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Clinical Trial Results:
A Single-Arm, Open-Label, Multicenter Clinical Trial of Nivolumab (BMS-936558) Combined with Ipilimumab in Previously Untreated Subjects With Histologically Confirmed Stage III (Unresectable) or Stage IV Melanoma

Summary
EudraCT number	2015-001274-17
Trial protocol	DE SE IE FI GB NO AT BE IT
Global end of trial date	10 Feb 2020

Results information
Results version number	v1(current)
This version publication date	21 May 2021
First version publication date	21 May 2021
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

CA209-401

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Bristol-Myers Squibb

Sponsor organisation address

Chaussée de la Hulpe 185, Brussels, Belgium, 1170

Public contact

EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, Clinical.Trials@bms.com

Scientific contact

Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.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

10 Feb 2020

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

10 Feb 2020

Was the trial ended prematurely?

Main objective of the trial

To Determine the Safety, Tolerability and Efficacy of Nivolumab combined with Ipilimumab Followed by Nivolumab Monotherapy of Subjects with Stage III or IV Melanoma

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.

Background therapy

Evidence for comparator

Actual start date of recruitment

20 Dec 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 74

Country: Number of subjects enrolled

Austria: 18

Country: Number of subjects enrolled

Belgium: 8

Country: Number of subjects enrolled

Sweden: 7

Country: Number of subjects enrolled

Switzerland: 76

Country: Number of subjects enrolled

Germany: 16

Country: Number of subjects enrolled

France: 107

Country: Number of subjects enrolled

Finland: 68

Country: Number of subjects enrolled

Ireland: 25

Country: Number of subjects enrolled

Italy: 100

Country: Number of subjects enrolled

Norway: 6

Country: Number of subjects enrolled

United Kingdom: 28

Worldwide total number of subjects

533

EEA total number of subjects

355

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)

342

From 65 to 84 years

191

85 years and over

Subject disposition

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Recruitment details

Screening details

total treated participants = 533 subgroups of the total treated participants were based on Eastern Cooperative Oncology Group (ECOG) Performance Status (PS), Brain Metastasis, and Disease Subtype: ECOG PS0-1 = 477 ECOG PS2 = 55 Brain Metastasis = 42 Mucosal = 32 Ocular/Uveal = 64 Cutaneous = 365 Acral = 10 Other = 62

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Nivolumab + Ipilimumab

Arm description

Part 1: Nivolumab 1 mg/kg IV + Ipilimumab 3 mg/kg IV Q3W x 4 doses up to 3 months Then Part 2: Nivolumab (3mg/kg or 240 mg) IV Q2W up to 21 months

Arm type

Experimental

Investigational medicinal product name

Nivolumab + Ipilimumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Part 1: Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg Q3W Part 2: Nivolumab (3mg/kg or 240 mg) Q2W

Number of subjects in period 1	Nivolumab + Ipilimumab
Started	533
Completed	0
Not completed	533
Adverse event, serious fatal	26
Disease progression	153
Adverse Event unrelated to study drug	23
Participant withdrew consent	5
Study drug toxicity	201
Other Reasons	95
Maximum Clinical Benefit	7
Pregnancy	1
Participant no longer met study criteria	7
Lost to follow-up	1
Poor/non-compliance	1
Participant request to discontinue study treatment	13

Baseline characteristics

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Reporting group title

Nivolumab + Ipilimumab

Reporting group description

Part 1: Nivolumab 1 mg/kg IV + Ipilimumab 3 mg/kg IV Q3W x 4 doses up to 3 months Then Part 2: Nivolumab (3mg/kg or 240 mg) IV Q2W up to 21 months

Reporting group values	Nivolumab + Ipilimumab	Total
Number of subjects	533	533
Age categorical
Units: Subjects
In utero	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0
Newborns (0-27 days)	0	0
Infants and toddlers (28 days-23 months)	0	0
Children (2-11 years)	0	0
Adolescents (12-17 years)	0	0
Adults (18-64 years)	342	342
From 65-84 years	191	191
85 years and over	0	0
Age Continuous
Units: Years
median (standard deviation)	59.0 ( 13.55 )	-
Sex: Female, Male
Units: Participants
Female	217	217
Male	316	316
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0
Asian	2	2
Native Hawaiian or Other Pacific Islander	0	0
Black or African American	0	0
White	521	521
More than one race	0	0
Unknown or Not Reported	10	10
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	5	5
Not Hispanic or Latino	515	515
Unknown or Not Reported	13	13

Subject analysis set title

Nivolumab + Ipilimumab ECOG PS0-1

Subject analysis set type

Sub-group analysis

Subject analysis set description

Part 1: Nivolumab 1 mg/kg IV + Ipilimumab 3 mg/kg IV Q3W x 4 doses up to 3 months Then Part 2: Nivolumab (3mg/kg or 240mg) IV Q2W up to 21 months Participants were grouped in to Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-1 subgroup

Subject analysis set title

Nivolumab + Ipilimumab ECOG PS2

Subject analysis set type

Sub-group analysis

Subject analysis set description

Nivolumab 1 mg/kg IV + Ipilimumab 3 mg/kg IV Q3W x 4 doses up to 3 months Then Part 2: Nivolumab (3mg/kg or 240mg) IV Q2W up to 21 months Participants were grouped in to Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-2 subgroup

Subject analysis set title

Nivolumab + Ipilimumab Brain Metastasis

Subject analysis set type

Sub-group analysis

Subject analysis set description

Nivolumab 1 mg/kg IV + Ipilimumab 3 mg/kg IV Q3W x 4 doses up to 3 months Then Part 2: Nivolumab (3mg/kg or 240mg) IV Q2W up to 21 months Participants were grouped in to Brain Metastasis subgroup

Subject analysis set title

Nivolumab + Ipilimumab Mucosal

Subject analysis set type

Sub-group analysis

Subject analysis set description

Nivolumab 1 mg/kg IV + Ipilimumab 3 mg/kg IV Q3W x 4 doses up to 3 months Then Part 2: Nivolumab (3mg/kg or 240mg) IV Q2W up to 21 months Participants were grouped in to Disease Subtype subgroup Mucosal

Subject analysis set title

Nivolumab + Ipilimumab Ocular/Uveal

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Nivolumab + Ipilimumab Cutaneous

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Nivolumab + Ipilimumab Acral

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Nivolumab + Ipilimumab Other

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis sets values	Nivolumab + Ipilimumab ECOG PS0-1	Nivolumab + Ipilimumab ECOG PS2	Nivolumab + Ipilimumab Brain Metastasis	Nivolumab + Ipilimumab Mucosal	Nivolumab + Ipilimumab Ocular/Uveal	Nivolumab + Ipilimumab Cutaneous	Nivolumab + Ipilimumab Acral	Nivolumab + Ipilimumab Other
Number of subjects	477	55	42	32	64	365	10	62
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0	0	0
Adults (18-64 years)	308	34	30	16	35	242	5	44
From 65-84 years	169	21	12	16	29	123	5	18
85 years and over	0	0	0	0	0	0	0	0
Age Continuous
Units: Years
median (standard deviation)	59.0 ( 13.25 )	55.0 ( 15.78 )	54.5 ( 14.25 )	64.0 ( 13.21 )	63.0 ( 13.67 )	58.0 ( 13.37 )	67.5 ( 11.95 )	55.5 ( 13.96 )
Sex: Female, Male
Units: Participants
Female	181	35	11	21	29	134	5	28
Male	296	20	31	11	35	231	5	34
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	0	0	0	0	0	0
Asian	1	1	0	0	0	2	0	0
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0	0	0
Black or African American	0	0	0	0	0	0	0	0
White	466	54	41	32	64	354	10	61
More than one race	0	0	0	0	0	0	0	0
Unknown or Not Reported	10	0	1	0	0	9	0	1
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	5	0	0	0	0	4	1	0
Not Hispanic or Latino	459	55	41	31	62	353	9	60
Unknown or Not Reported	13	0	1	1	2	8	0	2

End points

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Reporting group title

Nivolumab + Ipilimumab

Reporting group description

Part 1: Nivolumab 1 mg/kg IV + Ipilimumab 3 mg/kg IV Q3W x 4 doses up to 3 months Then Part 2: Nivolumab (3mg/kg or 240 mg) IV Q2W up to 21 months

Subject analysis set title

Nivolumab + Ipilimumab ECOG PS0-1

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Nivolumab + Ipilimumab ECOG PS2

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Nivolumab + Ipilimumab Brain Metastasis

Subject analysis set type

Sub-group analysis

Subject analysis set description

Nivolumab 1 mg/kg IV + Ipilimumab 3 mg/kg IV Q3W x 4 doses up to 3 months Then Part 2: Nivolumab (3mg/kg or 240mg) IV Q2W up to 21 months Participants were grouped in to Brain Metastasis subgroup

Subject analysis set title

Nivolumab + Ipilimumab Mucosal

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Nivolumab + Ipilimumab Ocular/Uveal

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Nivolumab + Ipilimumab Cutaneous

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Nivolumab + Ipilimumab Acral

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Nivolumab + Ipilimumab Other

Subject analysis set type

Sub-group analysis

Subject analysis set description

Primary: Incidence of Participants with High-Grade (CTCAE v4.0 Grade 3-5) Treatment-Related Select Adverse Events

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End point title

Incidence of Participants with High-Grade (CTCAE v4.0 Grade 3-5) Treatment-Related Select Adverse Events ^[1]

End point description

Incidence of participants with high-grade (CTCAE v4.0 grade 3-5) treatment-related, select adverse events of potentially immune-mediated etiology including pulmonary, gastrointestinal, skin, renal, hepatic, endocrine, infusion-related, or hypersensitivity

End point type

Primary

End point timeframe

From first dose to 30 days after last dose (up to approximately 37 months)

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: Only summary statistics planned for this endpoint.

End point values	Nivolumab + Ipilimumab	Nivolumab + Ipilimumab ECOG PS0-1	Nivolumab + Ipilimumab ECOG PS2	Nivolumab + Ipilimumab Brain Metastasis	Nivolumab + Ipilimumab Mucosal	Nivolumab + Ipilimumab Ocular/Uveal	Nivolumab + Ipilimumab Cutaneous	Nivolumab + Ipilimumab Acral	Nivolumab + Ipilimumab Other
Number of subjects analysed	533	477	55	42	32	64	365	10	62
Units: Participants
Pulmonary: Grade 3-4	7	7	0	0	0	1	6	0	0
Pulmonary: Grade 5	0	0	0	0	0	0	0	0	0
Gastrointestinal: Grade 3-4	83	79	4	5	5	9	57	1	11
Gastrointestinal: Grade 5	1	1	0	0	1	0	0	0	0
Skin: Grade 3-4	35	31	4	1	3	7	20	1	4
Skin: Grade 5	0	0	0	0	0	0	0	0	0
Renal: Grade 3-4	10	9	1	1	0	1	8	0	1
Renal: Grade 5	1	1	0	0	0	0	1	0	0
Hepatic: Grade 3-4	82	75	7	6	2	17	56	1	6
Hepatic: Grade 5	0	0	0	0	0	0	0	0	0
Endocrine: Grade 3-4	58	58	0	5	2	6	43	1	6
Endocrine: Grade 5	0	0	0	0	0	0	0	0	0
Hypersensitivity/Infusion Reaction: Grade 3-4	1	1	0	0	0	0	1	0	0
Hypersensitivity/Infusion Reaction: Grade 5	0	0	0	0	0	0	0	0	0

No statistical analyses for this end point

Secondary: Incidence of Participants with All High-Grade (Grades 3-5) Select Adverse Events

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End point title

Incidence of Participants with All High-Grade (Grades 3-5) Select Adverse Events

End point description

Incidence of participants with high-grade (grade 3-5) select adverse events including pulmonary, gastrointestinal, skin, renal, hepatic, infusion-related, or hypersensitivity

End point type

Secondary

End point timeframe

From first dose to 30 days after last dose (up to approximately 37 months)

End point values	Nivolumab + Ipilimumab	Nivolumab + Ipilimumab ECOG PS0-1	Nivolumab + Ipilimumab ECOG PS2	Nivolumab + Ipilimumab Brain Metastasis	Nivolumab + Ipilimumab Mucosal	Nivolumab + Ipilimumab Ocular/Uveal	Nivolumab + Ipilimumab Cutaneous	Nivolumab + Ipilimumab Acral	Nivolumab + Ipilimumab Other
Number of subjects analysed	533	477	55	42	32	64	365	10	62
Units: Participants
Pulmonary: Grade 3-4	8	8	0	0	0	1	7	0	0
Gastrointestinal: Grade 3-4	87	83	4	5	5	9	61	1	11
Gastrointestinal: Grade 5	1	1	0	0	1	0	0	0	0
Skin: Grade 3-4	39	35	4	1	3	8	22	1	5
Renal: Grade 3-4	13	12	1	1	0	1	10	1	1
Renal: Grade 5	1	1	0	0	0	0	1	0	0
Hepatic: Grade 3-4	101	93	8	11	4	21	67	1	8
Hepatic: Grade 5	1	1	0	0	0	1	0	0	0
Hypersensitivity/Infusion Reaction: Grade 3-4	2	2	0	0	0	0	1	0	1

