)
Number of subjects analysed	2	3	10
Units: mol/100 cells
arithmetic mean (standard deviation)	457075 ± 559841.9	297967.33 ± 171643.3	397795.4 ± 552536.9

No statistical analyses for this end point

Secondary: Percent Change From Baseline in Phosphorylation Inhibition of Crk Like Protein (CrkL) at Day 1, 8 and 15 - Part 1

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End point title

Percent Change From Baseline in Phosphorylation Inhibition of Crk Like Protein (CrkL) at Day 1, 8 and 15 - Part 1 ^[39]

End point description

CrkL is a protein, phosphorylation of which has been shown to correlate with CML cell growth; and conversely inhibition of their phosphorylation correlates with inhibition of tumor cell growth. Phosphorylation of CrkL was monitored in whole blood cells, as well as in the CD3+ (T cell), CD19+ (B cell) and CD34+ (blast cell) compartments by using FACS flow cytometry.9999 = not estimable, standard deviation was not estimable since only 1 participant was evaluable. Evaluable population included all enrolled participants who received at least 1 dose of study medication and had an adequate baseline efficacy assessment. 'N' signifies number of participants who were evaluable for this measure. n=number of participants evaluable for this measure at specified time points for each arm group respectively.

End point type

Secondary

End point timeframe

6 hours post-dose on Day 1, 0 (pre-dose), 6 hours post-dose on Day 8, 15

Notes
[39] - 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: Only data for Part 1 are presented for this endpoint.

End point values	Bosutinib 400 mg (Part 1)	Bosutinib 500 mg (Part 1)	Bosutinib 600 mg (Part 1)
Number of subjects analysed	1	3	9
Units: percent change
arithmetic mean (standard deviation)
Day 1: post-dose (n=1, 1, 9)	-34.66 ± 9999	287.52 ± 9999	97.79 ± 283.61
Day 8: pre-dose (n=1, 1, 9)	562.48 ± 9999	170.83 ± 9999	3.88 ± 128.97
Day 8: post-dose (n=1, 1, 9)	528.62 ± 9999	429.79 ± 9999	143.57 ± 289.18
Day 15: pre-dose (n=1, 2, 7)	177.87 ± 9999	-44.64 ± 8.56	119.23 ± 170.91
Day 15: post-dose (n=1, 3, 7)	-49.85 ± 9999	-21.13 ± 57.91	138.45 ± 278.24

No statistical analyses for this end point

Secondary: Percentage of Participants With Major Cytogenetic Response (MCyR) in Chronic Phase Second-line and Chronic Phase Third-line CML Population - Part 2

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End point title

Percentage of Participants With Major Cytogenetic Response (MCyR) in Chronic Phase Second-line and Chronic Phase Third-line CML Population - Part 2 ^[40]

End point description

CyR is based on the prevalence of Ph+ cells. MCyR was categorized as either CCyR or PCyR. CCyR was achieved when there was 0% Ph+ cells from at least 20 metaphases from conventional bone marrow cytogenetics or <1% positive cells from at least 200 cells analyzed from FISH. PCyR was achieved when 1 to 35% Ph+ cells were present. Cytogenetic evaluable population included all enrolled participants who received at least one dose of study medication and had an adequate baseline cytogenetic assessment.

End point type

Secondary

End point timeframe

Week 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks thereafter up to Year 4 (CP3L) or Year 5 (CP2L)

Notes
[40] - 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: Only data for Part 2 are presented for this endpoint.

End point values	Bosutinib 500 mg, CP2L-CML IM-R (Part 2)	Bosutinib 500 mg, CP2L-CML IM-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2)
Number of subjects analysed	182	80	5	36	45	26
Units: percentage of participants
number (confidence interval 95%)	58.8 (51.3 to 66)	61.3 (49.7 to 71.9)	40 (5.3 to 85.3)	38.9 (23.1 to 56.5)	42.2 (27.7 to 57.9)	38.5 (20.2 to 59.4)

No statistical analyses for this end point

Secondary: Kaplan-Meier Estimate of Retaining an Attained/Maintained Major Cytogenetic Response (MCyR) at Year 5 in Chronic Phase Second-line CML - Part 2

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End point title

Kaplan-Meier Estimate of Retaining an Attained/Maintained Major Cytogenetic Response (MCyR) at Year 5 in Chronic Phase Second-line CML - Part 2 ^[41]

End point description

MCyR was categorized as either CCyR or PCyR. CCyR was achieved when there was 0% Ph+ cells from at least 20 metaphases from conventional bone marrow cytogenetics or <1% positive cells from at least 200 cells analyzed from FISH. PCyR was achieved when 1 to 35% Ph+ cells were present. The Kaplan-Meier probability of retaining an attained/maintained MCyR at Year 5 is reported. Median durations were not reached as of the minimum follow-up. Duration of response in weeks =(date of confirmed loss of first attained response or last valid cytogenetic assessment for those censored - date of first attained response)/7. Subgroup of participants from evaluable population who had MCyR.

End point type

Secondary

End point timeframe

From first MCyR to loss of MCyR or censoring, assessed every 12 weeks up to 2 years and then every 24 weeks thereafter

Notes
[41] - 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: Only data for Part 2 are presented for this endpoint.

End point values	Bosutinib 500 mg, CP2L-CML IM-R (Part 2)	Bosutinib 500 mg, CP2L-CML IM-I (Part 2)
Number of subjects analysed	107	49
Units: % probability of retaining MCyR
number (confidence interval 95%)	67.2 (56.8 to 75.6)	79.8 (63.1 to 89.5)

No statistical analyses for this end point

Secondary: Time to Achieve Major Cytogenetic Response (MCyR) in Chronic Phase Second-line CML for Responders Only - Part 2

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End point title

Time to Achieve Major Cytogenetic Response (MCyR) in Chronic Phase Second-line CML for Responders Only - Part 2 ^[42]

End point description

MCyR was categorized as either CCyR or PCyR. CCyR was achieved when there was 0% Ph+ cells from at least 20 metaphases from conventional bone marrow cytogenetics or <1% positive cells from at least 200 cells analyzed from FISH. PCyR was achieved when 1 to 35% Ph+ cells were present. Time to MCyR was the interval from the date of first dose of study medication until the first date of achieving a given response. Time to response in weeks equals (=) (event date minus (-) first dose date plus (+) 1)divided (/)7, where the event date is the non-missing date of the first attained response for responders only. Cytogenetic evaluable population included all enrolled participants who received at least one dose of study medication and had an adequate baseline cytogenetic assessment.

End point type

Secondary

End point timeframe

Week 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks thereafter

Notes
[42] - 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: Only data for Part 2 are presented for this endpoint.

End point values	Bosutinib 500 mg, CP2L-CML IM-R (Part 2)	Bosutinib 500 mg, CP2L-CML IM-I (Part 2)
Number of subjects analysed	107	49
Units: weeks
median (confidence interval 95%)	12.3 (12.1 to 24)	12.1 (12 to 12.3)

No statistical analyses for this end point

Secondary: Kaplan-Meier Estimate of Maintaining Complete Hematologic Response (CHR) at Year 4 (CP3L and ADV) or Year 5 (CP2L) for Responders Only, Part 2 - Hematologic Evaluable Population

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End point title

Kaplan-Meier Estimate of Maintaining Complete Hematologic Response (CHR) at Year 4 (CP3L and ADV) or Year 5 (CP2L) for Responders Only, Part 2 - Hematologic Evaluable Population ^[43]

End point description

Hematologic response: if participants met all of the following criteria of CHR: White Blood Cells equal to or less than (≤) institutional upper limit of normal, no peripheral blood blasts or promyelocytes, myelocytes+metamyelocytes less than (<)5% in blood, absolute neutrophil count greater than or equal to (≥) 1.0×10^9 per liter (/L) , platelets ≥100×10^9/L & <450×10^9/L, <20% basophils in blood & no extramedually involvement (including hepato- or splenomegaly), ≤5% BM blasts (ADV only & applicable to CP if BM aspirate was performed). The duration of CHR was defined as the interval from the first date of response until the first date of confirmed loss of response. Duration of response in weeks =(date of confirmed loss of attained response or last valid hematologic assessment for those censored - date of first confirmed response)/7. The Kaplan-Meier estimate of maintaining CHR at the end of minimum follow-up is presented (CP2L: Year 5; CP3L & ADV: Year 4). -9999/9999 = not estimable.

End point type

Secondary

End point timeframe

From date of first confirmed CHR to loss of CHR or censoring, assessed at Day 1 and 7 of Week 1, Day 7 of Week 2, 3, 4, 8, 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks thereafter

Notes
[43] - 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: Only data for Part 2 are presented for this endpoint.

End point values	Bosutinib 500 mg, CP2L-CML IM-R (Part 2)	Bosutinib 500 mg, CP2L-CML IM-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2)	Bosutinib 500 mg, Ph+ ALL (Part 2)	Bosutinib 500 mg, AP-CML IM R/I (Part 2)	Bosutinib 500 mg, AP-CML Multi-TKI R/I (Part 2)	Bosutinib 500 mg, BP-CML IM R/I (Part 2)	Bosutinib 500 mg, BP-CML Multi-TKI R/I (Part 2)
Number of subjects analysed	169	76	4	26	37	19	2	17	7	9	1
Units: % estimate of maintaining response
number (confidence interval 95%)	61.5 (52.9 to 69.1)	78.2 (64.4 to 87.1)	50 (5.8 to 84.5)	56.5 (30.9 to 75.8)	69.9 (49.7 to 83.3)	61.9 (33.6 to 81)	100 (-9999 to 100)	47.1 (20.7 to 69.7)	64.3 (15.1 to 90.2)	9999 (9999 to 9999)	9999 (9999 to 9999)

No statistical analyses for this end point

Secondary: Duration of Complete Hematologic Response (CHR) for Responders Only, Part 2 - Hematologic Evaluable Population

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End point title

Duration of Complete Hematologic Response (CHR) for Responders Only, Part 2 - Hematologic Evaluable Population ^[44]

End point description

Hematologic response: if participants met all of the following criteria of CHR: White Blood Cells equal to or less than (≤) institutional upper limit of normal, no peripheral blood blasts or promyelocytes, myelocytes+metamyelocytes less than (<)5% in blood, absolute neutrophil count greater than or equal to (≥) 1.0×10^9 per liter (/L) , platelets <450×10^9/L, platelets ≥100×10^9/L, <20% basophils in blood and no extramedually involvement (including hepato- or splenomegaly), ≤5% BM blasts (required for ADV only and applicable to CP if BM aspirate was performed). The duration of CHR was defined as the interval from the first date of response until the first date of confirmed loss of response. Duration of response in weeks =(date of confirmed loss of attained response or last valid hematologic assessment for those censored - date of first confirmed response)/7. -9999/9999 = not estimable, median duration was not reached prior to minimum follow-up period.

End point type

Secondary

End point timeframe

Notes
[44] - 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: Only data for Part 2 are presented for this endpoint.

End point values	Bosutinib 500 mg, CP2L-CML IM-R (Part 2)	Bosutinib 500 mg, CP2L-CML IM-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2)	Bosutinib 500 mg, Ph+ ALL (Part 2)	Bosutinib 500 mg, AP-CML IM R/I (Part 2)	Bosutinib 500 mg, AP-CML Multi-TKI R/I (Part 2)	Bosutinib 500 mg, BP-CML IM R/I (Part 2)	Bosutinib 500 mg, BP-CML Multi-TKI R/I (Part 2)
Number of subjects analysed	169	76	4	26	37	19	2	17	7	9	1
Units: weeks
median (confidence interval 95%)	9999 (9999 to 9999)	9999 (9999 to 9999)	9999 (9.6 to 9999)	9999 (38.3 to 9999)	9999 (9999 to 9999)	9999 (56 to 9999)	9999 (9999 to 9999)	138 (24 to 9999)	9999 (102 to 9999)	28.6 (20.1 to 9999)	40 (-9999 to 9999)

No statistical analyses for this end point

Secondary: Time to Achieve Complete Hematologic Response (CHR) for Responders Only - Part 2

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End point title

Time to Achieve Complete Hematologic Response (CHR) for Responders Only - Part 2 ^[45]

End point description

The time to CHR was measured from the date of first dosing to the first date of response. Time to response in weeks = (event date - first dose date plus 1)/7, where the event date is the non-missing date of the first attained response for responders only. 9999 = not estimable Hematologic evaluable population included all enrolled participants who received at least one dose of study medication and had an adequate baseline hematologic assessment responders only.

End point type

Secondary

End point timeframe

Day 1 and 7 of Week 1, Day 7 of Week 2, 3, 4, 8, 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks thereafter

Notes
[45] - 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: Only data for Part 2 are presented for this endpoint.

End point values	Bosutinib 500 mg, CP2L-CML IM-R (Part 2)	Bosutinib 500 mg, CP2L-CML IM-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2)	Bosutinib 500 mg, Ph+ ALL (Part 2)	Bosutinib 500 mg, AP-CML IM R/I (Part 2)	Bosutinib 500 mg, AP-CML Multi-TKI R/I (Part 2)	Bosutinib 500 mg, BP-CML IM R/I (Part 2)	Bosutinib 500 mg, BP-CML Multi-TKI R/I (Part 2)
Number of subjects analysed	169	76	4	26	37	19	2	17	7	9	1
Units: weeks
median (confidence interval 95%)	2 (1.1 to 2.1)	1.3 (1.1 to 2.1)	1.6 (1.1 to 2.1)	1.2 (1.1 to 3)	1.3 (1.1 to 2.3)	2.4 (1.1 to 3.3)	10 (4 to 13)	12.1 (8.1 to 24)	12.1 (4.3 to 72)	8 (4 to 13)	12.1 (-9999 to 9999)

No statistical analyses for this end point

Secondary: Cumulative Incidence of Progression/Death - Part 2

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End point title

Cumulative Incidence of Progression/Death - Part 2 ^[46]

End point description

The cumulative incidence of on-treatment progression or death adjusting for the competing risk of treatment discontinuation without the event. Disease progression was determined by the investigator as the reason for treatment discontinuation and death was due to any cause within 30 days of last dose. Duration in months = (date of PD/death or last valid cytogenetic/hematologic assessment if censored - first dose date)/30.4. 95% confidence intervals were calculated using Gray’s method. One year = 12 months. 9999 = not estimable, in Part 2 participants in CP3L and ADV treatment groups were only evaluated up to Year 4. All-treated population included all enrolled participants who received at least one dose of study medication.

End point type

Secondary

End point timeframe

Years 1, 2, 3, 4, and 5 (CP2L only)

Notes
[46] - 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: Only data for Part 2 are presented for this endpoint.

End point values	Bosutinib 500 mg, CP2L-CML IM-R (Part 2)	Bosutinib 500 mg, CP2L-CML IM-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2)	Bosutinib 500 mg, Ph+ ALL (Part 2)	Bosutinib 500 mg, AP-CML IM R/I (Part 2)	Bosutinib 500 mg, AP-CML Multi-TKI R/I (Part 2)	Bosutinib 500 mg, BP-CML IM R/I (Part 2)	Bosutinib 500 mg, BP-CML Multi-TKI R/I (Part 2)
Number of subjects analysed	195	89	5	38	50	26	24	49	30	36	28
Units: percentage of participants
number (confidence interval 95%)
Year 1	10.8 (7.2 to 16.1)	4.5 (1.7 to 11.7)	20 (3.5 to 100)	23.7 (13.4 to 41.9)	12 (5.7 to 25.4)	23.1 (11.4 to 46.6)	58.3 (41.6 to 81.8)	28.6 (18.4 to 44.5)	20 (9.8 to 40.9)	47.2 (33.4 to 66.7)	71.4 (56.5 to 90.3)
Year 2	19 (14.2 to 25.4)	6.7 (3.1 to 14.6)	40 (13.7 to 100)	23.7 (13.4 to 41.9)	14 (7 to 27.8)	30.8 (17.3 to 54.8)	58.3 (41.6 to 81.8)	42.9 (31 to 59.2)	23.3 (12.2 to 44.6)	50 (36.1 to 69.3)	71.4 (56.5 to 90.3)
Year 3	22.1 (16.9 to 28.7)	9 (4.6 to 17.4)	40 (13.7 to 100)	23.7 (13.4 to 41.9)	16 (8.5 to 30.2)	34.6 (20.4 to 58.7)	58.3 (41.6 to 81.8)	44.9 (32.9 to 61.2)	26.7 (14.7 to 48.3)	50 (36.1 to 69.3)	75 (60.6 to 92.9)
Year 4	22.6 (17.4 to 29.3)	9 (4.6 to 17.4)	40 (13.7 to 100)	23.7 (13.4 to 41.9)	16 (8.5 to 30.2)	34.6 (20.4 to 58.7)	58.3 (41.6 to 81.8)	44.9 (32.9 to 61.2)	26.7 (14.7 to 48.3)	50 (36.1 to 69.3)	75 (60.6 to 92.9)
Year 5	23.1 (17.9 to 29.8)	10.1 (5.4 to 18.8)	9999 (9999 to 9999)	9999 (9999 to 9999)	9999 (9999 to 9999)	9999 (9999 to 9999)	9999 (9999 to 9999)	9999 (9999 to 9999)	9999 (9999 to 9999)	9999 (9999 to 9999)	9999 (9999 to 9999)

No statistical analyses for this end point

Secondary: Kaplan-Meier Estimate of Overall Survival (OS) - Part 2

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End point title

Kaplan-Meier Estimate of Overall Survival (OS) - Part 2 ^[47]

End point description

OS was based on Kaplan-Meier method. Survival was defined as the time period from the date of first dose of bosutinib to the date of death or date of last contact for those censored. One year = 12 months. 9999 = not estimable, in Part 2 participants in CP3L and ADV treatment groups were only evaluated up to Year 4. All-treated population included all enrolled participants who received at least 1 dose of study medication.