No statistical analyses for this end point

Secondary: Median Time to Onset (Grades 3-4) of Select Adverse Events

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End point title

Median Time to Onset (Grades 3-4) of Select Adverse Events

End point description

Median time to onset (grades 3-4) of select adverse events including pulmonary, gastrointestinal (GI), skin, renal, hepatic, endocrine, infusion-related, or hypersensitivity for all treated participants with at least one select adverse event from the category

End point type

Secondary

End point timeframe

From first dose to 30 days after last dose (up to approximately 37 months)

End point values	Nivolumab + Ipilimumab	Nivolumab + Ipilimumab ECOG PS0-1	Nivolumab + Ipilimumab ECOG PS2	Nivolumab + Ipilimumab Brain Metastasis	Nivolumab + Ipilimumab Mucosal	Nivolumab + Ipilimumab Ocular/Uveal	Nivolumab + Ipilimumab Cutaneous	Nivolumab + Ipilimumab Acral	Nivolumab + Ipilimumab Other
Number of subjects analysed	533 ^[2]	477 ^[3]	55 ^[4]	42 ^[5]	32 ^[6]	64 ^[7]	365 ^[8]	10 ^[9]	62 ^[10]
Units: Days
median (full range (min-max))
Pulmonary	51.5 (12 to 783)	51.5 (12 to 783)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	51.0 (51 to 51)	52.0 (12 to 783)	99999 (99999 to 99999)	99999 (99999 to 99999)
Gastrointestinal (GI)	49.0 (7 to 582)	49.0 (7 to 582)	61.0 (8 to 91)	83.0 (35 to 543)	42.5 (27 to 543)	39.0 (20 to 95)	49.0 (7 to 582)	7.0 (7 to 7)	79.0 (8 to 281)
Skin	32.0 (4 to 670)	35.0 (4 to 404)	17.5 (7 to 670)	14.0 (14 to 14)	48.0 (8 to 69)	36.5 (14 to 127)	17.5 (4 to 670)	89.0 (89 to 89)	100.0 (10 to 338)
Renal	52.5 (6 to 540)	43.0 (6 to 223)	540.0 (540 to 540)	106.0 (106 to 106)	99999 (99999 to 99999)	23.0 (23 to 23)	106.0 (14 to 540)	16.0 (16 to 16)	6.0 (6 to 6)
Hepatic	63.0 (5 to 724)	63.0 (5 to 724)	63.0 (13 to 83)	64.0 (41 to 724)	139.0 (22 to 475)	64.0 (16 to 111)	62.0 (5 to 588)	101.0 (101 to 101)	80.0 (8 to 724)
Endocrine	75 (7 to 369)	75.0 (7 to 369)	99999 (99999 to 99999)	67.0 (25 to 130)	153.0 (102 to 204)	70.0 (26 to 98)	71.5 (7 to 369)	114.0 (114 to 114)	39.5 (16 to 115)
Hypersensitivity/Infusion Reaction	291.5 (22 to 561)	291.5 (22 to 561)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	22.0 (22 to 22)	99999 (99999 to 99999)	561.0 (561 to 561)

Notes
[2] - Pulmonary=8 GI=88 Skin=39 Renal=14 Hepatic=102 Endocrine=59 Hypersensitivity/Infusion Reaction=2
[3] - Pulmonary=8 GI=84 Skin=35 Renal=13 Hepatic=94 Endocrine=59 Hypersensitivity/Infusion Reaction=2
[4] - Pulmonary=0 GI=4 Skin=4 Renal=1 Hepatic=8 Endocrine=0 Hypersensitivity/Infusion Reaction=0
[5] - Pulmonary=0 GI=42 Skin=1 Renal=1 Hepatic=11 Endocrine=5 Hypersensitivity/Infusion Reaction=0
[6] - Pulmonary=0 GI=6 Skin=3 Renal=0 Hepatic=4 Endocrine=2 Hypersensitivity/Infusion Reaction=0
[7] - Pulmonary=1 GI=9 Skin=8 Renal=1 Hepatic=22 Endocrine=6 Hypersensitivity/Infusion Reaction=0
[8] - Pulmonary=7 GI=61 Skin=22 Renal=11 Hepatic=67 Endocrine=44 Hypersensitivity/Infusion Reaction=1
[9] - Pulmonary=0 GI=10 Skin=1 Renal=1 Hepatic=1 Endocrine=1 Hypersensitivity/Infusion Reaction=1
[10] - Pulmonary=0 Gl=11 Skin=5 Renal=1 Hepatic=0 Endocrine=6 Hypersensitivity/Infusion Reaction=1

No statistical analyses for this end point

Secondary: Median Time to Resolution (Grades 3-4) of Select Adverse Events

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End point title

Median Time to Resolution (Grades 3-4) of Select Adverse Events

End point description

Median time to resolution (Grades 3-4) of select adverse events including pulmonary, gastrointestinal (GI), skin, renal, hepatic, endocrine, infusion-related, or hypersensitivity of all treated participants with at least one select adverse event from the category

End point type

Secondary

End point timeframe

From first dose to 30 days after last dose (up to approximately 37 months)

End point values	Nivolumab + Ipilimumab	Nivolumab + Ipilimumab ECOG PS0-1	Nivolumab + Ipilimumab ECOG PS2	Nivolumab + Ipilimumab Brain Metastasis	Nivolumab + Ipilimumab Mucosal	Nivolumab + Ipilimumab Ocular/Uveal	Nivolumab + Ipilimumab Cutaneous	Nivolumab + Ipilimumab Acral	Nivolumab + Ipilimumab Other
Number of subjects analysed	533 ^[11]	477 ^[12]	55 ^[13]	42 ^[14]	32 ^[15]	64 ^[16]	365 ^[17]	10 ^[18]	62 ^[19]
Units: Days
median (full range (min-max))
Pulmonary	19.0 (5 to 64)	19.0 (5 to 64)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	6.0 (6 to 6)	30.0 (5 to 64)	99999 (99999 to 99999)	99999 (99999 to 99999)
Gastrointestinal (GI)	22.0 (2 to 684)	22.0 (2 to 684)	99999 (99999 to 99999)	107.5 (18 to 666)	25.0 (6 to 437)	14.0 (6 to 183)	23.0 (2 to 684)	5.0 (5 to 5)	12.0 (4 to 214)
Skin	24.0 (4 to 690)	24.0 (4 to 690)	20.0 (10 to 186)	67.0 (67 to 67)	8.0 (5 to 44)	17.5 (4 to 690)	24.0 (8 to 455)	15.0 (15 to 15)	28.0 (4 to 287)
Renal	19 (3 to 66)	23.0 (3 to 66)	11.0 (11 to 11)	7.0 (7 to 7)	99999 (99999 to 99999)	23.0 (23 to 23)	11.0 (3 to 60)	99999 (99999 to 99999)	66.0 (66 to 66)
Hepatic	42.0 (1 to 889)	38.0 (1 to 889)	67.0 (3 to 225)	17.5 (2 to 285)	126.0 (1 to 625)	55.0 (1 to 612)	30.0 (2 to 889)	29.0 (29 to 29)	117.0 (15 to 285)
Endocrine	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)
Hypersensitivity/Infusion Reaction	4.5 (2 to 7)	4.5 (2 to 7)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	2.0 (2 to 2)	99999 (99999 to 99999)	7.0 (7 to 7)

Notes
[11] - Pulmonary=8 GI=88 Skin=39 Renal=14 Hepatic=102 Endocrine=59 Hypersensitivity/Infusion Reaction=2
[12] - Pulmonary=8 GI=84 Skin=35 Renal=13 Hepatic=94 Endocrine=59 Hypersensitivity/Infusion Reaction=2
[13] - Pulmonary=0 GI=4 Skin=4 Renal=1 Hepatic=8 Endocrine=0 Hypersensitivity/Infusion Reaction=0
[14] - Pulmonary=0 GI=5 Skin=1 Renal=1 Hepatic=11 Endocrine=5 Hypersensitivity/Infusion Reaction=0
[15] - Pulmonary=0 GI=6 Skin=3 Renal=0 Hepatic=4 Endocrine=2 Hypersensitivity/Infusion Reaction=0
[16] - Pulmonary=1 GI=9 Skin=8 Renal=1 Hepatic=22 Endocrine=6 Hypersensitivity/Infusion Reaction=0
[17] - Pulmonary=7 GI=61 Skin=22 Renal=11 Hepatic=67 Endocrine=44 Hypersensitivity/Infusion Reaction=1
[18] - Pulmonary=0 GI=1 Skin=1 Renal=1 Hepatic=1 Endocrine=1 Hypersensitivity/Infusion Reaction=0
[19] - Pulmonary=0 Gl=11 Skin=5 Renal=1 Hepatic=8 Endocrine=6 Hypersensitivity/Infusion Reaction=1

No statistical analyses for this end point

Secondary: Time to Resolution of an Adverse Event (AE)

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End point title

Time to Resolution of an Adverse Event (AE)

End point description

Resolution of an adverse event (AE) is defined as a participant experiencing complete resolution or improvement to the baseline of any grade AE including pulmonary, gastrointestinal (GI), skin, renal, hepatic, endocrine, infusion-related, or hypersensitivity all treated participants with at least one select adverse event from the category

End point type

Secondary

End point timeframe

From first dose to 30 days after last dose (up to approximately 37 months)

End point values	Nivolumab + Ipilimumab	Nivolumab + Ipilimumab ECOG PS0-1	Nivolumab + Ipilimumab ECOG PS2	Nivolumab + Ipilimumab Brain Metastasis	Nivolumab + Ipilimumab Mucosal	Nivolumab + Ipilimumab Ocular/Uveal	Nivolumab + Ipilimumab Cutaneous	Nivolumab + Ipilimumab Acral	Nivolumab + Ipilimumab Other
Number of subjects analysed	533 ^[20]	447 ^[21]	55 ^[22]	42 ^[23]	32 ^[24]	64 ^[25]	365 ^[26]	10 ^[27]	62 ^[28]
Units: Days
median (full range (min-max))
Pulmonary	35.0 (6 to 738)	43.0 (6 to 738)	7.5 (7 to 8)	99999 (99999 to 99999)	99999 (99999 to 99999)	19.0 (6 to 62)	43.0 (7 to 738)	99999 (99999 to 99999)	99999 (99999 to 99999)
Gastrointestinal (GI)	18.0 (1 to 1016)	18.0 (1 to 1016)	12.0 (1 to 468)	36.0 (1 to 720)	14.0 (1 to 527)	14.0 (1 to 183)	19.0 (1 to 1016)	5.0 (1 to 22)	36.0 (2 to 645)
Skin	89.0 (1 to 1175)	88.0 (1 to 1175)	99999 (99999 to 99999)	257.0 (1 to 1011)	84.0 (5 to 1055)	33.5 (4 to 775)	102.0 (1 to 1175)	46.0 (15 to 625)	59.5 (2 to 952)
Renal	56.0 (2 to 904)	56.0 (2 to 904)	11.0 (11 to 11)	5.5 (2 to 100)	9.5 (4 to 15)	27.5 (23 to 32)	56.0 (2 to 904)	99999 (99999 to 99999)	99999 (99999 to 99999)
Hepatic	44.0 (1 to 1008)	43.0 (1 to 1008)	80.5 (3 to 225)	20.5 (3 to 1008)	97.0 (1 to 650)	34.0 (1 to 612)	37.0 (3 to 912)	129.0 (31 to 129)	29.0 (8 to 1008)
Endocrine	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)
Hypersensitivity/Infusion Reaction	1.0 (1 to 7)	1.0 (1 to 7)	1.0 (1 to 1)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	1.0 (1 to 7)	99999 (99999 to 99999)	1.0 (1 to 7)

Notes
[20] - Pulmonary=28 GI=252 Skin=319 Renal=43 Hepatic=185 Endocrine=242 Hypersensitivity/Infusion Reaction=8
[21] - Pulmonary=26 GI=236 Skin=296 Renal=42 Hepatic=173 Endocrine=231 Hypersensitivity/Infusion Reaction=7
[22] - Pulmonary=2 GI=16 Skin=23 Renal=1 Hepatic=12 Endocrine=11 Hypersensitivity/Infusion Reaction=1
[23] - Pulmonary=2 GI=14 Skin=23 Renal=4 Hepatic=16 Endocrine=20 Hypersensitivity/Infusion Reaction=0
[24] - Pulmonary=2 GI=13 Skin=17 Renal=2 Hepatic=7 Endocrine=15 Hypersensitivity/Infusion Reaction=0
[25] - Pulmonary=3 GI=31 Skin=34 Renal=2 Hepatic=35 Endocrine=29 Hypersensitivity/Infusion Reaction=0
[26] - Pulmonary=21 GI=175 Skin=228 Renal=34 Hepatic=128 Endocrine=166 Hypersensitivity/Infusion Reaction=5
[27] - Pulmonary=0 GI=6 Skin=8 Renal=1 Hepatic=2 Endocrine=5 Hypersensitivity/Infusion Reaction=0
[28] - Pulmonary=2 GI=27 Skin=32 Renal=4 Hepatic=13 Endocrine=27 Hypersensitivity/Infusion Reaction=3

No statistical analyses for this end point

Secondary: Overall Survival (OS)

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End point title

Overall Survival (OS)

End point description

Overall survival is defined from the time of first dosing date to the date of death. A participant who has not died will be censored at the last known date alive

End point type

Secondary

End point timeframe

Up to approximately 37 months

End point values	Nivolumab + Ipilimumab	Nivolumab + Ipilimumab ECOG PS0-1	Nivolumab + Ipilimumab ECOG PS2	Nivolumab + Ipilimumab Brain Metastasis	Nivolumab + Ipilimumab Mucosal	Nivolumab + Ipilimumab Ocular/Uveal	Nivolumab + Ipilimumab Cutaneous	Nivolumab + Ipilimumab Acral	Nivolumab + Ipilimumab Other
Number of subjects analysed	533	477	55	42	32	64	365	10	62
Units: Months
median (confidence interval 95%)	99999 (33.91 to 99999)	99999 (34.76 to 99999)	11.01 (7.23 to 99999)	99999 (99999 to 99999)	12.55 (3.78 to 33.91)	15.21 (10.41 to 21.42)	99999 (99999 to 99999)	20.83 (1.15 to 99999)	34.76 (16.69 to 99999)

No statistical analyses for this end point

Secondary: Incidence of Participants with Adverse Events

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End point title

Incidence of Participants with Adverse Events

End point description

The assessment of safety is measured by the incidence of participants who experienced any grade of adverse events (AEs), treatment-related AEs, serious adverse events (SAEs), and deaths

End point type

Secondary

End point timeframe

From first dose to 30 days after last dose (up to approximately 37 months)

End point values	Nivolumab + Ipilimumab	Nivolumab + Ipilimumab ECOG PS0-1	Nivolumab + Ipilimumab ECOG PS2	Nivolumab + Ipilimumab Brain Metastasis	Nivolumab + Ipilimumab Mucosal	Nivolumab + Ipilimumab Ocular/Uveal	Nivolumab + Ipilimumab Cutaneous	Nivolumab + Ipilimumab Acral	Nivolumab + Ipilimumab Other
Number of subjects analysed	533	477	55	42	32	64	365	10	62
Units: Participants
Adverse Events (AEs)	533	477	55	42	32	64	365	10	62
Treatment-Related AEs	484	444	40	33	26	61	332	8	35
Serious Adverse Events (SAEs)	356	324	31	31	26	40	238	9	43
Deaths	199	169	29	13	20	41	107	6	25

No statistical analyses for this end point

Secondary: Incidence of Participants with Select Adverse Events

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End point title

Incidence of Participants with Select Adverse Events

End point description

The assessment of safety is measured by the incidence of participants who experienced any grade of select adverse events including pulmonary, gastrointestinal, skin, renal, hepatic, endocrine, infusion-related, or hypersensitivity

End point type

Secondary

End point timeframe

From first dose to 30 days after last dose (up to approximately 37 months)

End point values	Nivolumab + Ipilimumab	Nivolumab + Ipilimumab ECOG PS0-1	Nivolumab + Ipilimumab ECOG PS2	Nivolumab + Ipilimumab Brain Metastasis	Nivolumab + Ipilimumab Mucosal	Nivolumab + Ipilimumab Ocular/Uveal	Nivolumab + Ipilimumab Cutaneous	Nivolumab + Ipilimumab Acral	Nivolumab + Ipilimumab Other
Number of subjects analysed	533	477	55	42	32	64	365	10	62
Units: Participants
Pulmonary	28	26	2	2	2	3	21	0	2
Gastrointestinal	252	236	16	14	13	31	175	6	27
Skin	319	296	23	23	17	34	228	8	32
Renal	43	42	1	4	2	2	34	1	4
Hepatic	185	173	12	16	7	35	128	2	13
Endocrine	242	231	11	20	15	29	166	5	27
Hypersensitivity/Infusion Reaction	8	7	1	0	0	0	5	0	3

No statistical analyses for this end point

Secondary: Incidence of Participants with Laboratory Abnormalities - Liver

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End point title

Incidence of Participants with Laboratory Abnormalities - Liver

End point description

Safety assessment is measured by the incidence of participants who experienced a liver laboratory abnormality in Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Upper Limit of Normal (ULN) of all treated participants with at least one on-treatment measurement of the corresponding laboratory parameter

End point type

Secondary

End point timeframe

From first dose to 30 days after last dose (up to approximately 37 months)

End point values	Nivolumab + Ipilimumab	Nivolumab + Ipilimumab ECOG PS0-1	Nivolumab + Ipilimumab ECOG PS2	Nivolumab + Ipilimumab Brain Metastasis	Nivolumab + Ipilimumab Mucosal	Nivolumab + Ipilimumab Ocular/Uveal	Nivolumab + Ipilimumab Cutaneous	Nivolumab + Ipilimumab Acral	Nivolumab + Ipilimumab Other
Number of subjects analysed	490	442	48	37	29	56	338	10	57
Units: Participants
ALT OR AST > 3XULN	113	106	7	11	7	21	72	2	11
ALT OR AST > 5XULN	75	69	6	4	5	13	48	1	8
ALT OR AST > 10XULN	30	27	3	0	2	4	22	0	2
ALT OR AST > 20XULN	12	11	1	0	1	2	7	0	2
TOTAL BILIRUBIN > 2XULN	12	12	0	1	0	3	8	0	1
ALT/AST ELEVATED>3XULN;BILIRUBIN>2XULN IN 1 DAY	1	1	0	0	0	0	1	0	0
ALT/AST ELEVATED>3XULN;BILIRUBIN>2XULN IN 30 DAYS	4	4	0	0	0	0	4	0	0

No statistical analyses for this end point

Secondary: Incidence of Participants with Laboratory Abnormalities - Thyroid

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End point title

Incidence of Participants with Laboratory Abnormalities - Thyroid

End point description

Safety assessment is measured by the incidence of participants who experienced a thyroid laboratory abnormality in Free T3 (FT3), Free T4 (FT4), Lower Limit of Normal (LLN) of all treated participants with at least one on-treatment TSH measurement

End point type

Secondary

End point timeframe

From first dose to 30 days after last dose (up to approximately 37 months)

End point values	Nivolumab + Ipilimumab	Nivolumab + Ipilimumab ECOG PS0-1	Nivolumab + Ipilimumab ECOG PS2	Nivolumab + Ipilimumab Brain Metastasis	Nivolumab + Ipilimumab Mucosal	Nivolumab + Ipilimumab Ocular/Uveal	Nivolumab + Ipilimumab Cutaneous	Nivolumab + Ipilimumab Acral	Nivolumab + Ipilimumab Other
Number of subjects analysed	449	410	39	35	26	49	313	10	51
Units: Participants
TSH > ULN	130	123	7	12	8	12	91	4	15
TSH > ULN WITH TSH <= ULN AT BASELINE	113	108	5	11	6	10	79	3	15
TSH >ULN WITH ATLEAST ONE FT3/FT4 TEST VALUE <LLN	80	76	4	8	5	6	55	2	12
TSH >ULN WITH ALL OTHER FT3/FT4 TEST VALUES >= LLN	37	35	2	3	1	4	27	2	3
TSH > ULN WITH FT3/FT4 TEST MISSING	26	25	1	2	2	2	21	0	1
TSH < LLN	178	169	9	14	11	23	124	4	16
TSH <LLN WITH TSH >= LLN AT BASELINE	168	159	9	14	11	21	116	4	16
TSH <LLN WITH ATLEAST ONE FT3/FT4 TEST VALUE > ULN	101	98	3	7	8	12	72	2	7
TSH <LLN WITH ALL OTHER FT3/FT4 TEST VALUES <= ULN	59	53	6	5	3	8	40	1	7
TSH < LLN WITH FT3/FT4 TEST MISSING	26	25	1	2	0	4	19	1	2

No statistical analyses for this end point

Secondary: Objective Response Rate (ORR)

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End point title

Objective Response Rate (ORR)

End point description

Objective response rate is defined as the percentage of participants with a best overall response (BOR) of a complete response (CR) or partial response (PR) divided by the number of all treated participants

End point type

Secondary

End point timeframe

Up to approximately 37 months

End point values	Nivolumab + Ipilimumab	Nivolumab + Ipilimumab ECOG PS0-1	Nivolumab + Ipilimumab ECOG PS2	Nivolumab + Ipilimumab Brain Metastasis	Nivolumab + Ipilimumab Mucosal	Nivolumab + Ipilimumab Ocular/Uveal	Nivolumab + Ipilimumab Cutaneous	Nivolumab + Ipilimumab Acral	Nivolumab + Ipilimumab Other
Number of subjects analysed	533	477	55	42	32	64	365	10	62
Units: Percentage
number (confidence interval 95%)	44.5 (40.2 to 48.8)	46.1 (41.6 to 50.7)	30.9 (19.0 to 44.8)	52.4 (36.4 to 68.0)	43.8 (26.4 to 62.3)	9.4 (3.5 to 19.3)	51.2 (46.0 to 56.5)	30.0 (6.7 to 65.2)	43.5 (31.0 to 56.7)

No statistical analyses for this end point

Secondary: Progression Free Survival (PFS)

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End point title

Progression Free Survival (PFS)

End point description

Progression free survival per investigator assessment is defined as radiological evidence of progression, significant clinical symptomatic progression, or the need to introduce a non-study drug therapy.

End point type

Secondary

End point timeframe

Up to approximately 37 months

End point values	Nivolumab + Ipilimumab	Nivolumab + Ipilimumab ECOG PS0-1	Nivolumab + Ipilimumab ECOG PS2	Nivolumab + Ipilimumab Brain Metastasis	Nivolumab + Ipilimumab Mucosal	Nivolumab + Ipilimumab Ocular/Uveal	Nivolumab + Ipilimumab Cutaneous	Nivolumab + Ipilimumab Acral	Nivolumab + Ipilimumab Other
Number of subjects analysed	533	477	55	42	32	64	365	10	62
Units: Months
median (confidence interval 95%)	4.96 (3.45 to 6.77)	5.45 (3.78 to 7.69)	2.46 (1.77 to 3.75)	3.35 (1.81 to 99999)	2.94 (2.53 to 8.74)	2.83 (2.73 to 4.63)	6.77 (4.67 to 10.45)	2.56 (1.15 to 8.48)	5.22 (2.76 to 27.27)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse events were collected from start of first treatment dose up to 30 days post last treatment dose.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

23.0

Reporting group title

Nivolumab + Ipilimumab ECOG PS0-1

Reporting group description

Subjects received nivolumab 1 milligram/kilogram (mg/kg) intravenously (i.v) with a combination of ipilimumab 3 mg/kg every 3 weeks up to 12 weeks and subjects who entered after the implementation of amendment 4 were administered iv nivolumab 240 mg up to 24 months. Subjects were grouped in to Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-1 subgroup.

Reporting group title

Nivolumab + Ipilimumab ECOG PS2

Reporting group description

Subjects received nivolumab 1 mg/kg i.v with a combination of ipilimumab 3 mg/kg every 3 weeks up to 12 weeks and subjects who entered after the implementation of amendment 4 were administered iv nivolumab 240 mg up to 24 months. Subjects were grouped in to Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-2 subgroup.