End point type

Secondary

End point timeframe

Years 1, 2, 3, 4, and 5 (CP2L only)

Notes
[47] - 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: Only data for Part 2 are presented for this endpoint.

End point values	Bosutinib 500 mg, CP2L-CML IM-R (Part 2)	Bosutinib 500 mg, CP2L-CML IM-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2)	Bosutinib 500 mg, Ph+ ALL (Part 2)	Bosutinib 500 mg, AP-CML IM R/I (Part 2)	Bosutinib 500 mg, AP-CML Multi-TKI R/I (Part 2)	Bosutinib 500 mg, BP-CML IM R/I (Part 2)	Bosutinib 500 mg, BP-CML Multi-TKI R/I (Part 2)
Number of subjects analysed	195	89	5	38	50	26	24	49	30	36	28
Units: percentage of participants
number (confidence interval 95%)
Year 1	96.3 (92.5 to 98.2)	98.9 (92.1 to 99.8)	100 (100 to 100)	85.8 (69.2 to 93.8)	91.8 (79.7 to 96.6)	96.2 (75.7 to 99.4)	16.7 (5.2 to 33.7)	81.3 (67.2 to 89.8)	72.9 (53 to 85.4)	44.3 (27.4 to 59.9)	39.3 (21.7 to 56.5)
Year 2	88.2 (82.7 to 92.1)	97.7 (91 to 99.4)	80 (20.4 to 96.9)	79.7 (62 to 89.8)	83.3 (69.3 to 91.3)	92.3 (72.6 to 98)	8.3 (1.4 to 23.3)	72.7 (57.6 to 83.1)	59 (39.2 to 74.3)	41.3 (24.9 to 57)	25 (11.1 to 41.8)
Year 3	84.1 (77.8 to 88.7)	93 (83.9 to 97.1)	80 (20.4 to 96.9)	66.1 (44.5 to 80.9)	83.3 (69.3 to 91.3)	86.5 (62.9 to 95.6)	8.3 (1.4 to 23.3)	70.1 (54.7 to 81.1)	45.1 (25.4 to 63)	41.3 (24.9 to 57)	16.7 (5.6 to 32.9)
Year 4	81.5 (74.7 to 86.6)	93 (83.9 to 97.1)	80 (20.4 to 96.9)	66.1 (44.5 to 80.9)	79.3 (63.1 to 89)	86.5 (62.9 to 95.6)	8.3 (1.4 to 23.3)	65.7 (48.6 to 78.3)	45.1 (25.4 to 63)	20.7 (2 to 53.2)	16.7 (5.6 to 32.9)
Year 5	80.6 (73.6 to 85.9)	88.4 (76.6 to 94.5)	9999 (9999 to 9999)	9999 (9999 to 9999)	9999 (9999 to 9999)	9999 (9999 to 9999)	9999 (9999 to 9999)	9999 (9999 to 9999)	9999 (9999 to 9999)	9999 (9999 to 9999)	9999 (9999 to 9999)

No statistical analyses for this end point

Secondary: Percentage of Participants With Confirmed Complete Hematologic Response (CHR) - Part 2

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End point title

Percentage of Participants With Confirmed Complete Hematologic Response (CHR) - Part 2 ^[48]

End point description

Hematologic response: if participants met all of the following criteria of CHR: White Blood Cells ≤ institutional upper limit of normal, no peripheral blood blasts or promyelocytes, myelocytes+metamyelocytes <5% in blood, absolute neutrophil count ≥ 1.0×10^9/L , platelets <450×10^9/L, platelets ≥100×10^9/L, <20% basophils in blood and no extramedually involvement (including hepato- or splenomegaly), ≤5% BM blasts (required for ADV only and applicable to CP if BM aspirate was performed). Hematologic evaluable population included all enrolled participants who received at least one dose of study medication and had an adequate baseline hematologic assessment.

End point type

Secondary

End point timeframe

Day 1 and 7 of Week 1, Day 7 of Week 2, 3, 4, 8, 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks thereafter

Notes
[48] - 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: Only data for Part 2 are presented for this endpoint.

End point values	Bosutinib 500 mg, CP2L-CML IM-R (Part 2)	Bosutinib 500 mg, CP2L-CML IM-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2)	Bosutinib 500 mg, Ph+ ALL (Part 2)	Bosutinib 500 mg, AP-CML IM R/I (Part 2)	Bosutinib 500 mg, AP-CML Multi-TKI R/I (Part 2)	Bosutinib 500 mg, BP-CML IM R/I (Part 2)	Bosutinib 500 mg, BP-CML Multi-TKI R/I (Part 2)
Number of subjects analysed	194	89	5	38	49	25	22	43	29	34	26
Units: percentage of participants
number (confidence interval 95%)	87.1 (81.6 to 91.5)	85.4 (76.3 to 92)	80 (28.4 to 99.5)	68.4 (51.3 to 82.5)	75.5 (61.1 to 86.7)	76 (54.9 to 90.6)	9.1 (1.1 to 29.2)	39.5 (25 to 55.6)	24.1 (10.3 to 43.5)	26.5 (12.9 to 44.4)	3.8 (0.1 to 19.6)

No statistical analyses for this end point

Secondary: Percentage of Participants With Overall Hematologic Response (OHR) by Week 48 in Advanced Leukemia Hematologic Evaluable Population - Part 2

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End point title

Percentage of Participants With Overall Hematologic Response (OHR) by Week 48 in Advanced Leukemia Hematologic Evaluable Population - Part 2 ^[49]

End point description

OHR included CHR, no evidence of leukemia (≤5% bone marrow blasts, no peripheral blood blasts or promyelocytes, <5% myelocytes + metamyelocytes in blood, white blood cells ≤ institutional upper limit of normal, 450x10^9/L > platelets > 20x10^9/L, absolute neutrophil count ≥0.5x10^9/L, <20% basophils in blood, no extramedullary involvement [including liver or spleen]), minor hematologic response (acute lymphoblastic leukemia [ALL] patients only, defined as <15% blasts in marrow & blood, <30% blasts + promyelocytes in marrow & blood, <20% basophils in peripheral blood & no extramedullary disease other than spleen & liver) or return to chronic phase (AP/BP participants, defined as <15% blasts in both peripheral blood &bone marrow, <30% blasts + promyelocytes in both peripheral blood & bone marrow, <20% basophils in both peripheral blood & bone marrow, no extramedullary Involvement other than liver or spleen). Participants had to meet at least 1 criterion.

End point type

Secondary

End point timeframe

Day 1 and 7 of Week 1, Day 7 of Week 2, 3, 4, 8, 12, thereafter assessed every 12 weeks up to 1 year

Notes
[49] - 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: Only data for Part 2 are presented for this endpoint.

End point values	Bosutinib 500 mg, Ph+ ALL (Part 2)	Bosutinib 500 mg, AP-CML IM R/I (Part 2)	Bosutinib 500 mg, AP-CML Multi-TKI R/I (Part 2)	Bosutinib 500 mg, BP-CML IM R/I (Part 2)	Bosutinib 500 mg, BP-CML Multi-TKI R/I (Part 2)
Number of subjects analysed	22	43	29	34	26
Units: percentage of participants
number (confidence interval 95%)	9.1 (1.1 to 29.2)	67.4 (51.5 to 80.9)	41.4 (23.5 to 61.1)	38.2 (22.2 to 56.4)	15.4 (4.4 to 34.9)

No statistical analyses for this end point

Secondary: Percentage of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs)

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End point title

Percentage of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) ^[50]

End point description

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state. Safety population included all participants who receive at least one dose of study medication.

End point type

Secondary

End point timeframe

Baseline up to follow up visit (30 days after last dose of study treatment)

Notes
[50] - 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: Only data for Part 2 are presented for this endpoint.

End point values	Bosutinib 500 mg, CP2L-CML IM-R (Part 2)	Bosutinib 500 mg, CP2L-CML IM-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2)	Bosutinib 500 mg, Ph+ ALL (Part 2)	Bosutinib 500 mg, AP-CML IM R/I (Part 2)	Bosutinib 500 mg, AP-CML Multi-TKI R/I (Part 2)	Bosutinib 500 mg, BP-CML IM R/I (Part 2)	Bosutinib 500 mg, BP-CML Multi-TKI R/I (Part 2)
Number of subjects analysed	195	89	5	38	50	26	24	49	30	36	28
Units: percentage of participants
number (not applicable)
AEs	99.5	100	100	100	100	100	95.8	100	100	97.2	100
SAEs	41.5	38.2	20	39.5	38	19.2	70.8	49	63.3	55.6	60.7

No statistical analyses for this end point

Secondary: Duration of Potentially Clinically Important (PCI) Adverse Events (AEs)

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End point title

Duration of Potentially Clinically Important (PCI) Adverse Events (AEs) ^[51]

End point description

An AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. The event did not necessarily have a causal relationship with the treatment. PCI AEs included anemia, alanine aminotranferase (ALT), aspartate aminotransferase (AST), cardiac, diarrhea, edema, effusion, gastrointestinal, hemorrhage, hypersensitivity, hypertension, infection, liver, myelosuppression, nausea, neutropenia, rash, renal, thrombocytopenia, vomiting, and vascular events. Duration of AE was calculated as (stop date minus start date) plus 1 for non-missing and non-partial dates. 9999 = no events therefore duration not available. Safety population included all participants who receive at least one dose of study medication.

End point type

Secondary

End point timeframe

Baseline up to follow-up visit (30 days after last dose of study treatment)

Notes
[51] - 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: Only data for Part 2 are presented for this endpoint.

End point values	Bosutinib 500 mg, CP2L-CML IM-R (Part 2)	Bosutinib 500 mg, CP2L-CML IM-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2)	AP-CML Total (Part 2)	BP-CML Total (Part 2)	Bosutinib 500 mg, Ph+ ALL (Part 2)
Number of subjects analysed	195	89	5	38	50	26	79	64	24
Units: days
median (full range (min-max))
Anaemia	14 (1 to 1373)	36 (2 to 688)	38 (38 to 38)	19 (1 to 284)	13 (6 to 271)	61 (6 to 335)	12.5 (1 to 502)	4 (1 to 52)	7 (1 to 20)
ALT	29 (1 to 775)	15 (1 to 344)	9999 (9999 to 9999)	21.5 (7 to 236)	8 (5 to 87)	21 (4 to 42)	21.5 (7 to 252)	7.5 (1 to 41)	3 (1 to 5)
AST	29 (1 to 803)	13.5 (1 to 330)	9999 (9999 to 9999)	18 (14 to 22)	8.5 (8 to 22)	15 (8 to 21)	14 (1 to 188)	2 (2 to 2)	5 (5 to 5)
Diarrhoea	1 (1 to 2174)	2 (1 to 1121)	2 (1 to 59)	2 (1 to 189)	2 (1 to 413)	1 (1 to 289)	2 (1 to 910)	2 (1 to 211)	3 (1 to 500)
Effusion	18.5 (1 to 1428)	29 (5 to 657)	79.5 (14 to 421)	20 (7 to 842)	28 (1 to 907)	20 (5 to 258)	21 (4 to 1536)	58 (11 to 101)	5 (4 to 25)
Infection	10 (1 to 1026)	9.5 (1 to 546)	11.5 (1 to 46)	8 (1 to 85)	9 (2 to 366)	8 (1 to 183)	9 (1 to 281)	9.5 (1 to 78)	9 (1 to 39)
Nausea	2 (1 to 972)	4 (1 to 446)	4 (1 to 7)	2 (1 to 168)	14 (1 to 713)	2 (1 to 42)	6 (1 to 247)	6.5 (1 to 274)	9 (1 to 31)
Neutropenia	23 (1 to 506)	15 (1 to 337)	23 (13 to 70)	14.5 (4 to 81)	21 (3 to 504)	26 (7 to 92)	8 (1 to 252)	5 (1 to 52)	6.5 (5 to 8)
Oedema	29 (1 to 1416)	81.5 (1 to 1807)	4 (1 to 52)	1 (1 to 455)	12.5 (2 to 774)	28 (3 to 316)	88.5 (2 to 670)	11 (1 to 214)	5 (1 to 8)
Rash	15 (1 to 1622)	13 (1 to 965)	17 (7 to 52)	12 (1 to 348)	19 (1 to 1612)	12.5 (1 to 150)	13 (1 to 428)	7.5 (1 to 218)	12 (1 to 33)
Renal events	27 (1 to 831)	190 (7 to 903)	1167 (1167 to 1167)	162 (21 to 299)	11 (1 to 203)	56.5 (29 to 84)	26 (3 to 1403)	9 (1 to 27)	12 (12 to 12)
Thrombocytopenia	22 (1 to 1762)	15 (1 to 1541)	38.5 (14 to 120)	15 (1 to 336)	15 (2 to 420)	21.5 (6 to 350)	11.5 (1 to 889)	5 (1 to 176)	9 (3 to 43)
Vomiting	1 (1 to 165)	1 (1 to 36)	9999 (9999 to 9999)	1 (1 to 141)	2 (1 to 59)	7 (1 to 39)	1 (1 to 128)	1 (1 to 41)	1.5 (1 to 9)
Cardiac events	11 (1 to 1428)	6 (1 to 657)	9999 (9999 to 9999)	7.5 (1 to 842)	22 (1 to 907)	1 (1 to 1)	14 (1 to 1536)	3 (1 to 19)	1.5 (1 to 2)
Vascular events	3.5 (1 to 277)	6 (1 to 59)	9999 (9999 to 9999)	10.5 (3 to 18)	1.5 (1 to 266)	10 (10 to 10)	2 (1 to 22)	1 (1 to 14)	1 (1 to 19)
Hypertension	16 (1 to 1343)	1 (1 to 1659)	9999 (9999 to 9999)	7 (7 to 7)	1 (1 to 418)	9999 (9999 to 9999)	5 (1 to 204)	9999 (9999 to 9999)	2 (2 to 2)
Gastrointestinal events	1 (1 to 2174)	2 (1 to 1121)	2 (1 to 59)	2 (1 to 189)	2 (1 to 713)	2 (1 to 289)	2 (1 to 910)	3 (1 to 274)	4 (1 to 500)
Haemorrhage	10 (1 to 862)	16 (1 to 131)	23 (23 to 23)	4 (1 to 11)	27.5 (1 to 190)	7.5 (1 to 58)	6 (1 to 147)	4 (1 to 28)	3.5 (1 to 21)
Hypersensitivity	9 (6 to 38)	8 (7 to 9)	9999 (9999 to 9999)	7 (1 to 28)	6 (1 to 15)	5 (1 to 9)	1 (1 to 1)	9999 (9999 to 9999)	9999 (9999 to 9999)
Liver	29 (1 to 803)	16 (1 to 344)	8 (8 to 8)	25.5 (7 to 236)	9 (5 to 136)	21 (3 to 82)	16 (1 to 252)	8 (1 to 441)	5 (1 to 9)
Myelosuppression	22 (1 to 1762)	18 (1 to 1541)	28 (13 to 120)	15 (1 to 336)	15 (2 to 504)	27 (6 to 769)	11.5 (1 to 889)	5 (1 to 376)	7 (1 to 43)

No statistical analyses for this end point

Secondary: Number of Participants With Change From Baseline in Laboratory Tests Results

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End point title

Number of Participants With Change From Baseline in Laboratory Tests Results ^[52]

End point description

Laboratory assessments included urinalysis, complete blood count (CBC), prothrombin time/partial prothromboplastin time (PT/PPT), international normalized ratio (INR), blood chemistry and serum pregnancy test (β-HCG). Parameters of special interest included liver function tests and those related to myelosuppression. Potentially clinically important (PCI) laboratory values were defined as National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0 (NCI CTCAE v3.0) grade 3 or higher. Maximum CTCAE grade, and only participants who shifted to Grade 3/4 on-treatment, are reported. Safety population included all participants who receive at least one dose of study medication.

End point type

Secondary

End point timeframe

Week 1, 2, 3, 4, 8, 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks thereafter

Notes
[52] - 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: Only data for Part 2 are presented for this endpoint.

End point values	Bosutinib 500 mg, CP2L-CML IM-R (Part 2)	Bosutinib 500 mg, CP2L-CML IM-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2)	AP-CML Total (Part 2)	BP-CML Total (Part 2)	Bosutinib 500 mg, Ph+ ALL (Part 2)
Number of subjects analysed	195	89	5	38	50	26	79	64	24
Units: Percentage of Participants
number (not applicable)
Hemoglobin: shift from Normal to Grade 3	0.5	1.1	0	0	0	3.8	5.1	1.6	0
Hemoglobin: shift from Normal to Grade 4	1	0	0	0	0	0	0	0	0
Hemoglobin: shift from Grade 1 to Grade 3	3.6	10.1	0	2.6	0	0	7.6	6.3	8.3
Hemoglobin: shift from Grade 1 to Grade 4	1.5	0	0	0	4	0	1.3	3.1	0
Hemoglobin: shift from Grade 2 to Grade 3	3.1	6.7	0	7.9	0	0	10.1	15.6	16.7
Hemoglobin: shift from Grade 2 to Grade 4	2.1	1.1	0	0	4	0	2.5	4.7	4.2
Hemoglobin: shift from Grade 3 to Grade 4	0.5	0	0	0	0	0	5.1	4.7	0
Absolute neutrophils (ANC): Normal to Grade 3	7.2	9	0	5.3	4	11.5	10.1	3.1	0
ANC: shift from Normal to Grade 4	2.1	3.4	20	7.9	4	3.8	2.5	3.1	0
ANC: shift from Grade 1 to Grade 3	0	2.2	0	0	0	0	2.5	7.8	12.5
ANC: shift from Grade 1 to Grade 4	0.5	0	0	2.6	2	0	1.3	20.3	4.2
ANC: shift from Grade 2 to Grade 3	1	3.4	0	2.6	2	0	3.8	0	0
ANC: shift from Grade 2 to Grade 4	0	0	0	0	0	0	1.3	3.1	8.3
ANC: shift from Grade 3 to Grade 4	0	1.1	0	0	2	0	0	4.7	8.3
Platelet count: shift from Normal to Grade 3	13.3	13.5	0	15.8	12	7.7	11.4	4.7	4.2
Platelet count: shift from Normal to Grade 4	3.6	7.9	0	0	8	15.4	7.6	1.6	0
Platelet count: shift from Grade 1 to Grade 3	3.6	5.6	0	2.6	2	3.8	5.1	3.1	4.2
Platelet count: shift from Grade 1 to Grade 4	1.5	1.1	0	2.6	4	0	6.3	6.3	0
Platelet count: shift from Grade 2 to Grade 3	0.5	2.2	20	0	2	0	3.8	4.7	0
Platelet count: shift from Grade 2 to Grade 4	0.5	0	0	0	0	0	1.3	4.7	0
Platelet count: shift from Grade 3 to Grade 4	1	0	0	0	2	0	5.1	10.9	29.2
ALT: shift from Normal to Grade 3	8.7	12.4	0	0	10	15.4	5.1	1.6	0
ALT: shift from Grade 1 to Grade 3	1	0	0	0	0	0	3.8	0	0
AST: shift from Normal to Grade 3	4.1	7.9	0	0	0	7.7	2.5	1.6	0
AST: shift from Normal to Grade 4	0	0	0	0	0	3.8	0	0	0
AST: shift from Grade 1 to Grade 3	0	0	0	0	2	0	2.5	0	0
ALP: shift from Normal to Grade 3	0	0	0	0	0	0	1.3	0	0
ALP: shift from Grade 1 to Grade 3	0	0	0	0	0	0	0	1.6	0
Total bilirubin: shift from Normal to Grade 3	0	0	0	0	2	0	0	6.3	4.2
ALT: shift from Normal to Grade 4	0	2.2	0	0	0	3.8	0	0	0
Total bilirubin: shift from Grade 2 to Grade 3	0	0	0	0	2	0	0	0	0

No statistical analyses for this end point

Secondary: Number of Participants With On-treatment PCI Change From Baseline in Electrocardiogram (ECG) Findings

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End point title

Number of Participants With On-treatment PCI Change From Baseline in Electrocardiogram (ECG) Findings ^[53]

End point description

Criteria for PCI changes in ECG (12-lead) were defined as: no sinus rhythm; PR interval >=220 msec and increase of >=20 msec; QRS interval >=120 msec; QT interval corrected using the Fridericia formula (QTcF) and QT interval corrected using the Bazett formula (QTcB) >500 msec or increase of >60 msec; heart rate <=45 beats per minute (bpm) or >=120 bpm or decrease/increase of >=15 bpm. Safety population included all participants who receive at least one dose of study medication. 'N' (Number of Participants Analyzed) signifies number of participants who were evaluable for this measure.

End point type

Secondary

End point timeframe

Baseline, 0 (pre-dose), 2, 4, 6 hours on Day 1, 0 (pre-dose), 2, 4, 6, 20-23 hours on Day 21, and end of treatment visit

Notes
[53] - 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: Only data for Part 2 are presented for this endpoint.

End point values	Bosutinib 500 mg, CP2L-CML IM-R (Part 2)	Bosutinib 500 mg, CP2L-CML IM-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2)	AP-CML Total (Part 2)	BP-CML Total (Part 2)	Bosutinib 500 mg, Ph+ ALL (Part 2)
Number of subjects analysed	195	89	5	37	50	26	78	62	23
Units: Percentage of participants
number (not applicable)	32.3	23.6	20	24.3	22	23.1	39.7	59.7	34.8

No statistical analyses for this end point

Secondary: Number of Participants With Change From Baseline in Findings of Chest x-ray

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End point title

Number of Participants With Change From Baseline in Findings of Chest x-ray ^[54]

End point description

End point type

Secondary

End point timeframe

Baseline, Week 8, and end of treatment

Notes
[54] - 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: Only data for Part 2 are presented for this endpoint.

End point values	Bosutinib 500 mg, CP2L-CML IM-R (Part 2)	Bosutinib 500 mg, CP2L-CML IM-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2)	AP-CML Total (Part 2)	BP-CML Total (Part 2)	Bosutinib 500 mg, Ph+ ALL (Part 2)
Number of subjects analysed	0 ^[55]	0 ^[56]	0 ^[57]	0 ^[58]	0 ^[59]	0 ^[60]	0 ^[61]	0 ^[62]	0 ^[63]
Units: participants

Notes
[55] - Data not statistically summarized, but collected and reported in individual listings as planned.
[56] - Data not statistically summarized, but collected and reported in individual listings as planned.
[57] - Data not statistically summarized, but collected and reported in individual listings as planned.
[58] - Data not statistically summarized, but collected and reported in individual listings as planned.
[59] - Data not statistically summarized, but collected and reported in individual listings as planned.
[60] - Data not statistically summarized, but collected and reported in individual listings as planned.
[61] - Data not statistically summarized, but collected and reported in individual listings as planned.
[62] - Data not statistically summarized, but collected and reported in individual listings as planned.
[63] - Data not statistically summarized, but collected and reported in individual listings as planned.

No statistical analyses for this end point

Secondary: Number of Participants Who Received Concomitant Medications for Management of Adverse Events (AEs)

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End point title

Number of Participants Who Received Concomitant Medications for Management of Adverse Events (AEs) ^[64]

End point description

Number of participants taking any non-study medications which were administered from Study Day 1 to 30 days after last dose of study treatment as a management of an AE are reported. Safety population included all participants who receive at least one dose of study medication.

End point type

Secondary

End point timeframe

Baseline up to end of treatment

Notes
[64] - 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: Only data for Part 2 are presented for this endpoint.

End point values	Bosutinib 500 mg, CP2L-CML IM-R (Part 2)	Bosutinib 500 mg, CP2L-CML IM-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2)	AP-CML Total (Part 2)	BP-CML Total (Part 2)	Bosutinib 500 mg, Ph+ ALL (Part 2)
Number of subjects analysed	195	89	5	38	50	26	79	64	24
Units: participants
ALT	7	3	0	0	0	1	1	0	0
AST	5	3	0	2	3	4	2	0	0
Anemia	6	8	2	2	2	1	6	1	1
Cardiac events	13	4	0	2	6	0	7	2	1
Gastrointestinal toxicity - Diarrhoea	120	46	2	22	26	14	44	22	10
Effusion	11	5	1	3	9	1	9	2	0
Haemorrhage	12	3	0	1	0	1	4	6	3
Hypertension	15	4	0	2	4	1	7	2	2
Hypersensitivity reactions	5	2	0	4	2	2	1	1	0
Infection	92	39	4	11	18	10	37	30	7
Hepatic events	10	5	0	0	0	2	3	3	0
Gastrointestinal toxicity - Nausea	33	25	1	11	10	8	19	23	7
Neutropenia	2	5	1	5	1	1	6	5	2
Rash	44	37	2	8	16	3	20	9	2
Oedema	13	9	1	3	3	0	7	7	3
Renal	2	2	0	0	1	0	4	3	0
Thrombocytopenia	4	2	3	10	19	13	3	3	0
Vascular events	6	3	0	0	3	0	2	1	0
Gastrointestinal toxicity - Vomiting	25	9	0	5	7	4	17	14	4

No statistical analyses for this end point

Secondary: Number of Participants With Change From Baseline in Eastern Cooperative Oncology Group Performance Status (ECOG-PS)

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End point title

Number of Participants With Change From Baseline in Eastern Cooperative Oncology Group Performance Status (ECOG-PS) ^[65]

End point description

ECOG-PS measured on-therapy (time between first dose and last dose date with a 30-day lag) 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. Safety population included all participants who receive at least one dose of study medication.

End point type

Secondary

End point timeframe

Baseline, Week 1, 2, 8, 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks thereafter

Notes
[65] - 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: Only data for Part 2 are presented for this endpoint.

End point values	Bosutinib 500 mg, CP2L-CML IM-R (Part 2)	Bosutinib 500 mg, CP2L-CML IM-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2)	Bosutinib 500 mg, Ph+ ALL (Part 2)	Bosutinib 500 mg, AP-CML IM R/I (Part 2)	Bosutinib 500 mg, AP-CML Multi-TKI R/I (Part 2)	Bosutinib 500 mg, BP-CML IM R/I (Part 2)	Bosutinib 500 mg, BP-CML Multi-TKI R/I (Part 2)
Number of subjects analysed	195	89	5	38	50	26	24	49	30	36	28
Units: participants
Baseline: Grade 0, End of Treatment: Grade 0	92	36	2	21	20	19	2	17	9	9	2
Baseline: Grade 0, End of Treatment: Grade 1	50	25	0	5	8	5	4	11	5	47	2
Baseline: Grade 0, End of Treatment: Grade 2	3	3	0	0	1	0	2	0	1	0	1
Baseline: Grade 0, End of Treatment: Grade 3	4	2	0	1	1	0	0	1	0	0	0
Baseline: Grade 0, End of Treatment: Grade 4	2	0	0	0	0	0	0	0	0	0	0
Baseline: Grade 1, End of Treatment: Grade 0	0	0	0	2	0	0	1	0	1	3	1
Baseline: Grade 1, End of Treatment: Grade 1	32	13	2	7	13	2	3	14	7	7	5
Baseline: Grade 1, End of Treatment: Grade 2	10	6	1	1	5	0	3	2	5	0	6
Baseline: Grade 1, End of Treatment: Grade 3	0	2	0	0	0	0	0	2	0	0	3
Baseline: Grade 1, End of Treatment: Grade 4	2	0	0	0	0	0	0	0	1	1	0
Baseline: Grade 2, End of Treatment: Grade 0	0	0	0	0	0	0	0	0	0	1	0
Baseline: Grade 2, End of Treatment: Grade 1	0	0	0	0	0	0	0	1	0	0	1
Baseline: Grade 2, End of Treatment: Grade 2	0	1	0	0	0	0	4	0	0	6	1
Baseline: Grade 2, End of Treatment: Grade 3	0	0	0	0	0	0	0	0	1	2	1
Baseline: Grade 2, End of Treatment: Grade 4	0	0	0	0	0	0	1	0	0	0	1
Baseline: Missing	0	1	0	0	1	0	0	0	0	0	0
Baseline: Grade 0, End of Treatment: Missing	0	0	0	1	1	0	1	0	0	0	1
Baseline: Grade 1, End of Treatment: Missing	0	0	0	0	0	0	3	0	0	0	3

No statistical analyses for this end point

Secondary: Number of Participants With Change From Baseline in Physical Examinations and Vital Signs

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End point title

Number of Participants With Change From Baseline in Physical Examinations and Vital Signs ^[66]

End point description

Number of participants with PCI physical examinations and vital signs is reported during therapy and at post therapy. Criteria for PCI change in vital signs: heart rate value of <40 beats per min and value >150 beats per min, systolic blood pressure (SBP) of <80 or >210 millimeter of mercury (mmHg), diastolic blood pressure (DBP) of <40 or >130 mmHg, temperature <32 or >40 degree centigrade, respiratory rate of <10 or >50 breaths/min and criteria for PCI change in physical examination: >=10% increase or decrease of body weight in kilogram (kg). Where no participants in a cohort fulfilled the criteria, the n is not reported (NR). Safety population included all participants who receive at least one dose of study medication. 'N' (number of participants analyzed) signifies number of participants who were evaluable for this measure.

End point type

Secondary

End point timeframe

Baseline up to end of treatment

Notes
[66] - 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: Only data for Part 2 are presented for this endpoint.

End point values	Bosutinib 500 mg, CP2L-CML IM-R (Part 2)	Bosutinib 500 mg, CP2L-CML IM-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2)	AP-CML Total (Part 2)	BP-CML Total (Part 2)	Bosutinib 500 mg, Ph+ ALL (Part 2)
Number of subjects analysed	188	81	5	35	46	25	75	56	20
Units: participants
SBP >210 mmHg (n=188,81,5,35,45,25,NR,NR,NR)	2	0	0	0	0	0	0	0	0
Weight Increase ≥10% (n187,80,5,33,46,25,73,53,16)	30	5	1	4	3	4	8	4	1
Weight decrease ≥10% (n187,80,5,33,46,25,73,53,16)	41	13	0	2	7	0	17	5	0
SBP <80 mmHg (n=188,81,5,35,45,25,NR,NR,NR)	0	0	0	0	0	1	0	0	0
Temperature <32C (n=NR,NR,NR,5,34,45,25,NR,NR,NR)	0	0	0	0	0	1	0	0	0
Pulse <40bpm (n=180,72,NR,NR,NR,NR,NR,NR,NR)	0	1	0	0	0	0	0	0	0
Resp >50 breaths/min (NR,NR,5,31,42,20,NR,NR,NR)	0	0	0	0	1	1	0	0	0
Resp <10 breaths/min (NR,NR,5,31,42,20,NR,NR,NR)	0	0	0	0	0	1	0	0	0

No statistical analyses for this end point

Secondary: Number of Participants With Change From Baseline in Physical Examinations and Vital Signs and Number of Participants with PCI Values

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End point title

Number of Participants With Change From Baseline in Physical Examinations and Vital Signs and Number of Participants with PCI Values ^[67]

End point description

Number of participants with PCI physical examinations and vital signs is reported during therapy and at post therapy. Criteria for PCI change in vital signs: heart rate value of <40 beats per min and value >150 beats per min, SBP of <80 or >210 mmHg, DBP of <40 or >130 mmHg, temperature <32 or >40 degree centigrade, respiratory rate of <10 or >50 breaths/min and criteria for PCI change in physical examination: >=10% increase or decrease of body weight in kilogram (kg). Where no participants in a cohort fulfilled the criteria, the n is not reported (NR). Safety population included all participants who receive at least one dose of study medication. 'N' (number of participants analyzed) signifies number of participants who were evaluable for this measure.

End point type

Secondary

End point timeframe

Post-therapy

Notes
[67] - 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: Only data for Part 2 are presented for this endpoint.

End point values	Bosutinib 500 mg, CP2L-CML IM-R (Part 2)	Bosutinib 500 mg, CP2L-CML IM-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2)	AP-CML Total (Part 2)	BP-CML Total (Part 2)	Bosutinib 500 mg, Ph+ ALL (Part 2)
Number of subjects analysed	24	16	1	2	11	4	8	3	0 ^[68]
Units: participants
Pulse <40 bpm (n=24,13,NR,NR,NR,NR,NR,NR,NA)	1	0	0	0	0	0	0	0
SBP >210 mmHg (n=NR,NR,NR,NR,NR,NR,8,3,NA)	0	0	0	0	0	0	1	0
Weight increase 10% (n=24,15,1,2,11,4,6,3,NA)	1	0	0	0	0	0	0	1
Weight decrease 10% (n=24,15,1,2,11,4,6,3,NA)	3	1	0	0	1	0	1	0

Notes
[68] - No Ph+ ALL participants were analyzed post-therapy.