Reporting group title

Nivolumab + Ipilimumab Brain Metastasis

Reporting group description

Reporting group title

Nivolumab + Ipilimumab Mucosal

Reporting group description

Reporting group title

Nivolumab + Ipilimumab Ocular/Uveal

Reporting group description

Reporting group title

Nivolumab + Ipilimumab Cutaneous

Reporting group description

Reporting group title

Nivolumab + Ipilimumab Acral

Reporting group description

Reporting group title

Nivolumab + Ipilimumab Other

Reporting group description

Serious adverse events	Nivolumab + Ipilimumab ECOG PS0-1	Nivolumab + Ipilimumab ECOG PS2	Nivolumab + Ipilimumab Brain Metastasis	Nivolumab + Ipilimumab Mucosal	Nivolumab + Ipilimumab Ocular/Uveal	Nivolumab + Ipilimumab Cutaneous	Nivolumab + Ipilimumab Acral	Nivolumab + Ipilimumab Other
Total subjects affected by serious adverse events
subjects affected / exposed	355 / 477 (74.42%)	33 / 55 (60.00%)	32 / 42 (76.19%)	28 / 32 (87.50%)	47 / 64 (73.44%)	257 / 365 (70.41%)	10 / 10 (100.00%)	47 / 62 (75.81%)
number of deaths (all causes)	169	29	13	20	41	107	6	25
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Cancer pain
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	1 / 32 (3.13%)	0 / 64 (0.00%)	0 / 365 (0.00%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Chronic myeloid leukaemia
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	0 / 365 (0.00%)	1 / 10 (10.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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 / 0
Malignant neoplasm progression
subjects affected / exposed	86 / 477 (18.03%)	17 / 55 (30.91%)	15 / 42 (35.71%)	11 / 32 (34.38%)	16 / 64 (25.00%)	59 / 365 (16.16%)	3 / 10 (30.00%)	14 / 62 (22.58%)
occurrences causally related to treatment / all	0 / 102	0 / 19	0 / 16	0 / 14	0 / 19	0 / 67	0 / 4	0 / 17
deaths causally related to treatment / all	0 / 51	0 / 15	0 / 6	0 / 8	0 / 12	0 / 33	0 / 3	0 / 10
Metastases to liver
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	1 / 64 (1.56%)	0 / 365 (0.00%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Metastatic malignant melanoma
subjects affected / exposed	2 / 477 (0.42%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	2 / 365 (0.55%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 2	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
Neoplasm malignant
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	1 / 32 (3.13%)	0 / 64 (0.00%)	0 / 365 (0.00%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Prostate cancer
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Squamous cell carcinoma
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	0 / 365 (0.00%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tumour haemorrhage
subjects affected / exposed	2 / 477 (0.42%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 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
Oesophageal squamous cell carcinoma
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	2 / 477 (0.42%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	1 / 10 (10.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 2	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
Hypertension
subjects affected / exposed	2 / 477 (0.42%)	0 / 55 (0.00%)	1 / 42 (2.38%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 0	0 / 0	0 / 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
Hypotension
subjects affected / exposed	2 / 477 (0.42%)	0 / 55 (0.00%)	1 / 42 (2.38%)	0 / 32 (0.00%)	0 / 64 (0.00%)	2 / 365 (0.55%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 1	0 / 0	0 / 0	1 / 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
Peripheral arterial occlusive disease
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	1 / 42 (2.38%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Shock
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 1	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
Vasculitis
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Vein collapse
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Venous thrombosis
subjects affected / exposed	1 / 477 (0.21%)	1 / 55 (1.82%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	0 / 365 (0.00%)	0 / 10 (0.00%)	2 / 62 (3.23%)
occurrences causally related to treatment / all	0 / 1	0 / 1	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
Peripheral venous disease
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Thrombophlebitis superficial
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	0 / 365 (0.00%)	1 / 10 (10.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	3 / 477 (0.63%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	1 / 64 (1.56%)	1 / 365 (0.27%)	1 / 10 (10.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0	0 / 0	0 / 0	0 / 1	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
Chest pain
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	1 / 32 (3.13%)	0 / 64 (0.00%)	0 / 365 (0.00%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Fatigue
subjects affected / exposed	6 / 477 (1.26%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	1 / 64 (1.56%)	5 / 365 (1.37%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	4 / 7	0 / 0	0 / 0	0 / 0	2 / 2	2 / 5	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	0 / 365 (0.00%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperthermia
subjects affected / exposed	0 / 477 (0.00%)	1 / 55 (1.82%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Polyserositis
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	0 / 365 (0.00%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	18 / 477 (3.77%)	1 / 55 (1.82%)	2 / 42 (4.76%)	2 / 32 (6.25%)	2 / 64 (3.13%)	14 / 365 (3.84%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	13 / 20	0 / 1	1 / 2	0 / 2	1 / 2	11 / 16	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Multiple organ dysfunction syndrome
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	1 / 64 (1.56%)	0 / 365 (0.00%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Non-Cardiac chest pain
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 1	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
Oedema peripheral
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	1 / 64 (1.56%)	0 / 365 (0.00%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Sudden death
subjects affected / exposed	0 / 477 (0.00%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	1 / 64 (1.56%)	0 / 365 (0.00%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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 / 1	0 / 0	0 / 0	0 / 0
Vascular stent thrombosis
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	0 / 365 (0.00%)	1 / 10 (10.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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 / 0
Immune system disorders
Anaphylactic shock
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	0 / 365 (0.00%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	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
Cytokine release syndrome
subjects affected / exposed	2 / 477 (0.42%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	2 / 365 (0.55%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Drug hypersensitivity
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Haemophagocytic lymphohistiocytosis
subjects affected / exposed	2 / 477 (0.42%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	2 / 365 (0.55%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 0	0 / 0	1 / 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
Autoimmune endocrine disorder
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	1 / 32 (3.13%)	0 / 64 (0.00%)	0 / 365 (0.00%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Eosinophilic granulomatosis with polyangiitis
subjects affected / exposed	0 / 477 (0.00%)	1 / 55 (1.82%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Metrorrhagia
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	1 / 32 (3.13%)	0 / 64 (0.00%)	0 / 365 (0.00%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Dysmenorrhoea
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	1 / 42 (2.38%)	0 / 32 (0.00%)	0 / 64 (0.00%)	0 / 365 (0.00%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	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
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	5 / 477 (1.05%)	1 / 55 (1.82%)	1 / 42 (2.38%)	0 / 32 (0.00%)	0 / 64 (0.00%)	6 / 365 (1.64%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	2 / 6	0 / 1	0 / 2	0 / 0	0 / 0	2 / 7	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
Interstitial lung disease
subjects affected / exposed	2 / 477 (0.42%)	0 / 55 (0.00%)	1 / 42 (2.38%)	1 / 32 (3.13%)	0 / 64 (0.00%)	0 / 365 (0.00%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	2 / 2	0 / 0	1 / 1	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	6 / 477 (1.26%)	1 / 55 (1.82%)	2 / 42 (4.76%)	0 / 32 (0.00%)	1 / 64 (1.56%)	5 / 365 (1.37%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	0 / 7	0 / 1	0 / 2	0 / 0	0 / 1	0 / 6	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
Pleurisy
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	1 / 32 (3.13%)	0 / 64 (0.00%)	0 / 365 (0.00%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Pneumonia aspiration
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	10 / 477 (2.10%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	2 / 64 (3.13%)	7 / 365 (1.92%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	8 / 10	0 / 0	0 / 0	0 / 0	2 / 2	5 / 7	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	6 / 477 (1.26%)	1 / 55 (1.82%)	0 / 42 (0.00%)	0 / 32 (0.00%)	1 / 64 (1.56%)	5 / 365 (1.37%)	1 / 10 (10.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 6	0 / 1	0 / 0	0 / 0	0 / 1	0 / 5	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
Pulmonary haematoma
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	1 / 64 (1.56%)	0 / 365 (0.00%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Pulmonary oedema
subjects affected / exposed	2 / 477 (0.42%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Respiratory failure
subjects affected / exposed	2 / 477 (0.42%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	2 / 365 (0.55%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Immune-Mediated pneumonitis
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	0 / 365 (0.00%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleuritic pain
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	0 / 365 (0.00%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	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
Pneumothorax
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 477 (0.00%)	1 / 55 (1.82%)	0 / 42 (0.00%)	1 / 32 (3.13%)	0 / 64 (0.00%)	0 / 365 (0.00%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Confusional state
subjects affected / exposed	2 / 477 (0.42%)	0 / 55 (0.00%)	1 / 42 (2.38%)	1 / 32 (3.13%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 1	0 / 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
Psychotic disorder
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Organic brain syndrome
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	1 / 42 (2.38%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	8 / 477 (1.68%)	0 / 55 (0.00%)	1 / 42 (2.38%)	1 / 32 (3.13%)	3 / 64 (4.69%)	3 / 365 (0.82%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	8 / 8	0 / 0	1 / 1	1 / 1	3 / 3	3 / 3	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	1 / 64 (1.56%)	0 / 365 (0.00%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 1	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
General physical condition abnormal
subjects affected / exposed	4 / 477 (0.84%)	1 / 55 (1.82%)	0 / 42 (0.00%)	1 / 32 (3.13%)	0 / 64 (0.00%)	3 / 365 (0.82%)	1 / 10 (10.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 1	0 / 0	0 / 1	0 / 0	0 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Liver function test increased
subjects affected / exposed	2 / 477 (0.42%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	1 / 10 (10.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oxygen saturation decreased
subjects affected / exposed	0 / 477 (0.00%)	1 / 55 (1.82%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Transaminases increased
subjects affected / exposed	4 / 477 (0.84%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	4 / 365 (1.10%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	5 / 5	0 / 0	0 / 0	0 / 0	0 / 0	5 / 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
White blood cells urine positive
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Blood bilirubin increased
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
C-Reactive protein increased
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Injury, poisoning and procedural complications
Accidental overdose
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	1 / 42 (2.38%)	0 / 32 (0.00%)	0 / 64 (0.00%)	0 / 365 (0.00%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	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
Clavicle fracture
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Infusion related reaction
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 1	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
Overdose
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	1 / 32 (3.13%)	0 / 64 (0.00%)	0 / 365 (0.00%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Post procedural fever
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	0 / 365 (0.00%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	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
Subdural haematoma
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	1 / 64 (1.56%)	0 / 365 (0.00%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Cardiac disorders
Arrhythmia
subjects affected / exposed	0 / 477 (0.00%)	1 / 55 (1.82%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	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 / 1	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	4 / 477 (0.84%)	0 / 55 (0.00%)	2 / 42 (4.76%)	0 / 32 (0.00%)	0 / 64 (0.00%)	3 / 365 (0.82%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 2	0 / 0	0 / 0	0 / 3	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
Atrial flutter
subjects affected / exposed	2 / 477 (0.42%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	2 / 365 (0.55%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrioventricular block
subjects affected / exposed	0 / 477 (0.00%)	1 / 55 (1.82%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Cardiogenic shock
subjects affected / exposed	0 / 477 (0.00%)	1 / 55 (1.82%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	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 / 1	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	2 / 477 (0.42%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 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
Myocarditis
subjects affected / exposed	1 / 477 (0.21%)	1 / 55 (1.82%)	0 / 42 (0.00%)	0 / 32 (0.00%)	1 / 64 (1.56%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0	0 / 0	1 / 1	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Stress cardiomyopathy
subjects affected / exposed	2 / 477 (0.42%)	0 / 55 (0.00%)	0 / 42 (0.00%)	1 / 32 (3.13%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	2 / 2	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
Supraventricular tachycardia
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	1 / 64 (1.56%)	0 / 365 (0.00%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 1	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
Acute myocardial infarction
subjects affected / exposed	2 / 477 (0.42%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 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
Cardiac arrest
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Cardiac failure
subjects affected / exposed	2 / 477 (0.42%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	2 / 365 (0.55%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 2	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
Coronary artery disease
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	1 / 32 (3.13%)	0 / 64 (0.00%)	0 / 365 (0.00%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Pericardial effusion
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	0 / 365 (0.00%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	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
Sinus tachycardia
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	0 / 365 (0.00%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Ataxia
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 1	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
Autoimmune neuropathy
subjects affected / exposed	2 / 477 (0.42%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Autonomic neuropathy
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	1 / 42 (2.38%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1	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
Carpal tunnel syndrome
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Cerebral haemorrhage
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Cerebrospinal fluid leakage
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Cerebrovascular accident
subjects affected / exposed	3 / 477 (0.63%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	2 / 62 (3.23%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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
Cubital tunnel syndrome
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Dizziness
subjects affected / exposed	2 / 477 (0.42%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	2 / 365 (0.55%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 2	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
Facial paralysis
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Guillain-Barre syndrome
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 1	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
Headache
subjects affected / exposed	7 / 477 (1.47%)	1 / 55 (1.82%)	1 / 42 (2.38%)	1 / 32 (3.13%)	0 / 64 (0.00%)	7 / 365 (1.92%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	6 / 7	0 / 1	1 / 1	0 / 1	0 / 0	6 / 7	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
Intercostal neuralgia
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Peripheral sensory neuropathy
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	1 / 42 (2.38%)	1 / 32 (3.13%)	0 / 64 (0.00%)	0 / 365 (0.00%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Petit mal epilepsy
subjects affected / exposed	0 / 477 (0.00%)	1 / 55 (1.82%)	0 / 42 (0.00%)	0 / 32 (0.00%)	1 / 64 (1.56%)	0 / 365 (0.00%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	1 / 42 (2.38%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal cord compression
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	0 / 365 (0.00%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	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
Syncope
subjects affected / exposed	2 / 477 (0.42%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	2 / 365 (0.55%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 2	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
Central nervous system lesion
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Cognitive disorder
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Facial paresis
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Osmotic demyelination syndrome
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 1	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
Paraplegia
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	1 / 64 (1.56%)	0 / 365 (0.00%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Blood and lymphatic system disorders
Agranulocytosis
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Anaemia
subjects affected / exposed	2 / 477 (0.42%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	1 / 64 (1.56%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aplastic anaemia
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Autoimmune pancytopenia
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 1	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
Iron deficiency anaemia
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 2	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
Lymphopenia
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 1	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
Thrombocytopenia
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 1	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
Lymphadenopathy
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	0 / 365 (0.00%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	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
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	0 / 365 (0.00%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	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
Eye disorders
Autoimmune uveitis
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 1	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
Diplopia
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	1 / 32 (3.13%)	0 / 64 (0.00%)	0 / 365 (0.00%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Photopsia
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Retinal detachment
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 2	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
Cataract
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	1 / 64 (1.56%)	0 / 365 (0.00%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	5 / 477 (1.05%)	0 / 55 (0.00%)	0 / 42 (0.00%)	1 / 32 (3.13%)	1 / 64 (1.56%)	2 / 365 (0.55%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	0 / 5	0 / 0	0 / 0	0 / 1	0 / 1	0 / 2	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
Abdominal pain upper
subjects affected / exposed	2 / 477 (0.42%)	0 / 55 (0.00%)	0 / 42 (0.00%)	1 / 32 (3.13%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	2 / 2	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
Ascites
subjects affected / exposed	2 / 477 (0.42%)	0 / 55 (0.00%)	1 / 42 (2.38%)	0 / 32 (0.00%)	0 / 64 (0.00%)	2 / 365 (0.55%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	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
Autoimmune colitis
subjects affected / exposed	13 / 477 (2.73%)	1 / 55 (1.82%)	1 / 42 (2.38%)	1 / 32 (3.13%)	2 / 64 (3.13%)	7 / 365 (1.92%)	1 / 10 (10.00%)	3 / 62 (4.84%)
occurrences causally related to treatment / all	19 / 19	1 / 1	1 / 1	2 / 2	4 / 4	9 / 9	1 / 1	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chronic gastritis
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	1 / 42 (2.38%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	2 / 2	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	51 / 477 (10.69%)	2 / 55 (3.64%)	2 / 42 (4.76%)	3 / 32 (9.38%)	4 / 64 (6.25%)	39 / 365 (10.68%)	0 / 10 (0.00%)	7 / 62 (11.29%)
occurrences causally related to treatment / all	65 / 67	2 / 2	1 / 2	4 / 4	6 / 6	48 / 50	0 / 0	9 / 9
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
Colitis ulcerative
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	0 / 365 (0.00%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Diarrhoea
subjects affected / exposed	35 / 477 (7.34%)	2 / 55 (3.64%)	2 / 42 (4.76%)	1 / 32 (3.13%)	5 / 64 (7.81%)	30 / 365 (8.22%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	33 / 40	2 / 2	2 / 3	1 / 1	5 / 5	28 / 35	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dry mouth
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 1	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
Enteritis
subjects affected / exposed	3 / 477 (0.63%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	2 / 365 (0.55%)	1 / 10 (10.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	3 / 3	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Enterocolitis
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 1	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