No statistical analyses for this end point

Secondary: Overall Survival (OS) - Part 2

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End point title

Overall Survival (OS) - Part 2 ^[69]

End point description

OS was based on Kaplan-Meier method. Survival was defined as the time period from the date of first dose of bosutinib to the date of death or date of last contact for those censored. One year = 12 months. 9999 = not estimable, value not reached prior to minimum follow-up. All-treated population included all enrolled participants who received at least 1 dose of study medication.

End point type

Secondary

End point timeframe

Years 1, 2, 3, 4, and 5 (CP2L only)

Notes
[69] - 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: Only data for Part 2 are presented for this endpoint.

End point values	Bosutinib 500 mg, CP2L-CML IM-R (Part 2)	Bosutinib 500 mg, CP2L-CML IM-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2)	Bosutinib 500 mg, Ph+ ALL (Part 2)	Bosutinib 500 mg, AP-CML IM R/I (Part 2)	Bosutinib 500 mg, AP-CML Multi-TKI R/I (Part 2)	Bosutinib 500 mg, BP-CML IM R/I (Part 2)	Bosutinib 500 mg, BP-CML Multi-TKI R/I (Part 2)
Number of subjects analysed	195	89	5	38	50	26	24	49	30	36	28
Units: Months
number (confidence interval 95%)	9999 (9999 to 9999)	9999 (9999 to 9999)	9999 (21 to 9999)	9999 (34.4 to 9999)	9999 (9999 to 9999)	9999 (9999 to 9999)	3.6 (1.3 to 7.6)	9999 (9999 to 9999)	33.4 (14.6 to 9999)	11.2 (9.4 to 9999)	8.9 (4.1 to 17.4)

No statistical analyses for this end point

Secondary: Progression Free Survival (PFS) - Part 2

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End point title

Progression Free Survival (PFS) - Part 2 ^[70]

End point description

PFS was based on Kaplan-Meier method. Disease progression was determined by the investigator as the reason for treatment discontinuation and death was due to any cause within 30 days of last dose. Duration in months = (date of PD/death or last valid cytogenetic/hematologic assessment if censored first dose date)/30.4. One year = 12 months. 9999 = not estimable, value not reached prior to minimum follow-up. All-treated population included all enrolled participants who received at least one dose of study medication.

End point type

Secondary

End point timeframe

Years 1, 2, 3, 4, and 5 (CP2L only)

Notes
[70] - 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: Only data for Part 2 are presented for this endpoint.

End point values	Bosutinib 500 mg, CP2L-CML IM-R (Part 2)	Bosutinib 500 mg, CP2L-CML IM-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2)	Bosutinib 500 mg, Ph+ ALL (Part 2)	Bosutinib 500 mg, AP-CML IM R/I (Part 2)	Bosutinib 500 mg, AP-CML Multi-TKI R/I (Part 2)	Bosutinib 500 mg, BP-CML IM R/I (Part 2)	Bosutinib 500 mg, BP-CML Multi-TKI R/I (Part 2)
Number of subjects analysed	195	89	5	38	50	26	24	49	30	36	28
Units: Months
median (confidence interval 95%)	9999 (9999 to 9999)	9999 (9999 to 9999)	9999 (0.9 to 9999)	9999 (11.1 to 9999)	9999 (9999 to 9999)	9999 (14.1 to 9999)	1.5 (0.7 to 3.8)	20.4 (11.8 to 9999)	35.4 (14.6 to 9999)	7.9 (4 to 10.1)	1.8 (0.9 to 5.5)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse events (AEs) and serious AEs were assessed from informed consent through and including 30 days after last administration of study treatment or at the End of Treatment Visit, whichever comes last.

Adverse event reporting additional description

The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

18.0

Reporting group title

Bosutinib 500 mg, CP2L-CML IM-I (Part 2)

Reporting group description

Reporting group title

Bosutinib 500 mg, CP2L-CML IM-R (Part 2)

Reporting group description

Reporting group title

Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2)

Reporting group description

Reporting group title

Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2)

Reporting group description

Reporting group title

Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2)

Reporting group description

Reporting group title

Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2)

Reporting group description

Reporting group title

AP-CML Total (Part 2)

Reporting group description

Reporting group title

BP-CML Total (Part 2)

Reporting group description

Reporting group title

Bosutinib 500 mg, Ph+ ALL (Part 2)

Reporting group description

Bosutinib 500 mg was administered orally once-daily in participants with philadelphia chromosome-positive acute lymphocytic leukemia (Ph+ ALL)

Serious adverse events	Bosutinib 500 mg, CP2L-CML IM-I (Part 2)	Bosutinib 500 mg, CP2L-CML IM-R (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2)	AP-CML Total (Part 2)	BP-CML Total (Part 2)	Bosutinib 500 mg, Ph+ ALL (Part 2)
Total subjects affected by serious adverse events
subjects affected / exposed	34 / 89 (38.20%)	81 / 195 (41.54%)	15 / 38 (39.47%)	1 / 5 (20.00%)	19 / 50 (38.00%)	5 / 26 (19.23%)	43 / 79 (54.43%)	37 / 64 (57.81%)	17 / 24 (70.83%)
number of deaths (all causes)	2	8	2	0	3	0	11	13	8
number of deaths resulting from adverse events	1	1	0	0	1	0	2	0	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Blast cell crisis
subjects affected / exposed	1 / 89 (1.12%)	2 / 195 (1.03%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blast crisis in myelogenous leukaemia
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	2 / 64 (3.13%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 1	0 / 0
Basal cell carcinoma
subjects affected / exposed	1 / 89 (1.12%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 0	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	0 / 0	0 / 0
Squamous cell carcinoma
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	1 / 50 (2.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	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	0 / 0	0 / 0
Chloroma
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Chronic myelomonocytic leukaemia
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Colon cancer
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Colon cancer metastatic
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Gastric cancer
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	1 / 50 (2.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Keratoacanthoma
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	1 / 50 (2.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Leukaemia
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0
Lung adenocarcinoma
subjects affected / exposed	1 / 89 (1.12%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0
Melanocytic naevus
subjects affected / exposed	1 / 89 (1.12%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0
Neoplasm skin
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Non-small cell lung cancer
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	1 / 26 (3.85%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Prostate cancer
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Squamous cell carcinoma of skin
subjects affected / exposed	1 / 89 (1.12%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	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	0 / 0	0 / 0
Thyroid neoplasm
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Uterine Leiomyoma
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Bowen's disease
subjects affected / exposed	1 / 89 (1.12%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0
Angiomyolipoma
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Anogenital warts
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Central nervous system leukaemia
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Chronic myeloid leukaemia
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Laryngeal neoplasm
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Neoplasm prostate
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Paraproteinaemia
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Vascular disorders
Hypertension
subjects affected / exposed	0 / 89 (0.00%)	2 / 195 (1.03%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	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	0 / 0	0 / 0
Hypotension
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aortic stenosis
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Venous thrombosis
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Necrosis ischaemic
subjects affected / exposed	1 / 89 (1.12%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0
Peripheral arterial occlusive disease
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	1 / 26 (3.85%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Surgical and medical procedures
Allogenic bone marrow transplantation therapy
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Knee arthroplasty
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	2 / 89 (2.25%)	5 / 195 (2.56%)	1 / 38 (2.63%)	0 / 5 (0.00%)	1 / 50 (2.00%)	0 / 26 (0.00%)	4 / 79 (5.06%)	5 / 64 (7.81%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	1 / 2	4 / 11	0 / 2	0 / 0	0 / 1	0 / 0	2 / 5	1 / 10	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chest pain
subjects affected / exposed	1 / 89 (1.12%)	2 / 195 (1.03%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	3 / 79 (3.80%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	3 / 64 (4.69%)	2 / 24 (8.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	1 / 4	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
Asthenia
subjects affected / exposed	1 / 89 (1.12%)	3 / 195 (1.54%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 3	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	0 / 0	0 / 0
Disease progression
subjects affected / exposed	0 / 89 (0.00%)	3 / 195 (1.54%)	1 / 38 (2.63%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	4 / 79 (5.06%)	3 / 64 (4.69%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 1	0 / 0	0 / 0	0 / 0	0 / 6	0 / 5	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 3	0 / 1	0 / 0	0 / 0	0 / 0	0 / 4	0 / 3	0 / 1
Chills
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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	0 / 0	0 / 0
Multi-organ failure
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	2 / 79 (2.53%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	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 / 1	0 / 0	0 / 0
Oedema
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	1 / 50 (2.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 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	0 / 0	0 / 0
Pain
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	2 / 64 (3.13%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Adverse drug reaction
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Local swelling
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Malaise
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Mucosal inflammation
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Submandibular mass
subjects affected / exposed	1 / 89 (1.12%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0
Adhesion
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	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	0 / 0	0 / 0
Death
subjects affected / exposed	1 / 89 (1.12%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Drug hypersensitivity
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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	0 / 0	0 / 0
Hypersensitivity
subjects affected / exposed	1 / 89 (1.12%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0
Social circumstances
Pregnancy of partner
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	1 / 26 (3.85%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Reproductive system and breast disorders
Breast hyperplasia
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Cervical dysplasia
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Dysfunctional uterine bleeding
subjects affected / exposed	1 / 89 (1.12%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0
Pelvic pain
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Vaginal haemorrhage
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Menorrhagia
subjects affected / exposed	0 / 89 (0.00%)	2 / 195 (1.03%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	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	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pleural effusion
subjects affected / exposed	4 / 89 (4.49%)	8 / 195 (4.10%)	3 / 38 (7.89%)	0 / 5 (0.00%)	3 / 50 (6.00%)	1 / 26 (3.85%)	5 / 79 (6.33%)	2 / 64 (3.13%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 7	2 / 9	1 / 3	0 / 0	2 / 4	0 / 1	7 / 7	2 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	1 / 89 (1.12%)	5 / 195 (2.56%)	0 / 38 (0.00%)	0 / 5 (0.00%)	2 / 50 (4.00%)	0 / 26 (0.00%)	4 / 79 (5.06%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 10	0 / 0	0 / 0	3 / 4	0 / 0	1 / 5	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	0 / 89 (0.00%)	2 / 195 (1.03%)	0 / 38 (0.00%)	0 / 5 (0.00%)	1 / 50 (2.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 1	0 / 0	0 / 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	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	2 / 64 (3.13%)	2 / 24 (8.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 2	0 / 1
Asthma
subjects affected / exposed	1 / 89 (1.12%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	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	0 / 0	0 / 0
Acute respiratory failure
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	1 / 38 (2.63%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	1 / 89 (1.12%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0
Dyspnoea exertional
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Lung infiltration
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	1 / 38 (2.63%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Organising pneumonia
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Pleurisy
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Pleuritic pain
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Pulmonary fibrosis
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Pulmonary oedema
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	1 / 50 (2.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Lung disorder
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Psychiatric disorders
Confusional state
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Completed suicide
subjects affected / exposed	1 / 89 (1.12%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0
Hallucination, visual
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Mental status change
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	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	0 / 0	0 / 0
Investigations
Platelet count decreased
subjects affected / exposed	0 / 89 (0.00%)	2 / 195 (1.03%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	2 / 79 (2.53%)	0 / 64 (0.00%)	2 / 24 (8.33%)
occurrences causally related to treatment / all	0 / 0	0 / 5	0 / 0	0 / 0	0 / 0	0 / 0	13 / 17	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Alanine aminotransferase increased
subjects affected / exposed	1 / 89 (1.12%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	1 / 89 (1.12%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0
Blood bilirubin increased
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	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	0 / 0	0 / 0
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	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	0 / 0	0 / 0
Blood glucose increased
subjects affected / exposed	1 / 89 (1.12%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0
Blood pressure increased
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Haemoglobin decreased
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Hepatic enzyme increased
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Liver function test abnormal
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	4 / 4	0 / 0	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	0 / 0	0 / 0
Weight decreased
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Blood creatinine increased
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Intraocular pressure increased
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Injury, poisoning and procedural complications
Abdominal injury
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Cervical vertebral fracture
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Clavicle fracture
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Gastrointestinal stoma complication
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Overdose
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	1 / 38 (2.63%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Post procedural haematuria
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	1 / 38 (2.63%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 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	0 / 0	0 / 0
Post procedural swelling
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Rib fracture
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Road traffic accident
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Seroma
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	1 / 38 (2.63%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Subdural haemorrhage
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tooth fracture
subjects affected / exposed	1 / 89 (1.12%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0
Transfusion reaction
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Upper limb fracture
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Wound haematoma
subjects affected / exposed	1 / 89 (1.12%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0
Contusion
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Facial bone fracture
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Failure to anastomose
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	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	0 / 0	0 / 0
Injury
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0
Muscle injury
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Procedural haemorrhage
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Vascular pseudoaneurysm
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Congenital, familial and genetic disorders
Cytogenetic abnormality
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	1 / 26 (3.85%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	0 / 89 (0.00%)	3 / 195 (1.54%)	1 / 38 (2.63%)	0 / 5 (0.00%)	2 / 50 (4.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 1	0 / 0	1 / 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	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	0 / 89 (0.00%)	2 / 195 (1.03%)	0 / 38 (0.00%)	0 / 5 (0.00%)	1 / 50 (2.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 0	0 / 1	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 / 0	1 / 1	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	1 / 89 (1.12%)	3 / 195 (1.54%)	0 / 38 (0.00%)	0 / 5 (0.00%)	1 / 50 (2.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 7	0 / 0	0 / 0	1 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	2 / 89 (2.25%)	3 / 195 (1.54%)	1 / 38 (2.63%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 6	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Coronary artery disease
subjects affected / exposed	1 / 89 (1.12%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	1 / 50 (2.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0	0 / 0	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 / 1	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	1 / 38 (2.63%)	0 / 5 (0.00%)	1 / 50 (2.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	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 / 1	0 / 0	1 / 1	0 / 0	0 / 0
Pericardial effusion
subjects affected / exposed	1 / 89 (1.12%)	2 / 195 (1.03%)	0 / 38 (0.00%)	0 / 5 (0.00%)	2 / 50 (4.00%)	0 / 26 (0.00%)	2 / 79 (2.53%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 2	2 / 2	0 / 0	0 / 0	1 / 2	0 / 0	1 / 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	0 / 0	0 / 0
Pericarditis
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	1 / 50 (2.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	2 / 89 (2.25%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 2	1 / 1	0 / 0	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	0 / 0	0 / 0
Angina unstable
subjects affected / exposed	0 / 89 (0.00%)	2 / 195 (1.03%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	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	0 / 0	0 / 0
Arrhythmia
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	1 / 1	0 / 0	0 / 0
Left ventricular dysfunction
subjects affected / exposed	0 / 89 (0.00%)	2 / 195 (1.03%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	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	0 / 0	0 / 0
Pericardial haemorrhage
subjects affected / exposed	0 / 89 (0.00%)	2 / 195 (1.03%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	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	0 / 0	0 / 0
Tachycardia
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	2 / 79 (2.53%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0
Bradycardia
subjects affected / exposed	1 / 89 (1.12%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0
Cardiorenal syndrome
subjects affected / exposed	1 / 89 (1.12%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0
Coronary artery stenosis
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Extrasystoles
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Palpitations
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	1 / 50 (2.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Pleuropericarditis
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 5	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ventricular fibrillation
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Cardiac disorder
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Nervous system disorders
Headache
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	1 / 38 (2.63%)	0 / 5 (0.00%)	1 / 50 (2.00%)	0 / 26 (0.00%)	4 / 79 (5.06%)	2 / 64 (3.13%)	2 / 24 (8.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 4	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subarachnoid haemorrhage
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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 / 1	0 / 0	0 / 0
Cerebral haemorrhage
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	1 / 64 (1.56%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Hemiparesis
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Syncope
subjects affected / exposed	1 / 89 (1.12%)	3 / 195 (1.54%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 0	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	0 / 0	0 / 0
Carotid arteriosclerosis
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Cerebral infarction
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Cerebrovascular accident
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 1	0 / 0
Dizziness
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Encephalitis post varicella
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Intraventricular haemorrhage
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 1	0 / 0
Loss of consciousness
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Monoparesis
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Paraesthesia
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	1 / 50 (2.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 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	0 / 0	0 / 0
Partial seizures
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Speech disorder
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	1 / 50 (2.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Cerebellar infarction
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Encephalopathy
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Nervous system disorder
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	2 / 64 (3.13%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Parkinson's disease
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Radiculitis
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Trigeminal neuralgia
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Blood and lymphatic system disorders
Thrombocytopenia
subjects affected / exposed	0 / 89 (0.00%)	3 / 195 (1.54%)	1 / 38 (2.63%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	3 / 79 (3.80%)	0 / 64 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	4 / 5	1 / 1	0 / 0	0 / 0	0 / 0	1 / 4	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anaemia
subjects affected / exposed	0 / 89 (0.00%)	3 / 195 (1.54%)	1 / 38 (2.63%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	5 / 79 (6.33%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 6	0 / 0	0 / 0	0 / 0	0 / 0	0 / 5	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	3 / 64 (4.69%)	4 / 24 (16.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 4	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Leukocytosis
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	2 / 64 (3.13%)	2 / 24 (8.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	3 / 38 (7.89%)	1 / 5 (20.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 3	1 / 1	0 / 0	0 / 0	1 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Granulocytopenia
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Leukopenia
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Splenomegaly
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	1 / 38 (2.63%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Leukostasis syndrome
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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 / 1	0 / 0	0 / 0
Eye disorders
Diplopia
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Glaucoma
subjects affected / exposed	1 / 89 (1.12%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	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	0 / 0	0 / 0
Cataract
subjects affected / exposed	1 / 89 (1.12%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0
Visual acuity reduced
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Vitreous haemorrhage
subjects affected / exposed	1 / 89 (1.12%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	3 / 89 (3.37%)	4 / 195 (2.05%)	1 / 38 (2.63%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	1 / 64 (1.56%)	2 / 24 (8.33%)
occurrences causally related to treatment / all	2 / 3	3 / 5	1 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	1 / 38 (2.63%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	5 / 64 (7.81%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	2 / 5	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	2 / 64 (3.13%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	2 / 89 (2.25%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	4 / 64 (6.25%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	3 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	1 / 89 (1.12%)	2 / 195 (1.03%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	3 / 79 (3.80%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 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	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	2 / 89 (2.25%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	1 / 50 (2.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	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	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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	0 / 0	0 / 0
Rectal haemorrhage
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	1 / 26 (3.85%)	0 / 79 (0.00%)	0 / 64 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	1 / 1	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	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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	0 / 0	0 / 0
Gastritis
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	1 / 50 (2.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haematochezia
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	1 / 89 (1.12%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	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	0 / 0	0 / 0
Toothache
subjects affected / exposed	2 / 89 (2.25%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	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	0 / 0	0 / 0
Abdominal adhesions
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	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	0 / 0	0 / 0
Abdominal distension
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Colitis
subjects affected / exposed	1 / 89 (1.12%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	1 / 26 (3.85%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	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	0 / 0	0 / 0
Colitis ischaemic
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Colitis ulcerative
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	1 / 26 (3.85%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Dental caries
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Duodenal ulcer haemorrhage
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	1 / 38 (2.63%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 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	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Epigastric discomfort
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Food poisoning
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Gastritis erosive
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Ileus
subjects affected / exposed	1 / 89 (1.12%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0
Lower gastrointestinal haemorrhage
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	1 / 50 (2.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Melaena
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	1 / 89 (1.12%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	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	0 / 0	0 / 0
Proctitis
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	1 / 26 (3.85%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Retroperitoneal haemorrhage
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Abdominal pain lower
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Haemorrhoids
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Intestinal haemorrhage
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	1 / 38 (2.63%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Intestinal ischaemia
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	1 / 38 (2.63%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Large intestinal stenosis
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	1 / 50 (2.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	0 / 89 (0.00%)	3 / 195 (1.54%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 5	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	0 / 0	0 / 0
Hepatic function abnormal
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 0	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	0 / 0	0 / 0
Bile duct stone
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Gallbladder disorder
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Perforation bile duct
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	6 / 89 (6.74%)	2 / 195 (1.03%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	4 / 6	2 / 2	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	0 / 0	0 / 0
Urticaria
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	1 / 38 (2.63%)	0 / 5 (0.00%)	1 / 50 (2.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	1 / 1	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	0 / 0	0 / 0
Angioedema
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	1 / 50 (2.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Circumoral oedema
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Dermatitis
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Erythema multiforme
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	1 / 38 (2.63%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Skin lesion
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Rash generalised
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	1 / 50 (2.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Renal and urinary disorders
Renal failure
subjects affected / exposed	0 / 89 (0.00%)	2 / 195 (1.03%)	0 / 38 (0.00%)	0 / 5 (0.00%)	1 / 50 (2.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 3	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	0 / 0	0 / 0
Acute prerenal failure
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Calculus bladder
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	1 / 38 (2.63%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Cystitis haemorrhagic
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Haematuria
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Renal impairment
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	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	0 / 0	0 / 0
Tubulointerstitial nephritis
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Acute kidney injury
subjects affected / exposed	1 / 89 (1.12%)	4 / 195 (2.05%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	2 / 64 (3.13%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 6	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chronic kidney disease
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Prerenal failure
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Renal disorder
subjects affected / exposed	1 / 89 (1.12%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	2 / 89 (2.25%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	2 / 50 (4.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	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	0 / 0	0 / 0
Arthralgia
subjects affected / exposed	1 / 89 (1.12%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	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	0 / 0	0 / 0
Bone pain
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	1 / 50 (2.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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	0 / 0	0 / 0
Bone cyst
subjects affected / exposed	1 / 89 (1.12%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0
Groin pain
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Intervertebral disc protrusion
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	1 / 26 (3.85%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Myalgia
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Myositis
subjects affected / exposed	1 / 89 (1.12%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0
Neck pain
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Osteochondrosis
subjects affected / exposed	1 / 89 (1.12%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0
Spinal column stenosis
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Spinal osteoarthritis
subjects affected / exposed	1 / 89 (1.12%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0
Synovitis
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Foot deformity
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Lumbar spinal stenosis
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	1 / 38 (2.63%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Osteonecrosis
subjects affected / exposed	1 / 89 (1.12%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0
Rotator cuff syndrome
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	1 / 50 (2.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Infections and infestations
Pneumonia
subjects affected / exposed	5 / 89 (5.62%)	6 / 195 (3.08%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	9 / 79 (11.39%)	5 / 64 (7.81%)	3 / 24 (12.50%)
occurrences causally related to treatment / all	0 / 7	0 / 7	0 / 0	0 / 0	0 / 0	0 / 0	2 / 12	0 / 7	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	1 / 2
Sepsis
subjects affected / exposed	0 / 89 (0.00%)	3 / 195 (1.54%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	4 / 79 (5.06%)	1 / 64 (1.56%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 0	0 / 0	0 / 0	1 / 5	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
Urinary tract infection
subjects affected / exposed	0 / 89 (0.00%)	3 / 195 (1.54%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	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	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	2 / 64 (3.13%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Septic shock
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	1 / 89 (1.12%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	1 / 50 (2.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	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	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	1 / 89 (1.12%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	1 / 50 (2.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	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	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 89 (0.00%)	2 / 195 (1.03%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	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	0 / 0	0 / 0
Gastroenteritis viral
subjects affected / exposed	1 / 89 (1.12%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	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	0 / 0	0 / 0
Lung infection
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	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	0 / 0	0 / 0
Sinusitis
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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	0 / 1	0 / 0
Abscess limb
subjects affected / exposed	1 / 89 (1.12%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	1 / 38 (2.63%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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	0 / 0	0 / 0
Appendicitis perforated
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Brain abscess
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Bronchopneumonia
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	0 / 89 (0.00%)	2 / 195 (1.03%)	0 / 38 (0.00%)	0 / 5 (0.00%)	1 / 50 (2.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	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	0 / 0	0 / 0
Cystitis
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Enterococcal sepsis
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	0 / 89 (0.00%)	2 / 195 (1.03%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0	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	0 / 0	0 / 0
Escherichia bacteraemia
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Escherichia sepsis
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Febrile infection
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Fungal infection
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 1	0 / 0
Gastroenteritis
subjects affected / exposed	1 / 89 (1.12%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	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	0 / 0	0 / 0
Gingival abscess
subjects affected / exposed	1 / 89 (1.12%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0
Influenza
subjects affected / exposed	2 / 89 (2.25%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	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	0 / 0	0 / 0
Kidney infection
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Meningitis
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Orchitis
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Pharyngitis
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Pneumonia bacterial
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Pneumonia fungal
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Pneumonia necrotising
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Pseudomembranous colitis
subjects affected / exposed	1 / 89 (1.12%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0
Pseudomonal sepsis
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Pyelonephritis acute
subjects affected / exposed	0 / 89 (0.00%)	2 / 195 (1.03%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	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	0 / 0	0 / 0
Staphylococcal bacteraemia
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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	0 / 0	0 / 0
Staphylococcal sepsis
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Tooth abscess
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Tooth infection
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Urinary tract infection bacterial
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0
Infection
subjects affected / exposed	1 / 89 (1.12%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	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	0 / 0	0 / 0
Atypical pneunomia
subjects affected / exposed	1 / 89 (1.12%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0
Device related infection
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Infectious colitis
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Infectious pleural effusion
subjects affected / exposed	1 / 89 (1.12%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0
Perirectal abscess
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Post procedure infection
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Pulmonary mycosis
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	1 / 38 (2.63%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	1 / 64 (1.56%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	1 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Failure to thrive
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	3 / 64 (4.69%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Acidosis
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	1 / 1	0 / 0	0 / 0
Decreased appetite
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Gout
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	0 / 89 (0.00%)	2 / 195 (1.03%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	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	0 / 0	0 / 0
Hypophosphataemia
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Fluid retention
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	1 / 50 (2.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	2 / 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	0 / 0	0 / 0
Hypovolaemia
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0