Gastritis
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Gastrointestinal toxicity
subjects affected / exposed	2 / 477 (0.42%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	2 / 365 (0.55%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Intestinal obstruction
subjects affected / exposed	1 / 477 (0.21%)	1 / 55 (1.82%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 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
Intestinal perforation
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 1	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
Mouth haemorrhage
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	1 / 32 (3.13%)	0 / 64 (0.00%)	0 / 365 (0.00%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Nausea
subjects affected / exposed	6 / 477 (1.26%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	2 / 64 (3.13%)	4 / 365 (1.10%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	4 / 6	0 / 0	0 / 0	0 / 0	1 / 2	3 / 4	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
Pancreatic failure
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Pancreatitis
subjects affected / exposed	2 / 477 (0.42%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	2 / 365 (0.55%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 2	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
Pancreatitis acute
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	1 / 32 (3.13%)	0 / 64 (0.00%)	0 / 365 (0.00%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Rectal haemorrhage
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Small intestinal obstruction
subjects affected / exposed	3 / 477 (0.63%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	3 / 365 (0.82%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	4 / 477 (0.84%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	2 / 64 (3.13%)	3 / 365 (0.82%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	3 / 4	0 / 0	0 / 0	0 / 0	1 / 2	2 / 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
Abdominal hernia
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	0 / 365 (0.00%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	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
Autoimmune pancreatitis
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	1 / 64 (1.56%)	0 / 365 (0.00%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 1	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
Immune-Mediated enterocolitis
subjects affected / exposed	9 / 477 (1.89%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	8 / 365 (2.19%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	10 / 10	0 / 0	0 / 0	0 / 0	0 / 0	9 / 9	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Retroperitoneal haemorrhage
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Hepatobiliary disorders
Autoimmune hepatitis
subjects affected / exposed	16 / 477 (3.35%)	1 / 55 (1.82%)	1 / 42 (2.38%)	0 / 32 (0.00%)	2 / 64 (3.13%)	13 / 365 (3.56%)	0 / 10 (0.00%)	2 / 62 (3.23%)
occurrences causally related to treatment / all	20 / 20	2 / 2	1 / 1	0 / 0	2 / 2	18 / 18	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholangitis
subjects affected / exposed	2 / 477 (0.42%)	0 / 55 (0.00%)	0 / 42 (0.00%)	1 / 32 (3.13%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 2	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
Cholestasis
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	1 / 32 (3.13%)	0 / 64 (0.00%)	0 / 365 (0.00%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 1	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
Hepatic failure
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	1 / 64 (1.56%)	0 / 365 (0.00%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Hepatitis
subjects affected / exposed	3 / 477 (0.63%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	1 / 64 (1.56%)	2 / 365 (0.55%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	4 / 4	0 / 0	0 / 0	0 / 0	1 / 1	3 / 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
Hepatitis acute
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	1 / 64 (1.56%)	0 / 365 (0.00%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Hepatobiliary disease
subjects affected / exposed	0 / 477 (0.00%)	1 / 55 (1.82%)	1 / 42 (2.38%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1	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
Hepatocellular injury
subjects affected / exposed	7 / 477 (1.47%)	1 / 55 (1.82%)	0 / 42 (0.00%)	3 / 32 (9.38%)	1 / 64 (1.56%)	3 / 365 (0.82%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	8 / 9	1 / 1	0 / 0	5 / 5	1 / 1	2 / 3	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatotoxicity
subjects affected / exposed	3 / 477 (0.63%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	2 / 64 (3.13%)	0 / 365 (0.00%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	2 / 3	0 / 0	0 / 0	0 / 0	2 / 2	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
Cholecystitis
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Cholecystitis acute
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Drug-Induced liver injury
subjects affected / exposed	4 / 477 (0.84%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	1 / 64 (1.56%)	2 / 365 (0.55%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	4 / 4	0 / 0	0 / 0	0 / 0	1 / 1	2 / 2	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune-Mediated hepatitis
subjects affected / exposed	17 / 477 (3.56%)	0 / 55 (0.00%)	2 / 42 (4.76%)	0 / 32 (0.00%)	3 / 64 (4.69%)	11 / 365 (3.01%)	0 / 10 (0.00%)	3 / 62 (4.84%)
occurrences causally related to treatment / all	20 / 20	0 / 0	3 / 3	0 / 0	3 / 3	14 / 14	0 / 0	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Dermatitis
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Dermatitis allergic
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	1 / 64 (1.56%)	0 / 365 (0.00%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Drug eruption
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 1	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
Drug reaction with eosinophilia and systemic symptoms
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 1	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
Erythema
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 1	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
Lichen planus
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	0 / 365 (0.00%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pemphigoid
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	1 / 64 (1.56%)	0 / 365 (0.00%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 1	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
Psoriasis
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	1 / 32 (3.13%)	0 / 64 (0.00%)	0 / 365 (0.00%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 1	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
Rash
subjects affected / exposed	5 / 477 (1.05%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	1 / 64 (1.56%)	3 / 365 (0.82%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	4 / 5	0 / 0	0 / 0	0 / 0	1 / 1	2 / 3	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rash maculo-papular
subjects affected / exposed	4 / 477 (0.84%)	0 / 55 (0.00%)	1 / 42 (2.38%)	1 / 32 (3.13%)	0 / 64 (0.00%)	3 / 365 (0.82%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	5 / 5	0 / 0	1 / 1	1 / 1	0 / 0	4 / 4	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
Stevens-Johnson syndrome
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	0 / 365 (0.00%)	1 / 10 (10.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 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
Toxic skin eruption
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	1 / 64 (1.56%)	0 / 365 (0.00%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	10 / 477 (2.10%)	0 / 55 (0.00%)	2 / 42 (4.76%)	1 / 32 (3.13%)	1 / 64 (1.56%)	7 / 365 (1.92%)	1 / 10 (10.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	4 / 10	0 / 0	1 / 2	0 / 1	1 / 1	3 / 7	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
Haematuria
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	0 / 365 (0.00%)	1 / 10 (10.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Nephritis
subjects affected / exposed	2 / 477 (0.42%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	1 / 64 (1.56%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0	0 / 0	1 / 1	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
Renal failure
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 1	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
Tubulointerstitial nephritis
subjects affected / exposed	1 / 477 (0.21%)	1 / 55 (1.82%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract obstruction
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	1 / 42 (2.38%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune-Mediated renal disorder
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 1	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
Endocrine disorders
Adrenal insufficiency
subjects affected / exposed	6 / 477 (1.26%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	4 / 365 (1.10%)	1 / 10 (10.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	6 / 6	0 / 0	0 / 0	0 / 0	0 / 0	4 / 4	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Adrenocortical insufficiency acute
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	1 / 42 (2.38%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1	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
Hyperthyroidism
subjects affected / exposed	8 / 477 (1.68%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	8 / 365 (2.19%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	8 / 8	0 / 0	0 / 0	0 / 0	0 / 0	8 / 8	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
Hypophysitis
subjects affected / exposed	24 / 477 (5.03%)	0 / 55 (0.00%)	1 / 42 (2.38%)	1 / 32 (3.13%)	5 / 64 (7.81%)	15 / 365 (4.11%)	0 / 10 (0.00%)	3 / 62 (4.84%)
occurrences causally related to treatment / all	26 / 26	0 / 0	1 / 1	1 / 1	5 / 5	17 / 17	0 / 0	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypopituitarism
subjects affected / exposed	3 / 477 (0.63%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	3 / 365 (0.82%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	3 / 3	0 / 0	0 / 0	0 / 0	0 / 0	3 / 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
Lymphocytic hypophysitis
subjects affected / exposed	6 / 477 (1.26%)	0 / 55 (0.00%)	2 / 42 (4.76%)	0 / 32 (0.00%)	0 / 64 (0.00%)	6 / 365 (1.64%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	6 / 6	0 / 0	2 / 2	0 / 0	0 / 0	6 / 6	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
Primary adrenal insufficiency
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	1 / 42 (2.38%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1	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
Thyroiditis
subjects affected / exposed	2 / 477 (0.42%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thyroiditis acute
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 1	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
Immune-Mediated hyperthyroidism
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 1	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
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 1	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
Arthritis
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 1	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
Back pain
subjects affected / exposed	2 / 477 (0.42%)	1 / 55 (1.82%)	0 / 42 (0.00%)	1 / 32 (3.13%)	0 / 64 (0.00%)	2 / 365 (0.55%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 1	0 / 0	0 / 1	0 / 0	1 / 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
Bursitis
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Intervertebral disc degeneration
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	1 / 32 (3.13%)	0 / 64 (0.00%)	0 / 365 (0.00%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Intervertebral disc protrusion
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Jaw cyst
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	1 / 32 (3.13%)	0 / 64 (0.00%)	0 / 365 (0.00%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Musculoskeletal chest pain
subjects affected / exposed	0 / 477 (0.00%)	1 / 55 (1.82%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	1 / 32 (3.13%)	0 / 64 (0.00%)	0 / 365 (0.00%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Pathological fracture
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Rhabdomyolysis
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	1 / 32 (3.13%)	0 / 64 (0.00%)	0 / 365 (0.00%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 1	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
Rheumatic disorder
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	1 / 42 (2.38%)	0 / 32 (0.00%)	0 / 64 (0.00%)	0 / 365 (0.00%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal pain
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	1 / 32 (3.13%)	0 / 64 (0.00%)	0 / 365 (0.00%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Muscle disorder
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Muscular weakness
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Polyarthritis
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 1	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
Synovial cyst
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Infections and infestations
Abscess limb
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Alveolar osteitis
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	1 / 64 (1.56%)	0 / 365 (0.00%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Bronchitis
subjects affected / exposed	3 / 477 (0.63%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	3 / 365 (0.82%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis viral
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Campylobacter gastroenteritis
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Cellulitis
subjects affected / exposed	4 / 477 (0.84%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	4 / 365 (1.10%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 5	0 / 0	0 / 0	0 / 0	0 / 0	1 / 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
Clostridium difficile infection
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 2	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
Device related infection
subjects affected / exposed	0 / 477 (0.00%)	1 / 55 (1.82%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Encephalitis
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 1	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
Endocarditis
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	0 / 365 (0.00%)	1 / 10 (10.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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 / 0
Enteritis infectious
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Enterocolitis infectious
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	1 / 64 (1.56%)	0 / 365 (0.00%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Erysipelas
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Gastroenteritis
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 1	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
Gastrointestinal viral infection
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	1 / 64 (1.56%)	0 / 365 (0.00%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Herpes zoster
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	1 / 64 (1.56%)	0 / 365 (0.00%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 1	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
Infection
subjects affected / exposed	4 / 477 (0.84%)	0 / 55 (0.00%)	1 / 42 (2.38%)	0 / 32 (0.00%)	1 / 64 (1.56%)	3 / 365 (0.82%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 4	0 / 0	0 / 1	0 / 0	0 / 1	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
Influenza
subjects affected / exposed	3 / 477 (0.63%)	0 / 55 (0.00%)	1 / 42 (2.38%)	0 / 32 (0.00%)	0 / 64 (0.00%)	3 / 365 (0.82%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 1	0 / 0	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	3 / 477 (0.63%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	2 / 365 (0.55%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3	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
Meningitis aseptic
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 1	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
Pharyngitis
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Pneumococcal infection
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Pneumocystis jirovecii pneumonia
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Pneumonia
subjects affected / exposed	6 / 477 (1.26%)	0 / 55 (0.00%)	1 / 42 (2.38%)	0 / 32 (0.00%)	3 / 64 (4.69%)	3 / 365 (0.82%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 6	0 / 0	0 / 1	0 / 0	1 / 3	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural cellulitis
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	0 / 365 (0.00%)	1 / 10 (10.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 4	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 / 0
Pyoderma
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	0 / 365 (0.00%)	1 / 10 (10.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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 / 0
Respiratory tract infection
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Respiratory tract infection viral
subjects affected / exposed	2 / 477 (0.42%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	2 / 365 (0.55%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 2	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
Rhinovirus infection
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Sepsis
subjects affected / exposed	5 / 477 (1.05%)	1 / 55 (1.82%)	1 / 42 (2.38%)	0 / 32 (0.00%)	0 / 64 (0.00%)	5 / 365 (1.37%)	1 / 10 (10.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 5	0 / 1	0 / 1	0 / 0	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
Septic arthritis streptococcal
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	1 / 42 (2.38%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Sinusitis
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	1 / 32 (3.13%)	0 / 64 (0.00%)	0 / 365 (0.00%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Staphylococcal bacteraemia
subjects affected / exposed	0 / 477 (0.00%)	1 / 55 (1.82%)	0 / 42 (0.00%)	1 / 32 (3.13%)	0 / 64 (0.00%)	0 / 365 (0.00%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Staphylococcal sepsis
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Upper respiratory tract infection
subjects affected / exposed	2 / 477 (0.42%)	0 / 55 (0.00%)	1 / 42 (2.38%)	0 / 32 (0.00%)	0 / 64 (0.00%)	2 / 365 (0.55%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	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
Urinary tract infection
subjects affected / exposed	4 / 477 (0.84%)	0 / 55 (0.00%)	0 / 42 (0.00%)	1 / 32 (3.13%)	1 / 64 (1.56%)	2 / 365 (0.55%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 6	0 / 0	0 / 0	0 / 1	0 / 1	0 / 4	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
Urosepsis
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Viral infection
subjects affected / exposed	2 / 477 (0.42%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	2 / 365 (0.55%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 2	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
Wound infection
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Wound infection staphylococcal
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	0 / 365 (0.00%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	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
Abdominal abscess
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 1	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
Bronchopulmonary aspergillosis
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	1 / 42 (2.38%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cns ventriculitis
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	1 / 42 (2.38%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Escherichia urinary tract infection
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	0 / 365 (0.00%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	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
Lymphangitis
subjects affected / exposed	0 / 477 (0.00%)	1 / 55 (1.82%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Meningitis bacterial
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	1 / 42 (2.38%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oral candidiasis
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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
Osteomyelitis
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	1 / 42 (2.38%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia klebsiella
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	1 / 42 (2.38%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	2 / 477 (0.42%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	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
Diabetes mellitus
subjects affected / exposed	6 / 477 (1.26%)	0 / 55 (0.00%)	0 / 42 (0.00%)	1 / 32 (3.13%)	0 / 64 (0.00%)	5 / 365 (1.37%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	5 / 6	0 / 0	0 / 0	1 / 1	0 / 0	4 / 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
Diabetic ketoacidosis
subjects affected / exposed	2 / 477 (0.42%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Electrolyte imbalance
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	0 / 365 (0.00%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	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
Hypercalcaemia
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 1	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
Hyperglycaemia
subjects affected / exposed	5 / 477 (1.05%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	4 / 365 (1.10%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	1 / 5	0 / 0	0 / 0	0 / 0	0 / 0	0 / 4	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed	2 / 477 (0.42%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	1 / 10 (10.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Hypokalaemia
subjects affected / exposed	2 / 477 (0.42%)	0 / 55 (0.00%)	0 / 42 (0.00%)	1 / 32 (3.13%)	0 / 64 (0.00%)	0 / 365 (0.00%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	0 / 2	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
Hyponatraemia
subjects affected / exposed	3 / 477 (0.63%)	0 / 55 (0.00%)	1 / 42 (2.38%)	0 / 32 (0.00%)	0 / 64 (0.00%)	3 / 365 (0.82%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0	0 / 1	0 / 0	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
Ketoacidosis
subjects affected / exposed	3 / 477 (0.63%)	0 / 55 (0.00%)	1 / 42 (2.38%)	0 / 32 (0.00%)	0 / 64 (0.00%)	2 / 365 (0.55%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	3 / 3	0 / 0	1 / 1	0 / 0	0 / 0	2 / 2	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Malnutrition
subjects affected / exposed	2 / 477 (0.42%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	2 / 365 (0.55%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 0	0 / 0	1 / 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
Type 1 diabetes mellitus
subjects affected / exposed	2 / 477 (0.42%)	0 / 55 (0.00%)	2 / 42 (4.76%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	2 / 2	0 / 0	2 / 2	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Type 2 diabetes mellitus
subjects affected / exposed	2 / 477 (0.42%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	2 / 365 (0.55%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 2	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
Decreased appetite
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	1 / 32 (3.13%)	0 / 64 (0.00%)	0 / 365 (0.00%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	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