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

Non-serious adverse events	Bosutinib 500 mg, CP2L-CML IM-I (Part 2)	Bosutinib 500 mg, CP2L-CML IM-R (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2)	Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2)	AP-CML Total (Part 2)	BP-CML Total (Part 2)	Bosutinib 500 mg, Ph+ ALL (Part 2)
Total subjects affected by non serious adverse events
subjects affected / exposed	89 / 89 (100.00%)	194 / 195 (99.49%)	38 / 38 (100.00%)	5 / 5 (100.00%)	50 / 50 (100.00%)	26 / 26 (100.00%)	79 / 79 (100.00%)	62 / 64 (96.88%)	23 / 24 (95.83%)
Vascular disorders
Hypertension
subjects affected / exposed	6 / 89 (6.74%)	17 / 195 (8.72%)	2 / 38 (5.26%)	0 / 5 (0.00%)	5 / 50 (10.00%)	1 / 26 (3.85%)	6 / 79 (7.59%)	2 / 64 (3.13%)	2 / 24 (8.33%)
occurrences all number	14	32	2	0	7	1	8	2	2
Flushing
subjects affected / exposed	2 / 89 (2.25%)	1 / 195 (0.51%)	0 / 38 (0.00%)	1 / 5 (20.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences all number	2	1	0	1	0	0	0	0	0
Haematoma
subjects affected / exposed	2 / 89 (2.25%)	3 / 195 (1.54%)	0 / 38 (0.00%)	0 / 5 (0.00%)	1 / 50 (2.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	3 / 24 (12.50%)
occurrences all number	3	3	0	0	1	0	2	0	3
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	17 / 89 (19.10%)	58 / 195 (29.74%)	5 / 38 (13.16%)	1 / 5 (20.00%)	7 / 50 (14.00%)	3 / 26 (11.54%)	28 / 79 (35.44%)	22 / 64 (34.38%)	10 / 24 (41.67%)
occurrences all number	25	111	5	1	7	16	44	29	11
Fatigue
subjects affected / exposed	24 / 89 (26.97%)	49 / 195 (25.13%)	8 / 38 (21.05%)	3 / 5 (60.00%)	12 / 50 (24.00%)	2 / 26 (7.69%)	17 / 79 (21.52%)	13 / 64 (20.31%)	5 / 24 (20.83%)
occurrences all number	66	111	8	5	22	2	22	16	6
Asthenia
subjects affected / exposed	16 / 89 (17.98%)	25 / 195 (12.82%)	2 / 38 (5.26%)	2 / 5 (40.00%)	1 / 50 (2.00%)	4 / 26 (15.38%)	11 / 79 (13.92%)	3 / 64 (4.69%)	5 / 24 (20.83%)
occurrences all number	36	81	2	2	1	10	23	4	7
Oedema peripheral
subjects affected / exposed	11 / 89 (12.36%)	17 / 195 (8.72%)	1 / 38 (2.63%)	1 / 5 (20.00%)	4 / 50 (8.00%)	4 / 26 (15.38%)	6 / 79 (7.59%)	7 / 64 (10.94%)	5 / 24 (20.83%)
occurrences all number	16	25	1	1	7	5	13	8	5
Pain
subjects affected / exposed	5 / 89 (5.62%)	16 / 195 (8.21%)	2 / 38 (5.26%)	2 / 5 (40.00%)	2 / 50 (4.00%)	1 / 26 (3.85%)	6 / 79 (7.59%)	3 / 64 (4.69%)	2 / 24 (8.33%)
occurrences all number	14	19	11	2	2	1	9	4	3
Chest pain
subjects affected / exposed	7 / 89 (7.87%)	13 / 195 (6.67%)	1 / 38 (2.63%)	1 / 5 (20.00%)	2 / 50 (4.00%)	0 / 26 (0.00%)	6 / 79 (7.59%)	3 / 64 (4.69%)	2 / 24 (8.33%)
occurrences all number	10	18	1	1	3	0	8	4	2
Oedema
subjects affected / exposed	4 / 89 (4.49%)	9 / 195 (4.62%)	2 / 38 (5.26%)	0 / 5 (0.00%)	2 / 50 (4.00%)	0 / 26 (0.00%)	5 / 79 (6.33%)	2 / 64 (3.13%)	2 / 24 (8.33%)
occurrences all number	5	9	8	0	2	0	5	2	2
Chills
subjects affected / exposed	5 / 89 (5.62%)	13 / 195 (6.67%)	0 / 38 (0.00%)	0 / 5 (0.00%)	3 / 50 (6.00%)	0 / 26 (0.00%)	3 / 79 (3.80%)	2 / 64 (3.13%)	3 / 24 (12.50%)
occurrences all number	5	15	0	0	3	0	3	2	3
Chest discomfort
subjects affected / exposed	2 / 89 (2.25%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	2 / 50 (4.00%)	1 / 26 (3.85%)	4 / 79 (5.06%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences all number	3	1	0	0	2	1	4	2	0
Face oedema
subjects affected / exposed	2 / 89 (2.25%)	4 / 195 (2.05%)	0 / 38 (0.00%)	1 / 5 (20.00%)	0 / 50 (0.00%)	1 / 26 (3.85%)	1 / 79 (1.27%)	0 / 64 (0.00%)	1 / 24 (4.17%)
occurrences all number	2	4	0	3	0	1	1	0	1
Influenza like illness
subjects affected / exposed	5 / 89 (5.62%)	6 / 195 (3.08%)	1 / 38 (2.63%)	1 / 5 (20.00%)	3 / 50 (6.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences all number	6	6	2	1	5	0	1	1	0
Temperature intolerance
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	1 / 5 (20.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	0	0	1	0	0	1	0	0
Immune system disorders
Drug hypersensitivity
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	3 / 38 (7.89%)	0 / 5 (0.00%)	1 / 50 (2.00%)	1 / 26 (3.85%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	2	7	0	1	2	1	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	19 / 89 (21.35%)	46 / 195 (23.59%)	7 / 38 (18.42%)	2 / 5 (40.00%)	12 / 50 (24.00%)	4 / 26 (15.38%)	24 / 79 (30.38%)	8 / 64 (12.50%)	1 / 24 (4.17%)
occurrences all number	24	67	7	2	17	14	43	8	1
Dyspnoea
subjects affected / exposed	9 / 89 (10.11%)	23 / 195 (11.79%)	2 / 38 (5.26%)	1 / 5 (20.00%)	9 / 50 (18.00%)	1 / 26 (3.85%)	14 / 79 (17.72%)	12 / 64 (18.75%)	4 / 24 (16.67%)
occurrences all number	11	33	3	3	23	9	24	15	4
Oropharyngeal pain
subjects affected / exposed	10 / 89 (11.24%)	25 / 195 (12.82%)	2 / 38 (5.26%)	1 / 5 (20.00%)	3 / 50 (6.00%)	2 / 26 (7.69%)	8 / 79 (10.13%)	3 / 64 (4.69%)	2 / 24 (8.33%)
occurrences all number	12	28	3	2	5	6	14	5	2
Pleural effusion
subjects affected / exposed	7 / 89 (7.87%)	18 / 195 (9.23%)	3 / 38 (7.89%)	1 / 5 (20.00%)	13 / 50 (26.00%)	1 / 26 (3.85%)	8 / 79 (10.13%)	2 / 64 (3.13%)	2 / 24 (8.33%)
occurrences all number	14	25	12	5	27	3	11	2	3
Dyspnoea exertional
subjects affected / exposed	1 / 89 (1.12%)	7 / 195 (3.59%)	1 / 38 (2.63%)	1 / 5 (20.00%)	5 / 50 (10.00%)	0 / 26 (0.00%)	3 / 79 (3.80%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences all number	1	9	1	1	5	0	3	1	0
Epistaxis
subjects affected / exposed	1 / 89 (1.12%)	3 / 195 (1.54%)	1 / 38 (2.63%)	0 / 5 (0.00%)	0 / 50 (0.00%)	2 / 26 (7.69%)	3 / 79 (3.80%)	3 / 64 (4.69%)	2 / 24 (8.33%)
occurrences all number	1	4	1	0	0	2	7	4	3
Atelectasis
subjects affected / exposed	1 / 89 (1.12%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	1 / 50 (2.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	2 / 24 (8.33%)
occurrences all number	1	0	0	0	1	0	0	0	2
Nasal congestion
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	3 / 50 (6.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	0	0	0	3	0	1	0	0
Productive cough
subjects affected / exposed	2 / 89 (2.25%)	4 / 195 (2.05%)	0 / 38 (0.00%)	0 / 5 (0.00%)	5 / 50 (10.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	2 / 64 (3.13%)	0 / 24 (0.00%)
occurrences all number	2	4	0	0	5	0	0	4	0
Pulmonary hilum mass
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	1 / 5 (20.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Pulmonary mass
subjects affected / exposed	1 / 89 (1.12%)	0 / 195 (0.00%)	1 / 38 (2.63%)	0 / 5 (0.00%)	3 / 50 (6.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences all number	1	0	1	0	3	0	0	0	0
Rales
subjects affected / exposed	1 / 89 (1.12%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	1 / 50 (2.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	2 / 24 (8.33%)
occurrences all number	1	0	0	0	1	0	1	0	2
Rhinorrhoea
subjects affected / exposed	2 / 89 (2.25%)	4 / 195 (2.05%)	0 / 38 (0.00%)	1 / 5 (20.00%)	1 / 50 (2.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	2 / 64 (3.13%)	1 / 24 (4.17%)
occurrences all number	2	4	0	1	1	0	2	2	1
Psychiatric disorders
Insomnia
subjects affected / exposed	3 / 89 (3.37%)	6 / 195 (3.08%)	1 / 38 (2.63%)	3 / 5 (60.00%)	5 / 50 (10.00%)	1 / 26 (3.85%)	8 / 79 (10.13%)	5 / 64 (7.81%)	2 / 24 (8.33%)
occurrences all number	3	7	2	4	6	2	10	10	2
Anxiety
subjects affected / exposed	7 / 89 (7.87%)	8 / 195 (4.10%)	1 / 38 (2.63%)	0 / 5 (0.00%)	2 / 50 (4.00%)	1 / 26 (3.85%)	8 / 79 (10.13%)	3 / 64 (4.69%)	0 / 24 (0.00%)
occurrences all number	7	11	1	0	2	7	8	3	0
Depression
subjects affected / exposed	4 / 89 (4.49%)	9 / 195 (4.62%)	0 / 38 (0.00%)	1 / 5 (20.00%)	3 / 50 (6.00%)	2 / 26 (7.69%)	2 / 79 (2.53%)	5 / 64 (7.81%)	0 / 24 (0.00%)
occurrences all number	4	11	0	1	3	2	2	5	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	21 / 89 (23.60%)	42 / 195 (21.54%)	6 / 38 (15.79%)	1 / 5 (20.00%)	6 / 50 (12.00%)	5 / 26 (19.23%)	11 / 79 (13.92%)	4 / 64 (6.25%)	2 / 24 (8.33%)
occurrences all number	54	107	9	1	15	17	43	8	2
Platelet count decreased
subjects affected / exposed	11 / 89 (12.36%)	16 / 195 (8.21%)	1 / 38 (2.63%)	0 / 5 (0.00%)	1 / 50 (2.00%)	2 / 26 (7.69%)	5 / 79 (6.33%)	4 / 64 (6.25%)	2 / 24 (8.33%)
occurrences all number	50	53	2	0	8	3	38	6	3
Weight decreased
subjects affected / exposed	8 / 89 (8.99%)	27 / 195 (13.85%)	0 / 38 (0.00%)	0 / 5 (0.00%)	7 / 50 (14.00%)	0 / 26 (0.00%)	6 / 79 (7.59%)	3 / 64 (4.69%)	0 / 24 (0.00%)
occurrences all number	12	29	0	0	7	0	8	3	0
Blood creatinine increased
subjects affected / exposed	8 / 89 (8.99%)	18 / 195 (9.23%)	4 / 38 (10.53%)	1 / 5 (20.00%)	6 / 50 (12.00%)	4 / 26 (15.38%)	6 / 79 (7.59%)	3 / 64 (4.69%)	0 / 24 (0.00%)
occurrences all number	19	27	5	1	11	4	8	7	0
Lipase increased
subjects affected / exposed	9 / 89 (10.11%)	17 / 195 (8.72%)	3 / 38 (7.89%)	0 / 5 (0.00%)	2 / 50 (4.00%)	2 / 26 (7.69%)	6 / 79 (7.59%)	3 / 64 (4.69%)	0 / 24 (0.00%)
occurrences all number	16	29	3	0	8	5	10	7	0
Blood alkaline phosphatase increased
subjects affected / exposed	3 / 89 (3.37%)	6 / 195 (3.08%)	3 / 38 (7.89%)	0 / 5 (0.00%)	0 / 50 (0.00%)	3 / 26 (11.54%)	5 / 79 (6.33%)	3 / 64 (4.69%)	1 / 24 (4.17%)
occurrences all number	5	7	5	0	0	3	16	3	1
Amylase increased
subjects affected / exposed	3 / 89 (3.37%)	12 / 195 (6.15%)	2 / 38 (5.26%)	0 / 5 (0.00%)	1 / 50 (2.00%)	3 / 26 (11.54%)	1 / 79 (1.27%)	3 / 64 (4.69%)	0 / 24 (0.00%)
occurrences all number	7	15	2	0	1	4	2	6	0
Aspartate aminotransferase increased
subjects affected / exposed	18 / 89 (20.22%)	38 / 195 (19.49%)	2 / 38 (5.26%)	0 / 5 (0.00%)	3 / 50 (6.00%)	4 / 26 (15.38%)	12 / 79 (15.19%)	4 / 64 (6.25%)	1 / 24 (4.17%)
occurrences all number	39	81	2	0	5	6	37	4	1
Blood creatine phosphokinase increased
subjects affected / exposed	1 / 89 (1.12%)	14 / 195 (7.18%)	1 / 38 (2.63%)	0 / 5 (0.00%)	0 / 50 (0.00%)	1 / 26 (3.85%)	3 / 79 (3.80%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences all number	1	24	2	0	0	12	4	0	0
Haemoglobin decreased
subjects affected / exposed	10 / 89 (11.24%)	6 / 195 (3.08%)	1 / 38 (2.63%)	0 / 5 (0.00%)	0 / 50 (0.00%)	3 / 26 (11.54%)	2 / 79 (2.53%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences all number	23	11	3	0	0	3	3	0	0
Weight increased
subjects affected / exposed	3 / 89 (3.37%)	12 / 195 (6.15%)	3 / 38 (7.89%)	0 / 5 (0.00%)	1 / 50 (2.00%)	0 / 26 (0.00%)	2 / 79 (2.53%)	3 / 64 (4.69%)	0 / 24 (0.00%)
occurrences all number	5	18	4	0	4	0	6	3	0
White blood cell count decreased
subjects affected / exposed	9 / 89 (10.11%)	6 / 195 (3.08%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	3 / 79 (3.80%)	4 / 64 (6.25%)	1 / 24 (4.17%)
occurrences all number	25	9	0	0	0	0	5	15	1
Blood urea increased
subjects affected / exposed	1 / 89 (1.12%)	3 / 195 (1.54%)	2 / 38 (5.26%)	0 / 5 (0.00%)	2 / 50 (4.00%)	0 / 26 (0.00%)	2 / 79 (2.53%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences all number	1	3	2	0	2	0	4	2	0
Blood uric acid increased
subjects affected / exposed	1 / 89 (1.12%)	11 / 195 (5.64%)	2 / 38 (5.26%)	0 / 5 (0.00%)	2 / 50 (4.00%)	0 / 26 (0.00%)	4 / 79 (5.06%)	0 / 64 (0.00%)	1 / 24 (4.17%)
occurrences all number	1	13	2	0	2	0	6	0	2
Gamma-glutamyltransferase increased
subjects affected / exposed	2 / 89 (2.25%)	4 / 195 (2.05%)	3 / 38 (7.89%)	0 / 5 (0.00%)	0 / 50 (0.00%)	1 / 26 (3.85%)	2 / 79 (2.53%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences all number	2	6	3	0	0	3	2	0	0
Globulins decreased
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	1 / 38 (2.63%)	0 / 5 (0.00%)	0 / 50 (0.00%)	2 / 26 (7.69%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	0	2	0	0	2	0	0	0