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

Non-serious adverse events	Nivolumab + Ipilimumab ECOG PS0-1	Nivolumab + Ipilimumab ECOG PS2	Nivolumab + Ipilimumab Brain Metastasis	Nivolumab + Ipilimumab Mucosal	Nivolumab + Ipilimumab Ocular/Uveal	Nivolumab + Ipilimumab Cutaneous	Nivolumab + Ipilimumab Acral	Nivolumab + Ipilimumab Other
Total subjects affected by non serious adverse events
subjects affected / exposed	463 / 477 (97.06%)	51 / 55 (92.73%)	40 / 42 (95.24%)	30 / 32 (93.75%)	61 / 64 (95.31%)	354 / 365 (96.99%)	10 / 10 (100.00%)	60 / 62 (96.77%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma
subjects affected / exposed	4 / 477 (0.84%)	1 / 55 (1.82%)	0 / 42 (0.00%)	2 / 32 (6.25%)	0 / 64 (0.00%)	3 / 365 (0.82%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences all number	4	1	0	2	0	3	0	0
Hepatic neoplasm
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	0 / 365 (0.00%)	1 / 10 (10.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0	0	0	1	0
Malignant neoplasm progression
subjects affected / exposed	11 / 477 (2.31%)	2 / 55 (3.64%)	2 / 42 (4.76%)	1 / 32 (3.13%)	4 / 64 (6.25%)	6 / 365 (1.64%)	0 / 10 (0.00%)	2 / 62 (3.23%)
occurrences all number	11	2	2	1	4	6	0	2
Vascular disorders
Hypertension
subjects affected / exposed	30 / 477 (6.29%)	0 / 55 (0.00%)	2 / 42 (4.76%)	1 / 32 (3.13%)	6 / 64 (9.38%)	19 / 365 (5.21%)	0 / 10 (0.00%)	4 / 62 (6.45%)
occurrences all number	35	0	2	1	7	23	0	4
Hot flush
subjects affected / exposed	18 / 477 (3.77%)	0 / 55 (0.00%)	3 / 42 (7.14%)	1 / 32 (3.13%)	1 / 64 (1.56%)	12 / 365 (3.29%)	0 / 10 (0.00%)	4 / 62 (6.45%)
occurrences all number	21	0	4	2	1	14	0	4
Lymphoedema
subjects affected / exposed	3 / 477 (0.63%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	2 / 10 (20.00%)	0 / 62 (0.00%)
occurrences all number	3	0	0	0	0	1	2	0
Lymphorrhoea
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	0 / 365 (0.00%)	1 / 10 (10.00%)	0 / 62 (0.00%)
occurrences all number	2	0	0	0	0	0	2	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	88 / 477 (18.45%)	14 / 55 (25.45%)	9 / 42 (21.43%)	6 / 32 (18.75%)	13 / 64 (20.31%)	66 / 365 (18.08%)	2 / 10 (20.00%)	15 / 62 (24.19%)
occurrences all number	128	16	12	6	14	103	5	16
Chills
subjects affected / exposed	27 / 477 (5.66%)	1 / 55 (1.82%)	2 / 42 (4.76%)	4 / 32 (12.50%)	2 / 64 (3.13%)	19 / 365 (5.21%)	0 / 10 (0.00%)	3 / 62 (4.84%)
occurrences all number	31	1	2	4	2	23	0	3
Fatigue
subjects affected / exposed	182 / 477 (38.16%)	5 / 55 (9.09%)	13 / 42 (30.95%)	9 / 32 (28.13%)	19 / 64 (29.69%)	136 / 365 (37.26%)	1 / 10 (10.00%)	22 / 62 (35.48%)
occurrences all number	255	6	20	15	29	185	1	31
Influenza like illness
subjects affected / exposed	41 / 477 (8.60%)	0 / 55 (0.00%)	1 / 42 (2.38%)	3 / 32 (9.38%)	3 / 64 (4.69%)	31 / 365 (8.49%)	1 / 10 (10.00%)	3 / 62 (4.84%)
occurrences all number	61	0	2	6	3	48	1	3
Oedema peripheral
subjects affected / exposed	41 / 477 (8.60%)	4 / 55 (7.27%)	3 / 42 (7.14%)	4 / 32 (12.50%)	8 / 64 (12.50%)	26 / 365 (7.12%)	2 / 10 (20.00%)	5 / 62 (8.06%)
occurrences all number	47	4	5	6	8	30	2	5
Pyrexia
subjects affected / exposed	116 / 477 (24.32%)	19 / 55 (34.55%)	7 / 42 (16.67%)	7 / 32 (21.88%)	13 / 64 (20.31%)	95 / 365 (26.03%)	2 / 10 (20.00%)	18 / 62 (29.03%)
occurrences all number	149	25	11	9	15	118	10	22
Gait disturbance
subjects affected / exposed	2 / 477 (0.42%)	1 / 55 (1.82%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	1 / 10 (10.00%)	1 / 62 (1.61%)
occurrences all number	2	1	0	0	0	1	1	1
Hyperthermia
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	0 / 365 (0.00%)	1 / 10 (10.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0	0	0	1	0
Malaise
subjects affected / exposed	3 / 477 (0.63%)	3 / 55 (5.45%)	0 / 42 (0.00%)	0 / 32 (0.00%)	1 / 64 (1.56%)	4 / 365 (1.10%)	1 / 10 (10.00%)	0 / 62 (0.00%)
occurrences all number	8	3	0	0	1	5	5	0
Non-Cardiac chest pain
subjects affected / exposed	5 / 477 (1.05%)	0 / 55 (0.00%)	1 / 42 (2.38%)	2 / 32 (6.25%)	0 / 64 (0.00%)	3 / 365 (0.82%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences all number	5	0	1	2	0	3	0	0
Reproductive system and breast disorders
Rectocele
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	0 / 365 (0.00%)	1 / 10 (10.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0	0	0	1	0
Vaginal haemorrhage
subjects affected / exposed	2 / 477 (0.42%)	1 / 55 (1.82%)	0 / 42 (0.00%)	2 / 32 (6.25%)	0 / 64 (0.00%)	0 / 365 (0.00%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences all number	3	1	0	3	0	0	0	1
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	106 / 477 (22.22%)	10 / 55 (18.18%)	7 / 42 (16.67%)	3 / 32 (9.38%)	13 / 64 (20.31%)	82 / 365 (22.47%)	2 / 10 (20.00%)	16 / 62 (25.81%)
occurrences all number	131	11	7	3	16	100	3	20
Dyspnoea
subjects affected / exposed	62 / 477 (13.00%)	5 / 55 (9.09%)	3 / 42 (7.14%)	4 / 32 (12.50%)	9 / 64 (14.06%)	44 / 365 (12.05%)	2 / 10 (20.00%)	8 / 62 (12.90%)
occurrences all number	76	5	5	6	12	52	2	9
Epistaxis
subjects affected / exposed	8 / 477 (1.68%)	0 / 55 (0.00%)	1 / 42 (2.38%)	0 / 32 (0.00%)	1 / 64 (1.56%)	6 / 365 (1.64%)	1 / 10 (10.00%)	0 / 62 (0.00%)
occurrences all number	8	0	1	0	1	6	1	0
Haemoptysis
subjects affected / exposed	3 / 477 (0.63%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	2 / 365 (0.55%)	1 / 10 (10.00%)	0 / 62 (0.00%)
occurrences all number	3	0	0	0	0	2	1	0
Oropharyngeal pain
subjects affected / exposed	23 / 477 (4.82%)	2 / 55 (3.64%)	0 / 42 (0.00%)	2 / 32 (6.25%)	4 / 64 (6.25%)	13 / 365 (3.56%)	1 / 10 (10.00%)	5 / 62 (8.06%)
occurrences all number	24	2	0	2	4	13	1	6
Pleural effusion
subjects affected / exposed	6 / 477 (1.26%)	1 / 55 (1.82%)	0 / 42 (0.00%)	1 / 32 (3.13%)	0 / 64 (0.00%)	5 / 365 (1.37%)	1 / 10 (10.00%)	0 / 62 (0.00%)
occurrences all number	6	1	0	1	0	5	1	0
Pulmonary embolism
subjects affected / exposed	13 / 477 (2.73%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	2 / 64 (3.13%)	7 / 365 (1.92%)	1 / 10 (10.00%)	3 / 62 (4.84%)
occurrences all number	13	0	0	0	2	7	1	3
Pulmonary pain
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	0 / 365 (0.00%)	1 / 10 (10.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0	0	0	1	0
Psychiatric disorders
Insomnia
subjects affected / exposed	60 / 477 (12.58%)	6 / 55 (10.91%)	5 / 42 (11.90%)	3 / 32 (9.38%)	4 / 64 (6.25%)	55 / 365 (15.07%)	0 / 10 (0.00%)	4 / 62 (6.45%)
occurrences all number	72	7	5	3	4	68	0	4
Anxiety
subjects affected / exposed	23 / 477 (4.82%)	0 / 55 (0.00%)	3 / 42 (7.14%)	1 / 32 (3.13%)	4 / 64 (6.25%)	15 / 365 (4.11%)	0 / 10 (0.00%)	3 / 62 (4.84%)
occurrences all number	24	0	3	1	4	16	0	3
Depression
subjects affected / exposed	10 / 477 (2.10%)	0 / 55 (0.00%)	2 / 42 (4.76%)	0 / 32 (0.00%)	0 / 64 (0.00%)	9 / 365 (2.47%)	1 / 10 (10.00%)	0 / 62 (0.00%)
occurrences all number	10	0	2	0	0	9	1	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	98 / 477 (20.55%)	12 / 55 (21.82%)	9 / 42 (21.43%)	5 / 32 (15.63%)	21 / 64 (32.81%)	73 / 365 (20.00%)	1 / 10 (10.00%)	10 / 62 (16.13%)
occurrences all number	129	15	14	7	26	96	1	14
Amylase increased
subjects affected / exposed	41 / 477 (8.60%)	4 / 55 (7.27%)	2 / 42 (4.76%)	1 / 32 (3.13%)	6 / 64 (9.38%)	34 / 365 (9.32%)	0 / 10 (0.00%)	4 / 62 (6.45%)
occurrences all number	50	9	2	1	9	43	0	6
Aspartate aminotransferase increased
subjects affected / exposed	84 / 477 (17.61%)	8 / 55 (14.55%)	8 / 42 (19.05%)	4 / 32 (12.50%)	17 / 64 (26.56%)	63 / 365 (17.26%)	1 / 10 (10.00%)	7 / 62 (11.29%)
occurrences all number	105	14	10	4	23	81	1	10
Blood alkaline phosphatase increased
subjects affected / exposed	29 / 477 (6.08%)	2 / 55 (3.64%)	3 / 42 (7.14%)	3 / 32 (9.38%)	6 / 64 (9.38%)	20 / 365 (5.48%)	0 / 10 (0.00%)	2 / 62 (3.23%)
occurrences all number	32	3	4	3	6	23	0	3
Lipase increased
subjects affected / exposed	78 / 477 (16.35%)	7 / 55 (12.73%)	11 / 42 (26.19%)	4 / 32 (12.50%)	8 / 64 (12.50%)	64 / 365 (17.53%)	0 / 10 (0.00%)	9 / 62 (14.52%)
occurrences all number	112	11	17	8	8	96	0	11
Weight decreased