Haematocrit decreased
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	1 / 5 (20.00%)	0 / 50 (0.00%)	1 / 26 (3.85%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	0	0	1	0	1	0	0	0
Neutrophil count decreased
subjects affected / exposed	5 / 89 (5.62%)	3 / 195 (1.54%)	0 / 38 (0.00%)	0 / 5 (0.00%)	1 / 50 (2.00%)	0 / 26 (0.00%)	3 / 79 (3.80%)	1 / 64 (1.56%)	2 / 24 (8.33%)
occurrences all number	15	10	0	0	4	0	5	1	3
White blood cells urine positive
subjects affected / exposed	0 / 89 (0.00%)	3 / 195 (1.54%)	0 / 38 (0.00%)	1 / 5 (20.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	4	0	1	0	0	0	0	0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	7 / 89 (7.87%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	2 / 50 (4.00%)	0 / 26 (0.00%)	2 / 79 (2.53%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences all number	9	1	0	0	2	0	2	0	0
Procedural pain
subjects affected / exposed	2 / 89 (2.25%)	5 / 195 (2.56%)	0 / 38 (0.00%)	1 / 5 (20.00%)	2 / 50 (4.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences all number	4	5	0	1	2	0	0	0	0
Cardiac disorders
Pericardial effusion
subjects affected / exposed	2 / 89 (2.25%)	3 / 195 (1.54%)	1 / 38 (2.63%)	1 / 5 (20.00%)	4 / 50 (8.00%)	0 / 26 (0.00%)	4 / 79 (5.06%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences all number	2	6	1	1	7	0	7	1	0
Mitral valve incompetence
subjects affected / exposed	1 / 89 (1.12%)	1 / 195 (0.51%)	0 / 38 (0.00%)	1 / 5 (20.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences all number	1	1	0	1	0	0	0	0	0
Tachycardia
subjects affected / exposed	0 / 89 (0.00%)	3 / 195 (1.54%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	1 / 26 (3.85%)	0 / 79 (0.00%)	4 / 64 (6.25%)	0 / 24 (0.00%)
occurrences all number	0	3	0	0	0	1	0	5	0
Nervous system disorders
Headache
subjects affected / exposed	18 / 89 (20.22%)	35 / 195 (17.95%)	7 / 38 (18.42%)	1 / 5 (20.00%)	15 / 50 (30.00%)	8 / 26 (30.77%)	12 / 79 (15.19%)	13 / 64 (20.31%)	6 / 24 (25.00%)
occurrences all number	50	88	13	1	26	15	18	18	7
Dizziness
subjects affected / exposed	9 / 89 (10.11%)	16 / 195 (8.21%)	5 / 38 (13.16%)	2 / 5 (40.00%)	8 / 50 (16.00%)	3 / 26 (11.54%)	11 / 79 (13.92%)	7 / 64 (10.94%)	2 / 24 (8.33%)
occurrences all number	17	23	5	5	11	5	11	7	2
Hypoaesthesia
subjects affected / exposed	2 / 89 (2.25%)	11 / 195 (5.64%)	0 / 38 (0.00%)	0 / 5 (0.00%)	1 / 50 (2.00%)	1 / 26 (3.85%)	3 / 79 (3.80%)	2 / 64 (3.13%)	1 / 24 (4.17%)
occurrences all number	2	19	0	0	1	1	3	2	3
Paraesthesia
subjects affected / exposed	3 / 89 (3.37%)	11 / 195 (5.64%)	0 / 38 (0.00%)	1 / 5 (20.00%)	3 / 50 (6.00%)	0 / 26 (0.00%)	2 / 79 (2.53%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences all number	4	11	0	1	4	0	3	1	0
Dysgeusia
subjects affected / exposed	2 / 89 (2.25%)	3 / 195 (1.54%)	0 / 38 (0.00%)	1 / 5 (20.00%)	1 / 50 (2.00%)	1 / 26 (3.85%)	2 / 79 (2.53%)	1 / 64 (1.56%)	1 / 24 (4.17%)
occurrences all number	3	3	0	1	1	1	2	1	1
Neuropathy peripheral
subjects affected / exposed	1 / 89 (1.12%)	3 / 195 (1.54%)	0 / 38 (0.00%)	1 / 5 (20.00%)	1 / 50 (2.00%)	0 / 26 (0.00%)	3 / 79 (3.80%)	1 / 64 (1.56%)	1 / 24 (4.17%)
occurrences all number	1	4	0	1	1	0	3	1	1
Sensory disturbance
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	1 / 5 (20.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Somnolence
subjects affected / exposed	2 / 89 (2.25%)	4 / 195 (2.05%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	2 / 26 (7.69%)	2 / 79 (2.53%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences all number	4	4	0	0	0	2	2	1	0
Syncope
subjects affected / exposed	1 / 89 (1.12%)	3 / 195 (1.54%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	2 / 24 (8.33%)
occurrences all number	1	3	0	0	0	0	1	0	2
Blood and lymphatic system disorders
Thrombocytopenia
subjects affected / exposed	32 / 89 (35.96%)	61 / 195 (31.28%)	9 / 38 (23.68%)	3 / 5 (60.00%)	18 / 50 (36.00%)	12 / 26 (46.15%)	35 / 79 (44.30%)	18 / 64 (28.13%)	5 / 24 (20.83%)
occurrences all number	155	278	35	4	92	44	170	104	8
Anaemia
subjects affected / exposed	24 / 89 (26.97%)	45 / 195 (23.08%)	7 / 38 (18.42%)	2 / 5 (40.00%)	7 / 50 (14.00%)	6 / 26 (23.08%)	33 / 79 (41.77%)	19 / 64 (29.69%)	10 / 24 (41.67%)
occurrences all number	55	162	14	2	17	11	98	75	16
Neutropenia
subjects affected / exposed	13 / 89 (14.61%)	26 / 195 (13.33%)	8 / 38 (21.05%)	1 / 5 (20.00%)	6 / 50 (12.00%)	7 / 26 (26.92%)	12 / 79 (15.19%)	16 / 64 (25.00%)	2 / 24 (8.33%)
occurrences all number	52	72	25	4	22	12	67	39	2
Leukopenia
subjects affected / exposed	8 / 89 (8.99%)	19 / 195 (9.74%)	4 / 38 (10.53%)	0 / 5 (0.00%)	1 / 50 (2.00%)	0 / 26 (0.00%)	7 / 79 (8.86%)	9 / 64 (14.06%)	2 / 24 (8.33%)
occurrences all number	35	35	13	0	1	0	19	17	6
Leukocytosis
subjects affected / exposed	0 / 89 (0.00%)	7 / 195 (3.59%)	1 / 38 (2.63%)	0 / 5 (0.00%)	2 / 50 (4.00%)	0 / 26 (0.00%)	4 / 79 (5.06%)	4 / 64 (6.25%)	2 / 24 (8.33%)
occurrences all number	0	10	1	0	2	0	6	4	2
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	2 / 89 (2.25%)	3 / 195 (1.54%)	2 / 38 (5.26%)	0 / 5 (0.00%)	1 / 50 (2.00%)	1 / 26 (3.85%)	1 / 79 (1.27%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences all number	2	4	3	0	1	1	1	1	0
Eye disorders
Eye oedema
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	0 / 38 (0.00%)	1 / 5 (20.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	1	0	1	0	0	0	0	0
Scleral haemorrhage
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	1 / 5 (20.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences all number	0	0	0	1	0	0	0	1	0
Visual acuity reduced
subjects affected / exposed	1 / 89 (1.12%)	3 / 195 (1.54%)	2 / 38 (5.26%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences all number	1	3	2	0	0	0	0	1	0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	76 / 89 (85.39%)	166 / 195 (85.13%)	30 / 38 (78.95%)	5 / 5 (100.00%)	42 / 50 (84.00%)	22 / 26 (84.62%)	67 / 79 (84.81%)	41 / 64 (64.06%)	15 / 24 (62.50%)
occurrences all number	513	1710	189	10	209	280	243	128	29
Nausea
subjects affected / exposed	46 / 89 (51.69%)	85 / 195 (43.59%)	20 / 38 (52.63%)	2 / 5 (40.00%)	23 / 50 (46.00%)	12 / 26 (46.15%)	36 / 79 (45.57%)	30 / 64 (46.88%)	12 / 24 (50.00%)
occurrences all number	98	290	65	2	42	39	97	57	19
Vomiting
subjects affected / exposed	32 / 89 (35.96%)	73 / 195 (37.44%)	14 / 38 (36.84%)	0 / 5 (0.00%)	24 / 50 (48.00%)	7 / 26 (26.92%)	35 / 79 (44.30%)	26 / 64 (40.63%)	11 / 24 (45.83%)
occurrences all number	52	237	32	0	40	16	75	45	19
Abdominal pain
subjects affected / exposed	24 / 89 (26.97%)	50 / 195 (25.64%)	8 / 38 (21.05%)	0 / 5 (0.00%)	12 / 50 (24.00%)	8 / 26 (30.77%)	19 / 79 (24.05%)	11 / 64 (17.19%)	3 / 24 (12.50%)
occurrences all number	37	121	12	0	20	37	26	26	3
Abdominal pain upper
subjects affected / exposed	17 / 89 (19.10%)	41 / 195 (21.03%)	8 / 38 (21.05%)	0 / 5 (0.00%)	9 / 50 (18.00%)	4 / 26 (15.38%)	9 / 79 (11.39%)	7 / 64 (10.94%)	0 / 24 (0.00%)
occurrences all number	34	121	34	0	44	17	16	15	0
Constipation
subjects affected / exposed	17 / 89 (19.10%)	22 / 195 (11.28%)	2 / 38 (5.26%)	2 / 5 (40.00%)	7 / 50 (14.00%)	3 / 26 (11.54%)	14 / 79 (17.72%)	9 / 64 (14.06%)	4 / 24 (16.67%)
occurrences all number	29	35	5	2	11	8	25	11	5
Dyspepsia
subjects affected / exposed	7 / 89 (7.87%)	21 / 195 (10.77%)	7 / 38 (18.42%)	0 / 5 (0.00%)	4 / 50 (8.00%)	1 / 26 (3.85%)	9 / 79 (11.39%)	1 / 64 (1.56%)	1 / 24 (4.17%)
occurrences all number	14	52	30	0	6	1	12	2	1
Abdominal distension
subjects affected / exposed	8 / 89 (8.99%)	17 / 195 (8.72%)	2 / 38 (5.26%)	0 / 5 (0.00%)	4 / 50 (8.00%)	3 / 26 (11.54%)	1 / 79 (1.27%)	4 / 64 (6.25%)	0 / 24 (0.00%)
occurrences all number	11	68	2	0	5	11	1	6	0
Flatulence
subjects affected / exposed	6 / 89 (6.74%)	4 / 195 (2.05%)	3 / 38 (7.89%)	0 / 5 (0.00%)	3 / 50 (6.00%)	1 / 26 (3.85%)	2 / 79 (2.53%)	2 / 64 (3.13%)	0 / 24 (0.00%)
occurrences all number	19	11	5	0	5	1	2	3	0
Abdominal discomfort
subjects affected / exposed	9 / 89 (10.11%)	8 / 195 (4.10%)	1 / 38 (2.63%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	4 / 79 (5.06%)	1 / 64 (1.56%)	2 / 24 (8.33%)
occurrences all number	18	11	2	0	0	0	4	1	2
Toothache
subjects affected / exposed	6 / 89 (6.74%)	12 / 195 (6.15%)	2 / 38 (5.26%)	1 / 5 (20.00%)	2 / 50 (4.00%)	0 / 26 (0.00%)	3 / 79 (3.80%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences all number	9	17	3	1	3	0	3	0	0
Aphthous stomatitis
subjects affected / exposed	2 / 89 (2.25%)	2 / 195 (1.03%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	2 / 26 (7.69%)	0 / 79 (0.00%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences all number	2	2	0	0	0	4	0	1	0
Gastrointestinal sounds abnormal
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	1 / 38 (2.63%)	1 / 5 (20.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	0	1	1	0	0	0	0	0
Gingival bleeding
subjects affected / exposed	1 / 89 (1.12%)	5 / 195 (2.56%)	1 / 38 (2.63%)	0 / 5 (0.00%)	0 / 50 (0.00%)	2 / 26 (7.69%)	0 / 79 (0.00%)	1 / 64 (1.56%)	1 / 24 (4.17%)
occurrences all number	1	7	4	0	0	2	0	1	2
Gingival pain
subjects affected / exposed	2 / 89 (2.25%)	2 / 195 (1.03%)	2 / 38 (5.26%)	1 / 5 (20.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences all number	3	3	3	1	0	0	0	0	0
Haemorrhoids
subjects affected / exposed	2 / 89 (2.25%)	7 / 195 (3.59%)	1 / 38 (2.63%)	0 / 5 (0.00%)	0 / 50 (0.00%)	3 / 26 (11.54%)	4 / 79 (5.06%)	2 / 64 (3.13%)	1 / 24 (4.17%)
occurrences all number	2	12	2	0	0	4	4	2	1
Mouth ulceration
subjects affected / exposed	3 / 89 (3.37%)	6 / 195 (3.08%)	0 / 38 (0.00%)	0 / 5 (0.00%)	1 / 50 (2.00%)	2 / 26 (7.69%)	1 / 79 (1.27%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences all number	3	7	0	0	1	4	1	1	0
Stomatitis
subjects affected / exposed	0 / 89 (0.00%)	2 / 195 (1.03%)	1 / 38 (2.63%)	0 / 5 (0.00%)	1 / 50 (2.00%)	1 / 26 (3.85%)	2 / 79 (2.53%)	2 / 64 (3.13%)	2 / 24 (8.33%)
occurrences all number	0	3	3	0	1	1	2	2	2
Tongue oedema
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	1 / 5 (20.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Hepatobiliary disorders
Hyperbilirubinaemia
subjects affected / exposed	1 / 89 (1.12%)	4 / 195 (2.05%)	0 / 38 (0.00%)	1 / 5 (20.00%)	1 / 50 (2.00%)	0 / 26 (0.00%)	2 / 79 (2.53%)	5 / 64 (7.81%)	1 / 24 (4.17%)
occurrences all number	2	4	0	1	3	0	2	8	1
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	36 / 89 (40.45%)	63 / 195 (32.31%)	10 / 38 (26.32%)	2 / 5 (40.00%)	18 / 50 (36.00%)	3 / 26 (11.54%)	27 / 79 (34.18%)	20 / 64 (31.25%)	4 / 24 (16.67%)
occurrences all number	93	116	14	5	31	9	53	24	6
Pruritus
subjects affected / exposed	9 / 89 (10.11%)	18 / 195 (9.23%)	9 / 38 (23.68%)	0 / 5 (0.00%)	8 / 50 (16.00%)	3 / 26 (11.54%)	6 / 79 (7.59%)	4 / 64 (6.25%)	0 / 24 (0.00%)
occurrences all number	17	31	16	0	9	4	19	4	0
Dry skin
subjects affected / exposed	4 / 89 (4.49%)	16 / 195 (8.21%)	1 / 38 (2.63%)	0 / 5 (0.00%)	4 / 50 (8.00%)	3 / 26 (11.54%)	3 / 79 (3.80%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences all number	6	23	1	0	6	4	3	1	0
Skin lesion
subjects affected / exposed	4 / 89 (4.49%)	10 / 195 (5.13%)	2 / 38 (5.26%)	0 / 5 (0.00%)	2 / 50 (4.00%)	2 / 26 (7.69%)	4 / 79 (5.06%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences all number	4	19	7	0	2	2	8	1	0
Alopecia
subjects affected / exposed	3 / 89 (3.37%)	11 / 195 (5.64%)	0 / 38 (0.00%)	1 / 5 (20.00%)	3 / 50 (6.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	2 / 64 (3.13%)	0 / 24 (0.00%)