subjects affected / exposed	54 / 477 (11.32%)	4 / 55 (7.27%)	4 / 42 (9.52%)	4 / 32 (12.50%)	6 / 64 (9.38%)	44 / 365 (12.05%)	1 / 10 (10.00%)	3 / 62 (4.84%)
occurrences all number	59	4	4	4	6	46	2	5
Blood bilirubin increased
subjects affected / exposed	16 / 477 (3.35%)	4 / 55 (7.27%)	1 / 42 (2.38%)	0 / 32 (0.00%)	4 / 64 (6.25%)	16 / 365 (4.38%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences all number	31	6	1	0	6	31	0	0
Blood lactate dehydrogenase increased
subjects affected / exposed	17 / 477 (3.56%)	1 / 55 (1.82%)	1 / 42 (2.38%)	0 / 32 (0.00%)	3 / 64 (4.69%)	12 / 365 (3.29%)	1 / 10 (10.00%)	2 / 62 (3.23%)
occurrences all number	18	1	1	0	3	13	1	2
Blood potassium decreased
subjects affected / exposed	6 / 477 (1.26%)	1 / 55 (1.82%)	1 / 42 (2.38%)	2 / 32 (6.25%)	1 / 64 (1.56%)	3 / 365 (0.82%)	1 / 10 (10.00%)	0 / 62 (0.00%)
occurrences all number	7	1	1	2	1	4	1	0
Blood thyroid stimulating hormone decreased
subjects affected / exposed	9 / 477 (1.89%)	1 / 55 (1.82%)	1 / 42 (2.38%)	0 / 32 (0.00%)	2 / 64 (3.13%)	6 / 365 (1.64%)	1 / 10 (10.00%)	1 / 62 (1.61%)
occurrences all number	9	2	1	0	3	6	1	1
Blood thyroid stimulating hormone increased
subjects affected / exposed	12 / 477 (2.52%)	1 / 55 (1.82%)	3 / 42 (7.14%)	0 / 32 (0.00%)	3 / 64 (4.69%)	8 / 365 (2.19%)	0 / 10 (0.00%)	2 / 62 (3.23%)
occurrences all number	14	1	3	0	3	10	0	2
Blood uric acid increased
subjects affected / exposed	3 / 477 (0.63%)	0 / 55 (0.00%)	1 / 42 (2.38%)	1 / 32 (3.13%)	0 / 64 (0.00%)	0 / 365 (0.00%)	1 / 10 (10.00%)	1 / 62 (1.61%)
occurrences all number	4	0	1	2	0	0	1	1
C-Reactive protein increased
subjects affected / exposed	13 / 477 (2.73%)	1 / 55 (1.82%)	1 / 42 (2.38%)	1 / 32 (3.13%)	0 / 64 (0.00%)	9 / 365 (2.47%)	1 / 10 (10.00%)	3 / 62 (4.84%)
occurrences all number	14	1	1	1	0	10	1	3
Gamma-Glutamyltransferase increased
subjects affected / exposed	30 / 477 (6.29%)	3 / 55 (5.45%)	5 / 42 (11.90%)	2 / 32 (6.25%)	1 / 64 (1.56%)	27 / 365 (7.40%)	1 / 10 (10.00%)	2 / 62 (3.23%)
occurrences all number	31	3	5	2	1	28	1	2
Haemoglobin decreased
subjects affected / exposed	4 / 477 (0.84%)	3 / 55 (5.45%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	6 / 365 (1.64%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences all number	5	5	0	0	0	8	0	2
Hepatic enzyme increased
subjects affected / exposed	2 / 477 (0.42%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	1 / 10 (10.00%)	0 / 62 (0.00%)
occurrences all number	2	0	0	0	0	1	1	0
Liver function test increased
subjects affected / exposed	4 / 477 (0.84%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	3 / 365 (0.82%)	1 / 10 (10.00%)	0 / 62 (0.00%)
occurrences all number	5	0	0	0	0	4	1	0
Neutrophil count decreased
subjects affected / exposed	5 / 477 (1.05%)	1 / 55 (1.82%)	0 / 42 (0.00%)	1 / 32 (3.13%)	1 / 64 (1.56%)	3 / 365 (0.82%)	1 / 10 (10.00%)	0 / 62 (0.00%)
occurrences all number	5	1	0	1	1	3	1	0
Thyroxine increased
subjects affected / exposed	3 / 477 (0.63%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	2 / 365 (0.55%)	1 / 10 (10.00%)	0 / 62 (0.00%)
occurrences all number	3	0	0	0	0	2	1	0
Transaminases increased
subjects affected / exposed	14 / 477 (2.94%)	0 / 55 (0.00%)	2 / 42 (4.76%)	0 / 32 (0.00%)	5 / 64 (7.81%)	7 / 365 (1.92%)	0 / 10 (0.00%)	2 / 62 (3.23%)
occurrences all number	16	0	2	0	5	9	0	2
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	3 / 477 (0.63%)	1 / 55 (1.82%)	0 / 42 (0.00%)	1 / 32 (3.13%)	0 / 64 (0.00%)	1 / 365 (0.27%)	1 / 10 (10.00%)	1 / 62 (1.61%)
occurrences all number	4	1	0	1	0	1	1	2
Cardiac disorders
Atrial tachycardia
subjects affected / exposed	2 / 477 (0.42%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	1 / 64 (1.56%)	0 / 365 (0.00%)	1 / 10 (10.00%)	0 / 62 (0.00%)
occurrences all number	2	0	0	0	1	0	1	0
Tachycardia
subjects affected / exposed	16 / 477 (3.35%)	3 / 55 (5.45%)	0 / 42 (0.00%)	2 / 32 (6.25%)	1 / 64 (1.56%)	15 / 365 (4.11%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences all number	17	3	0	2	1	16	0	1
Nervous system disorders
Headache
subjects affected / exposed	113 / 477 (23.69%)	9 / 55 (16.36%)	14 / 42 (33.33%)	5 / 32 (15.63%)	13 / 64 (20.31%)	91 / 365 (24.93%)	3 / 10 (30.00%)	10 / 62 (16.13%)
occurrences all number	145	10	19	5	18	115	4	12
Dizziness
subjects affected / exposed	27 / 477 (5.66%)	0 / 55 (0.00%)	4 / 42 (9.52%)	1 / 32 (3.13%)	2 / 64 (3.13%)	18 / 365 (4.93%)	0 / 10 (0.00%)	6 / 62 (9.68%)
occurrences all number	31	0	5	1	2	22	0	6
Paraesthesia
subjects affected / exposed	26 / 477 (5.45%)	1 / 55 (1.82%)	2 / 42 (4.76%)	0 / 32 (0.00%)	3 / 64 (4.69%)	24 / 365 (6.58%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences all number	29	2	2	0	3	28	0	0
Somnolence
subjects affected / exposed	4 / 477 (0.84%)	3 / 55 (5.45%)	0 / 42 (0.00%)	0 / 32 (0.00%)	1 / 64 (1.56%)	5 / 365 (1.37%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences all number	4	3	0	0	1	5	0	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	58 / 477 (12.16%)	9 / 55 (16.36%)	3 / 42 (7.14%)	3 / 32 (9.38%)	7 / 64 (10.94%)	39 / 365 (10.68%)	3 / 10 (30.00%)	15 / 62 (24.19%)
occurrences all number	78	10	3	3	9	51	5	20
Lymphadenopathy
subjects affected / exposed	7 / 477 (1.47%)	0 / 55 (0.00%)	1 / 42 (2.38%)	0 / 32 (0.00%)	0 / 64 (0.00%)	5 / 365 (1.37%)	1 / 10 (10.00%)	1 / 62 (1.61%)
occurrences all number	8	0	1	0	0	6	1	1
Lymphopenia
subjects affected / exposed	7 / 477 (1.47%)	1 / 55 (1.82%)	0 / 42 (0.00%)	1 / 32 (3.13%)	0 / 64 (0.00%)	6 / 365 (1.64%)	1 / 10 (10.00%)	0 / 62 (0.00%)
occurrences all number	7	1	0	1	0	6	1	0
Eye disorders
Eyelash discolouration
subjects affected / exposed	3 / 477 (0.63%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	2 / 365 (0.55%)	1 / 10 (10.00%)	0 / 62 (0.00%)
occurrences all number	3	0	0	0	0	2	1	0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	76 / 477 (15.93%)	2 / 55 (3.64%)	2 / 42 (4.76%)	3 / 32 (9.38%)	10 / 64 (15.63%)	55 / 365 (15.07%)	2 / 10 (20.00%)	8 / 62 (12.90%)
occurrences all number	105	3	7	3	13	77	2	13
Abdominal pain upper
subjects affected / exposed	35 / 477 (7.34%)	4 / 55 (7.27%)	3 / 42 (7.14%)	3 / 32 (9.38%)	10 / 64 (15.63%)	23 / 365 (6.30%)	2 / 10 (20.00%)	1 / 62 (1.61%)
occurrences all number	41	5	3	3	14	26	2	1
Constipation
subjects affected / exposed	83 / 477 (17.40%)	7 / 55 (12.73%)	12 / 42 (28.57%)	7 / 32 (21.88%)	7 / 64 (10.94%)	66 / 365 (18.08%)	1 / 10 (10.00%)	9 / 62 (14.52%)
occurrences all number	100	7	15	9	7	79	1	11
Diarrhoea
subjects affected / exposed	214 / 477 (44.86%)	15 / 55 (27.27%)	13 / 42 (30.95%)	13 / 32 (40.63%)	28 / 64 (43.75%)	158 / 365 (43.29%)	5 / 10 (50.00%)	25 / 62 (40.32%)
occurrences all number	383	25	22	19	46	293	8	42
Dry mouth
subjects affected / exposed	51 / 477 (10.69%)	1 / 55 (1.82%)	2 / 42 (4.76%)	2 / 32 (6.25%)	5 / 64 (7.81%)	37 / 365 (10.14%)	1 / 10 (10.00%)	7 / 62 (11.29%)
occurrences all number	58	1	2	2	7	41	1	8
Nausea
subjects affected / exposed	151 / 477 (31.66%)	11 / 55 (20.00%)	10 / 42 (23.81%)	8 / 32 (25.00%)	24 / 64 (37.50%)	111 / 365 (30.41%)	5 / 10 (50.00%)	15 / 62 (24.19%)
occurrences all number	210	15	14	14	34	148	6	24
Vomiting
subjects affected / exposed	85 / 477 (17.82%)	8 / 55 (14.55%)	9 / 42 (21.43%)	5 / 32 (15.63%)	7 / 64 (10.94%)	69 / 365 (18.90%)	2 / 10 (20.00%)	10 / 62 (16.13%)
occurrences all number	112	11	14	10	8	90	4	11
Abdominal distension
subjects affected / exposed	13 / 477 (2.73%)	0 / 55 (0.00%)	0 / 42 (0.00%)	1 / 32 (3.13%)	1 / 64 (1.56%)	7 / 365 (1.92%)	2 / 10 (20.00%)	2 / 62 (3.23%)
occurrences all number	13	0	0	1	1	7	2	2
Colitis
subjects affected / exposed	29 / 477 (6.08%)	3 / 55 (5.45%)	1 / 42 (2.38%)	2 / 32 (6.25%)	5 / 64 (7.81%)	20 / 365 (5.48%)	0 / 10 (0.00%)	5 / 62 (8.06%)
occurrences all number	37	3	1	3	5	26	0	6
Dyspepsia
subjects affected / exposed	19 / 477 (3.98%)	1 / 55 (1.82%)	0 / 42 (0.00%)	1 / 32 (3.13%)	4 / 64 (6.25%)	12 / 365 (3.29%)	0 / 10 (0.00%)	3 / 62 (4.84%)
occurrences all number	24	1	0	1	6	14	0	4
Dysphagia