occurrences all number	4	14	0	1	4	0	1	2	0
Night sweats
subjects affected / exposed	1 / 89 (1.12%)	2 / 195 (1.03%)	2 / 38 (5.26%)	0 / 5 (0.00%)	3 / 50 (6.00%)	1 / 26 (3.85%)	2 / 79 (2.53%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences all number	1	2	2	0	3	2	2	0	0
Angioedema
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	1 / 5 (20.00%)	1 / 50 (2.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	0	0	3	4	0	0	0	0
Dermatitis
subjects affected / exposed	0 / 89 (0.00%)	4 / 195 (2.05%)	2 / 38 (5.26%)	0 / 5 (0.00%)	0 / 50 (0.00%)	1 / 26 (3.85%)	2 / 79 (2.53%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences all number	0	6	4	0	0	2	2	1	0
Ecchymosis
subjects affected / exposed	1 / 89 (1.12%)	0 / 195 (0.00%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	2 / 26 (7.69%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences all number	1	0	0	0	0	2	0	0	0
Erythema
subjects affected / exposed	7 / 89 (7.87%)	5 / 195 (2.56%)	1 / 38 (2.63%)	0 / 5 (0.00%)	2 / 50 (4.00%)	2 / 26 (7.69%)	4 / 79 (5.06%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences all number	8	6	1	0	2	8	6	1	0
Hyperhidrosis
subjects affected / exposed	3 / 89 (3.37%)	3 / 195 (1.54%)	1 / 38 (2.63%)	0 / 5 (0.00%)	3 / 50 (6.00%)	1 / 26 (3.85%)	2 / 79 (2.53%)	3 / 64 (4.69%)	0 / 24 (0.00%)
occurrences all number	4	3	2	0	4	3	3	5	0
Nail disorder
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	1 / 38 (2.63%)	0 / 5 (0.00%)	0 / 50 (0.00%)	2 / 26 (7.69%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	0	1	0	0	2	0	0	0
Petechiae
subjects affected / exposed	0 / 89 (0.00%)	3 / 195 (1.54%)	0 / 38 (0.00%)	0 / 5 (0.00%)	1 / 50 (2.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	3 / 64 (4.69%)	3 / 24 (12.50%)
occurrences all number	0	4	0	0	1	0	2	3	4
Skin burning sensation
subjects affected / exposed	0 / 89 (0.00%)	2 / 195 (1.03%)	0 / 38 (0.00%)	1 / 5 (20.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	6	0	1	0	0	0	0	0
Skin depigmentation
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	1 / 5 (20.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0	0
Swelling face
subjects affected / exposed	1 / 89 (1.12%)	1 / 195 (0.51%)	1 / 38 (2.63%)	1 / 5 (20.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences all number	1	1	1	1	0	0	0	0	0
Renal and urinary disorders
Dysuria
subjects affected / exposed	4 / 89 (4.49%)	6 / 195 (3.08%)	3 / 38 (7.89%)	0 / 5 (0.00%)	0 / 50 (0.00%)	2 / 26 (7.69%)	1 / 79 (1.27%)	2 / 64 (3.13%)	1 / 24 (4.17%)
occurrences all number	4	9	3	0	0	2	1	3	1
Pollakiuria
subjects affected / exposed	2 / 89 (2.25%)	2 / 195 (1.03%)	0 / 38 (0.00%)	1 / 5 (20.00%)	1 / 50 (2.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences all number	2	2	0	2	1	0	1	0	0
Renal failure
subjects affected / exposed	1 / 89 (1.12%)	3 / 195 (1.54%)	1 / 38 (2.63%)	0 / 5 (0.00%)	1 / 50 (2.00%)	0 / 26 (0.00%)	5 / 79 (6.33%)	1 / 64 (1.56%)	1 / 24 (4.17%)
occurrences all number	1	4	3	0	1	0	5	1	1
Urinary retention
subjects affected / exposed	1 / 89 (1.12%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	2 / 26 (7.69%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences all number	1	1	0	0	0	2	0	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	17 / 89 (19.10%)	31 / 195 (15.90%)	5 / 38 (13.16%)	0 / 5 (0.00%)	10 / 50 (20.00%)	6 / 26 (23.08%)	12 / 79 (15.19%)	8 / 64 (12.50%)	3 / 24 (12.50%)
occurrences all number	21	40	6	0	19	23	24	11	4
Back pain
subjects affected / exposed	16 / 89 (17.98%)	22 / 195 (11.28%)	5 / 38 (13.16%)	1 / 5 (20.00%)	5 / 50 (10.00%)	3 / 26 (11.54%)	8 / 79 (10.13%)	4 / 64 (6.25%)	4 / 24 (16.67%)
occurrences all number	25	31	22	1	5	5	13	7	4
Pain in extremity
subjects affected / exposed	4 / 89 (4.49%)	27 / 195 (13.85%)	2 / 38 (5.26%)	0 / 5 (0.00%)	5 / 50 (10.00%)	3 / 26 (11.54%)	9 / 79 (11.39%)	6 / 64 (9.38%)	3 / 24 (12.50%)
occurrences all number	9	45	3	0	8	12	18	8	4
Myalgia
subjects affected / exposed	7 / 89 (7.87%)	16 / 195 (8.21%)	3 / 38 (7.89%)	0 / 5 (0.00%)	1 / 50 (2.00%)	1 / 26 (3.85%)	7 / 79 (8.86%)	6 / 64 (9.38%)	2 / 24 (8.33%)
occurrences all number	11	21	3	0	2	1	7	8	2
Bone pain
subjects affected / exposed	3 / 89 (3.37%)	11 / 195 (5.64%)	3 / 38 (7.89%)	0 / 5 (0.00%)	5 / 50 (10.00%)	1 / 26 (3.85%)	1 / 79 (1.27%)	7 / 64 (10.94%)	3 / 24 (12.50%)
occurrences all number	4	13	4	0	7	1	1	8	4
Musculoskeletal pain
subjects affected / exposed	3 / 89 (3.37%)	8 / 195 (4.10%)	5 / 38 (13.16%)	0 / 5 (0.00%)	3 / 50 (6.00%)	2 / 26 (7.69%)	5 / 79 (6.33%)	3 / 64 (4.69%)	1 / 24 (4.17%)
occurrences all number	3	13	6	0	4	2	7	6	1
Muscle spasms
subjects affected / exposed	7 / 89 (7.87%)	7 / 195 (3.59%)	2 / 38 (5.26%)	0 / 5 (0.00%)	5 / 50 (10.00%)	1 / 26 (3.85%)	4 / 79 (5.06%)	1 / 64 (1.56%)	2 / 24 (8.33%)
occurrences all number	14	11	3	0	5	12	5	1	4
Groin pain
subjects affected / exposed	0 / 89 (0.00%)	1 / 195 (0.51%)	2 / 38 (5.26%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	2	4	0	0	0	0	0	1
Joint swelling
subjects affected / exposed	2 / 89 (2.25%)	1 / 195 (0.51%)	0 / 38 (0.00%)	1 / 5 (20.00%)	1 / 50 (2.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	1 / 64 (1.56%)	1 / 24 (4.17%)
occurrences all number	2	1	0	1	2	0	1	1	1
Musculoskeletal chest pain
subjects affected / exposed	1 / 89 (1.12%)	2 / 195 (1.03%)	2 / 38 (5.26%)	0 / 5 (0.00%)	1 / 50 (2.00%)	0 / 26 (0.00%)	3 / 79 (3.80%)	1 / 64 (1.56%)	1 / 24 (4.17%)
occurrences all number	1	3	2	0	1	0	3	1	1
Musculoskeletal stiffness
subjects affected / exposed	1 / 89 (1.12%)	0 / 195 (0.00%)	1 / 38 (2.63%)	1 / 5 (20.00%)	1 / 50 (2.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences all number	1	0	1	1	1	0	0	0	0
Neck pain
subjects affected / exposed	2 / 89 (2.25%)	4 / 195 (2.05%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	2 / 26 (7.69%)	1 / 79 (1.27%)	4 / 64 (6.25%)	0 / 24 (0.00%)
occurrences all number	2	9	0	0	0	5	2	5	0
Infections and infestations
Nasopharyngitis
subjects affected / exposed	13 / 89 (14.61%)	25 / 195 (12.82%)	3 / 38 (7.89%)	1 / 5 (20.00%)	5 / 50 (10.00%)	4 / 26 (15.38%)	7 / 79 (8.86%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences all number	18	34	3	1	5	5	9	1	0
Upper respiratory tract infection
subjects affected / exposed	9 / 89 (10.11%)	19 / 195 (9.74%)	3 / 38 (7.89%)	2 / 5 (40.00%)	7 / 50 (14.00%)	0 / 26 (0.00%)	8 / 79 (10.13%)	2 / 64 (3.13%)	0 / 24 (0.00%)
occurrences all number	12	35	8	2	13	0	19	3	0
Influenza
subjects affected / exposed	6 / 89 (6.74%)	21 / 195 (10.77%)	4 / 38 (10.53%)	1 / 5 (20.00%)	4 / 50 (8.00%)	3 / 26 (11.54%)	5 / 79 (6.33%)	0 / 64 (0.00%)	1 / 24 (4.17%)
occurrences all number	9	33	7	1	4	3	9	0	1
Urinary tract infection
subjects affected / exposed	8 / 89 (8.99%)	20 / 195 (10.26%)	1 / 38 (2.63%)	1 / 5 (20.00%)	2 / 50 (4.00%)	2 / 26 (7.69%)	1 / 79 (1.27%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences all number	15	32	1	1	2	2	5	1	0
Bronchitis
subjects affected / exposed	3 / 89 (3.37%)	13 / 195 (6.67%)	1 / 38 (2.63%)	1 / 5 (20.00%)	2 / 50 (4.00%)	1 / 26 (3.85%)	6 / 79 (7.59%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences all number	3	14	1	1	3	2	6	0	0
Sinusitis
subjects affected / exposed	3 / 89 (3.37%)	7 / 195 (3.59%)	2 / 38 (5.26%)	1 / 5 (20.00%)	4 / 50 (8.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences all number	3	7	2	1	5	0	1	1	0
Gastrointestinal infection
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	2 / 38 (5.26%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	0	5	0	0	0	1	0	0
Gingivitis
subjects affected / exposed	2 / 89 (2.25%)	4 / 195 (2.05%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	2 / 26 (7.69%)	0 / 79 (0.00%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences all number	3	5	0	0	0	2	0	1	0
Lower respiratory tract infection
subjects affected / exposed	1 / 89 (1.12%)	1 / 195 (0.51%)	1 / 38 (2.63%)	1 / 5 (20.00%)	1 / 50 (2.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences all number	1	1	1	1	2	0	0	0	0
Oral candidiasis
subjects affected / exposed	2 / 89 (2.25%)	1 / 195 (0.51%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	4 / 79 (5.06%)	2 / 64 (3.13%)	0 / 24 (0.00%)
occurrences all number	2	1	0	0	0	0	4	2	0
Oral herpes
subjects affected / exposed	3 / 89 (3.37%)	3 / 195 (1.54%)	1 / 38 (2.63%)	0 / 5 (0.00%)	0 / 50 (0.00%)	1 / 26 (3.85%)	6 / 79 (7.59%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences all number	3	3	1	0	0	1	6	1	0
Pharyngitis
subjects affected / exposed	5 / 89 (5.62%)	6 / 195 (3.08%)	2 / 38 (5.26%)	1 / 5 (20.00%)	0 / 50 (0.00%)	1 / 26 (3.85%)	1 / 79 (1.27%)	1 / 64 (1.56%)	0 / 24 (0.00%)
occurrences all number	5	6	3	1	0	2	1	1	0
Pneumonia
subjects affected / exposed	2 / 89 (2.25%)	2 / 195 (1.03%)	1 / 38 (2.63%)	0 / 5 (0.00%)	3 / 50 (6.00%)	1 / 26 (3.85%)	2 / 79 (2.53%)	4 / 64 (6.25%)	1 / 24 (4.17%)
occurrences all number	2	2	1	0	3	1	2	4	1
Respiratory tract infection viral
subjects affected / exposed	3 / 89 (3.37%)	4 / 195 (2.05%)	0 / 38 (0.00%)	0 / 5 (0.00%)	0 / 50 (0.00%)	3 / 26 (11.54%)	2 / 79 (2.53%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences all number	6	5	0	0	0	7	2	0	0
Wound infection
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	0 / 38 (0.00%)	1 / 5 (20.00%)	0 / 50 (0.00%)	0 / 26 (0.00%)	0 / 79 (0.00%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	12 / 89 (13.48%)	29 / 195 (14.87%)	3 / 38 (7.89%)	1 / 5 (20.00%)	7 / 50 (14.00%)	4 / 26 (15.38%)	7 / 79 (8.86%)	12 / 64 (18.75%)	1 / 24 (4.17%)
occurrences all number	16	45	6	1	10	5	15	12	2
Hypokalaemia
subjects affected / exposed	5 / 89 (5.62%)	10 / 195 (5.13%)	0 / 38 (0.00%)	0 / 5 (0.00%)	3 / 50 (6.00%)	2 / 26 (7.69%)	2 / 79 (2.53%)	6 / 64 (9.38%)	2 / 24 (8.33%)
occurrences all number	7	15	0	0	7	5	8	10	4
Hypophosphataemia
subjects affected / exposed	0 / 89 (0.00%)	12 / 195 (6.15%)	0 / 38 (0.00%)	1 / 5 (20.00%)	1 / 50 (2.00%)	1 / 26 (3.85%)	5 / 79 (6.33%)	3 / 64 (4.69%)	2 / 24 (8.33%)
occurrences all number	0	22	0	1	2	2	12	6	2
Hyperuricaemia
subjects affected / exposed	6 / 89 (6.74%)	6 / 195 (3.08%)	1 / 38 (2.63%)	1 / 5 (20.00%)	5 / 50 (10.00%)	0 / 26 (0.00%)	3 / 79 (3.80%)	2 / 64 (3.13%)	0 / 24 (0.00%)
occurrences all number	15	9	2	1	7	0	3	8	0
Hypocalcaemia
subjects affected / exposed	0 / 89 (0.00%)	8 / 195 (4.10%)	0 / 38 (0.00%)	0 / 5 (0.00%)	1 / 50 (2.00%)	0 / 26 (0.00%)	2 / 79 (2.53%)	5 / 64 (7.81%)	1 / 24 (4.17%)
occurrences all number	0	9	0	0	3	0	2	8	1
Hyperglycaemia
subjects affected / exposed	2 / 89 (2.25%)	8 / 195 (4.10%)	2 / 38 (5.26%)	0 / 5 (0.00%)	1 / 50 (2.00%)	2 / 26 (7.69%)	4 / 79 (5.06%)	1 / 64 (1.56%)	2 / 24 (8.33%)
occurrences all number	3	11	2	0	1	3	6	2	2
Hyperkalaemia
subjects affected / exposed	2 / 89 (2.25%)	6 / 195 (3.08%)	0 / 38 (0.00%)	0 / 5 (0.00%)	1 / 50 (2.00%)	4 / 26 (15.38%)	4 / 79 (5.06%)	3 / 64 (4.69%)	0 / 24 (0.00%)
occurrences all number	3	16	0	0	1	7	11	4	0
Hypernatraemia
subjects affected / exposed	0 / 89 (0.00%)	0 / 195 (0.00%)	2 / 38 (5.26%)	0 / 5 (0.00%)	1 / 50 (2.00%)	0 / 26 (0.00%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	0	3	0	1	0	1	0	0
Hypoglycaemia
subjects affected / exposed	1 / 89 (1.12%)	2 / 195 (1.03%)	2 / 38 (5.26%)	1 / 5 (20.00%)	0 / 50 (0.00%)	1 / 26 (3.85%)	1 / 79 (1.27%)	0 / 64 (0.00%)	0 / 24 (0.00%)
occurrences all number	1	2	2	1	0	1	1	0	0
Hypomagnesaemia
subjects affected / exposed	1 / 89 (1.12%)	3 / 195 (1.54%)	1 / 38 (2.63%)	0 / 5 (0.00%)	1 / 50 (2.00%)	0 / 26 (0.00%)	2 / 79 (2.53%)	4 / 64 (6.25%)	0 / 24 (0.00%)
occurrences all number	1	3	1	0	1	0	2	4	0

More information

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Were there any global substantial amendments to the protocol? Yes

20 Oct 2006

This amendment updated the protocol with new safety and efficacy information. This amendment also increased the size of the MTD cohort (i.e., those enrolled at Part 2) to approximately 330 participants.

10 Jun 2008

Removed physical examination at Week 12 and q12 week visits. Removed pharmacodynamic and pharmacogenomic testing in Part 2. Added requirement that participants in Taiwan will be monitored with ECGs every 12 weeks during treatment in order to accommodate the request of local regulatory authorities. Removed the pharmacokinetic sample collected at Week 2. Updated the background information about imatinib. Added background information for dasatinib and nilotinib. Added rationale for inclusion of participants who have failed dasatinib or nilotinib. Updated the data for Phase 1 study 3160A1-100-US in solid tumor participants. Provided an update on interim analyses of efficacy that were performed on all cohorts meeting pre-specified targets of evaluable participants enrolled. Provided a rationale to exclude participants with known T315I mutation. Modified previous objective to include newly added CP nilotinib-resistant cohort. Added a secondary endpoint for the new AP and BP cohorts. Added imatinib-resistant/intolerant and nilotinib-resistant participants to the CP exploratory cohorts. Added explanation of treatment of initial participants in China in order to accommodate the request of local regulatory authorities. Added guidance regarding systemic steroid use and potassium and magnesium supplementation. Removed Vitamin K and PIVKA-II testing for participants with grade 2 increased INR or >1 unit (if taking OAT), as this testing is not readily available at most institutions. Other minor changes such as further clarifications, protocol section renumbering, and corrections of spelling and grammatical errors were added throughout the protocol.

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.

Analyses of progression free survival and overall survival was based on all-treated population, instead of evaluable population which was the primary efficacy population as per planned analyses.

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Clinical trials

Clinical Trial Results: A Phase 1/2 Study of Bosutinib (SKI-606) in Philadelphia Chromosome Positive Leukemias

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of Participants With Dose Limiting Toxicity (DLT)

Primary: Number of Participants With Dose Limiting Toxicity (DLT)

Primary: Maximum Tolerated Dose (MTD)

Primary: Maximum Tolerated Dose (MTD)

Primary: Maximum Observed Plasma Concentration (Cmax) - Part 1

Primary: Maximum Observed Plasma Concentration (Cmax) - Part 1

Primary: Time to Reach Maximum Observed Plasma Concentration (Tmax) - Part 1

Primary: Time to Reach Maximum Observed Plasma Concentration (Tmax) - Part 1

Primary: Plasma Decay Half-Life (t1/2) - Part 1

Primary: Plasma Decay Half-Life (t1/2) - Part 1

Primary: Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC(0-48)] - Part 1

Primary: Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC(0-48)] - Part 1

Primary: Area under the Concentration-Time Curve (AUC) - Part 1

Primary: Area under the Concentration-Time Curve (AUC) - Part 1

Primary: Apparent Oral Clearance (CL/F) - Part 1

Primary: Apparent Oral Clearance (CL/F) - Part 1

Primary: Apparent Volume of Distribution (Vz/F) - Part 1

Primary: Apparent Volume of Distribution (Vz/F) - Part 1

Primary: Maximum Observed Plasma Concentration at Steady State (Cmax,ss) - Part 1

Primary: Maximum Observed Plasma Concentration at Steady State (Cmax,ss) - Part 1

Primary: Time to Reach Maximum Observed Plasma Concentration at Steady State (Tmax,ss) - Part 1

Primary: Time to Reach Maximum Observed Plasma Concentration at Steady State (Tmax,ss) - Part 1

Primary: Plasma Decay Half-Life at Steady State (t1/2,ss) - Part 1

Primary: Plasma Decay Half-Life at Steady State (t1/2,ss) - Part 1

Primary: Area under the Concentration-Time Curve at Steady State (AUCss) - Part 1

Primary: Area under the Concentration-Time Curve at Steady State (AUCss) - Part 1

Primary: Apparent Oral Clearance at Steady State (CL/F,ss) - Part 1

Primary: Apparent Oral Clearance at Steady State (CL/F,ss) - Part 1

Primary: Accumulation Ratio (R)

Primary: Accumulation Ratio (R)

Primary: Percentage of Participants With MCyR at Week 24 in Chronic Phase Second-line Imatinib Resistant CML Population - Part 2

Primary: Percentage of Participants With MCyR at Week 24 in Chronic Phase Second-line Imatinib Resistant CML Population - Part 2

Secondary: Percentage of Participants With Major Cytogenetic Response (MCyR) - Part 1

Secondary: Percentage of Participants With Major Cytogenetic Response (MCyR) - Part 1

Secondary: Phosphorylation Inhibition of Breakpoint Cluster Region-Abelson Kinase (bcr-Abl) - Part 1

Secondary: Phosphorylation Inhibition of Breakpoint Cluster Region-Abelson Kinase (bcr-Abl) - Part 1

Secondary: Phosphorylation Inhibition of Crk Like (CrkL) Protein at Baseline - Part 1

Secondary: Phosphorylation Inhibition of Crk Like (CrkL) Protein at Baseline - Part 1

Secondary: Percent Change From Baseline in Phosphorylation Inhibition of Crk Like Protein (CrkL) at Day 1, 8 and 15 - Part 1

Secondary: Percent Change From Baseline in Phosphorylation Inhibition of Crk Like Protein (CrkL) at Day 1, 8 and 15 - Part 1

Secondary: Percentage of Participants With Major Cytogenetic Response (MCyR) in Chronic Phase Second-line and Chronic Phase Third-line CML Population - Part 2

Secondary: Percentage of Participants With Major Cytogenetic Response (MCyR) in Chronic Phase Second-line and Chronic Phase Third-line CML Population - Part 2

Secondary: Kaplan-Meier Estimate of Retaining an Attained/Maintained Major Cytogenetic Response (MCyR) at Year 5 in Chronic Phase Second-line CML - Part 2

Secondary: Kaplan-Meier Estimate of Retaining an Attained/Maintained Major Cytogenetic Response (MCyR) at Year 5 in Chronic Phase Second-line CML - Part 2

Secondary: Time to Achieve Major Cytogenetic Response (MCyR) in Chronic Phase Second-line CML for Responders Only - Part 2

Secondary: Time to Achieve Major Cytogenetic Response (MCyR) in Chronic Phase Second-line CML for Responders Only - Part 2

Secondary: Kaplan-Meier Estimate of Maintaining Complete Hematologic Response (CHR) at Year 4 (CP3L and ADV) or Year 5 (CP2L) for Responders Only, Part 2 - Hematologic Evaluable Population

Secondary: Kaplan-Meier Estimate of Maintaining Complete Hematologic Response (CHR) at Year 4 (CP3L and ADV) or Year 5 (CP2L) for Responders Only, Part 2 - Hematologic Evaluable Population

Secondary: Duration of Complete Hematologic Response (CHR) for Responders Only, Part 2 - Hematologic Evaluable Population

Secondary: Duration of Complete Hematologic Response (CHR) for Responders Only, Part 2 - Hematologic Evaluable Population

Secondary: Time to Achieve Complete Hematologic Response (CHR) for Responders Only - Part 2

Secondary: Time to Achieve Complete Hematologic Response (CHR) for Responders Only - Part 2

Secondary: Cumulative Incidence of Progression/Death - Part 2

Secondary: Cumulative Incidence of Progression/Death - Part 2

Secondary: Kaplan-Meier Estimate of Overall Survival (OS) - Part 2

Secondary: Kaplan-Meier Estimate of Overall Survival (OS) - Part 2

Secondary: Percentage of Participants With Confirmed Complete Hematologic Response (CHR) - Part 2

Secondary: Percentage of Participants With Confirmed Complete Hematologic Response (CHR) - Part 2

Secondary: Percentage of Participants With Overall Hematologic Response (OHR) by Week 48 in Advanced Leukemia Hematologic Evaluable Population - Part 2

Secondary: Percentage of Participants With Overall Hematologic Response (OHR) by Week 48 in Advanced Leukemia Hematologic Evaluable Population - Part 2

Secondary: Percentage of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs)

Secondary: Percentage of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs)

Secondary: Duration of Potentially Clinically Important (PCI) Adverse Events (AEs)

Secondary: Duration of Potentially Clinically Important (PCI) Adverse Events (AEs)

Secondary: Number of Participants With Change From Baseline in Laboratory Tests Results

Secondary: Number of Participants With Change From Baseline in Laboratory Tests Results

Secondary: Number of Participants With On-treatment PCI Change From Baseline in Electrocardiogram (ECG) Findings

Secondary: Number of Participants With On-treatment PCI Change From Baseline in Electrocardiogram (ECG) Findings

Secondary: Number of Participants With Change From Baseline in Findings of Chest x-ray

Secondary: Number of Participants With Change From Baseline in Findings of Chest x-ray

Clinical Trial Results:
A Phase 1/2 Study of Bosutinib (SKI-606) in Philadelphia Chromosome Positive Leukemias