subjects affected / exposed	12 / 477 (2.52%)	0 / 55 (0.00%)	1 / 42 (2.38%)	3 / 32 (9.38%)	1 / 64 (1.56%)	7 / 365 (1.92%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences all number	13	0	1	3	1	8	0	1
Haematemesis
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	0 / 365 (0.00%)	1 / 10 (10.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0	0	0	1	0
Haemorrhoidal haemorrhage
subjects affected / exposed	2 / 477 (0.42%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	1 / 10 (10.00%)	0 / 62 (0.00%)
occurrences all number	3	0	0	0	0	1	2	0
Mouth ulceration
subjects affected / exposed	7 / 477 (1.47%)	0 / 55 (0.00%)	0 / 42 (0.00%)	2 / 32 (6.25%)	0 / 64 (0.00%)	5 / 365 (1.37%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences all number	7	0	0	2	0	5	0	0
Stomatitis
subjects affected / exposed	28 / 477 (5.87%)	4 / 55 (7.27%)	2 / 42 (4.76%)	4 / 32 (12.50%)	2 / 64 (3.13%)	24 / 365 (6.58%)	0 / 10 (0.00%)	2 / 62 (3.23%)
occurrences all number	31	4	2	4	2	27	0	2
Hepatobiliary disorders
Hepatocellular injury
subjects affected / exposed	17 / 477 (3.56%)	1 / 55 (1.82%)	1 / 42 (2.38%)	2 / 32 (6.25%)	2 / 64 (3.13%)	11 / 365 (3.01%)	0 / 10 (0.00%)	3 / 62 (4.84%)
occurrences all number	21	1	2	2	2	14	0	4
Hypertransaminasaemia
subjects affected / exposed	2 / 477 (0.42%)	2 / 55 (3.64%)	1 / 42 (2.38%)	2 / 32 (6.25%)	0 / 64 (0.00%)	2 / 365 (0.55%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences all number	2	2	1	2	0	2	0	0
Liver tenderness
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	0 / 365 (0.00%)	1 / 10 (10.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0	0	0	1	0
Skin and subcutaneous tissue disorders
Pruritus
subjects affected / exposed	139 / 477 (29.14%)	11 / 55 (20.00%)	12 / 42 (28.57%)	11 / 32 (34.38%)	13 / 64 (20.31%)	106 / 365 (29.04%)	4 / 10 (40.00%)	16 / 62 (25.81%)
occurrences all number	180	15	14	11	24	133	8	19
Rash
subjects affected / exposed	80 / 477 (16.77%)	7 / 55 (12.73%)	6 / 42 (14.29%)	4 / 32 (12.50%)	8 / 64 (12.50%)	63 / 365 (17.26%)	3 / 10 (30.00%)	9 / 62 (14.52%)
occurrences all number	92	8	7	4	8	75	3	10
Rash macular
subjects affected / exposed	32 / 477 (6.71%)	2 / 55 (3.64%)	2 / 42 (4.76%)	4 / 32 (12.50%)	2 / 64 (3.13%)	24 / 365 (6.58%)	1 / 10 (10.00%)	3 / 62 (4.84%)
occurrences all number	36	3	2	4	2	26	2	5
Rash maculo-papular
subjects affected / exposed	61 / 477 (12.79%)	6 / 55 (10.91%)	5 / 42 (11.90%)	3 / 32 (9.38%)	6 / 64 (9.38%)	50 / 365 (13.70%)	2 / 10 (20.00%)	6 / 62 (9.68%)
occurrences all number	84	7	8	5	7	69	3	7
Rash pruritic
subjects affected / exposed	32 / 477 (6.71%)	2 / 55 (3.64%)	0 / 42 (0.00%)	3 / 32 (9.38%)	1 / 64 (1.56%)	29 / 365 (7.95%)	1 / 10 (10.00%)	0 / 62 (0.00%)
occurrences all number	43	4	0	3	1	42	1	0
Vitiligo
subjects affected / exposed	62 / 477 (13.00%)	9 / 55 (16.36%)	7 / 42 (16.67%)	2 / 32 (6.25%)	1 / 64 (1.56%)	58 / 365 (15.89%)	1 / 10 (10.00%)	9 / 62 (14.52%)
occurrences all number	70	9	7	3	1	63	1	11
Acne
subjects affected / exposed	3 / 477 (0.63%)	0 / 55 (0.00%)	1 / 42 (2.38%)	0 / 32 (0.00%)	0 / 64 (0.00%)	2 / 365 (0.55%)	1 / 10 (10.00%)	0 / 62 (0.00%)
occurrences all number	3	0	1	0	0	2	1	0
Alopecia
subjects affected / exposed	17 / 477 (3.56%)	1 / 55 (1.82%)	1 / 42 (2.38%)	2 / 32 (6.25%)	1 / 64 (1.56%)	11 / 365 (3.01%)	2 / 10 (20.00%)	2 / 62 (3.23%)
occurrences all number	21	1	1	2	1	15	2	2
Dry skin
subjects affected / exposed	28 / 477 (5.87%)	1 / 55 (1.82%)	2 / 42 (4.76%)	2 / 32 (6.25%)	2 / 64 (3.13%)	21 / 365 (5.75%)	2 / 10 (20.00%)	2 / 62 (3.23%)
occurrences all number	30	1	2	2	2	22	3	2
Eczema
subjects affected / exposed	23 / 477 (4.82%)	0 / 55 (0.00%)	5 / 42 (11.90%)	2 / 32 (6.25%)	0 / 64 (0.00%)	18 / 365 (4.93%)	0 / 10 (0.00%)	3 / 62 (4.84%)
occurrences all number	27	0	6	3	0	21	0	3
Erythema
subjects affected / exposed	27 / 477 (5.66%)	0 / 55 (0.00%)	6 / 42 (14.29%)	4 / 32 (12.50%)	2 / 64 (3.13%)	17 / 365 (4.66%)	1 / 10 (10.00%)	3 / 62 (4.84%)
occurrences all number	27	0	6	4	2	17	1	3
Hair colour changes
subjects affected / exposed	9 / 477 (1.89%)	0 / 55 (0.00%)	2 / 42 (4.76%)	2 / 32 (6.25%)	0 / 64 (0.00%)	5 / 365 (1.37%)	0 / 10 (0.00%)	2 / 62 (3.23%)
occurrences all number	9	0	2	2	0	5	0	2
Hyperhidrosis
subjects affected / exposed	20 / 477 (4.19%)	2 / 55 (3.64%)	1 / 42 (2.38%)	1 / 32 (3.13%)	2 / 64 (3.13%)	17 / 365 (4.66%)	1 / 10 (10.00%)	1 / 62 (1.61%)
occurrences all number	21	2	1	1	2	18	1	1
Nail dystrophy
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	0 / 365 (0.00%)	1 / 10 (10.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0	0	0	1	0
Plantar erythema
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	0 / 365 (0.00%)	1 / 10 (10.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0	0	0	1	0
Renal and urinary disorders
Dysuria
subjects affected / exposed	2 / 477 (0.42%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	1 / 10 (10.00%)	0 / 62 (0.00%)
occurrences all number	2	0	0	0	0	1	1	0
Endocrine disorders
Hyperthyroidism
subjects affected / exposed	98 / 477 (20.55%)	2 / 55 (3.64%)	7 / 42 (16.67%)	7 / 32 (21.88%)	14 / 64 (21.88%)	71 / 365 (19.45%)	0 / 10 (0.00%)	8 / 62 (12.90%)
occurrences all number	102	2	9	7	14	73	0	10
Hypophysitis
subjects affected / exposed	29 / 477 (6.08%)	3 / 55 (5.45%)	3 / 42 (7.14%)	1 / 32 (3.13%)	1 / 64 (1.56%)	27 / 365 (7.40%)	0 / 10 (0.00%)	3 / 62 (4.84%)
occurrences all number	30	3	3	1	1	28	0	3
Hypothyroidism
subjects affected / exposed	118 / 477 (24.74%)	6 / 55 (10.91%)	8 / 42 (19.05%)	10 / 32 (31.25%)	12 / 64 (18.75%)	84 / 365 (23.01%)	2 / 10 (20.00%)	16 / 62 (25.81%)
occurrences all number	129	7	10	11	13	91	2	19
Adrenal insufficiency
subjects affected / exposed	23 / 477 (4.82%)	2 / 55 (3.64%)	1 / 42 (2.38%)	2 / 32 (6.25%)	2 / 64 (3.13%)	18 / 365 (4.93%)	2 / 10 (20.00%)	1 / 62 (1.61%)
occurrences all number	25	2	1	2	2	20	2	1
Immune-Mediated hyperthyroidism
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	0 / 365 (0.00%)	1 / 10 (10.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0	0	0	1	0
Thyroiditis
subjects affected / exposed	14 / 477 (2.94%)	1 / 55 (1.82%)	0 / 42 (0.00%)	2 / 32 (6.25%)	0 / 64 (0.00%)	12 / 365 (3.29%)	0 / 10 (0.00%)	1 / 62 (1.61%)
occurrences all number	14	1	0	2	0	12	0	1
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	77 / 477 (16.14%)	2 / 55 (3.64%)	5 / 42 (11.90%)	2 / 32 (6.25%)	9 / 64 (14.06%)	56 / 365 (15.34%)	1 / 10 (10.00%)	11 / 62 (17.74%)
occurrences all number	108	2	9	2	11	81	5	11
Back pain
subjects affected / exposed	50 / 477 (10.48%)	4 / 55 (7.27%)	7 / 42 (16.67%)	1 / 32 (3.13%)	4 / 64 (6.25%)	44 / 365 (12.05%)	1 / 10 (10.00%)	4 / 62 (6.45%)
occurrences all number	60	5	8	2	5	53	1	4
Musculoskeletal pain
subjects affected / exposed	32 / 477 (6.71%)	1 / 55 (1.82%)	2 / 42 (4.76%)	1 / 32 (3.13%)	3 / 64 (4.69%)	23 / 365 (6.30%)	2 / 10 (20.00%)	4 / 62 (6.45%)
occurrences all number	36	1	3	1	3	26	2	5
Myalgia
subjects affected / exposed	37 / 477 (7.76%)	4 / 55 (7.27%)	3 / 42 (7.14%)	2 / 32 (6.25%)	4 / 64 (6.25%)	29 / 365 (7.95%)	0 / 10 (0.00%)	6 / 62 (9.68%)
occurrences all number	45	4	3	2	6	34	0	7
Pain in extremity
subjects affected / exposed	33 / 477 (6.92%)	3 / 55 (5.45%)	2 / 42 (4.76%)	6 / 32 (18.75%)	4 / 64 (6.25%)	19 / 365 (5.21%)	3 / 10 (30.00%)	4 / 62 (6.45%)
occurrences all number	45	3	3	10	4	23	5	6
Haematoma muscle
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	0 / 365 (0.00%)	1 / 10 (10.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0	0	0	1	0
Joint swelling
subjects affected / exposed	8 / 477 (1.68%)	0 / 55 (0.00%)	1 / 42 (2.38%)	1 / 32 (3.13%)	0 / 64 (0.00%)	5 / 365 (1.37%)	1 / 10 (10.00%)	1 / 62 (1.61%)
occurrences all number	8	0	1	1	0	5	1	1
Limb mass
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	0 / 365 (0.00%)	1 / 10 (10.00%)	0 / 62 (0.00%)
occurrences all number	1	0	0	0	0	0	1	0
Musculoskeletal chest pain
subjects affected / exposed	10 / 477 (2.10%)	1 / 55 (1.82%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	8 / 365 (2.19%)	1 / 10 (10.00%)	2 / 62 (3.23%)
occurrences all number	10	1	0	0	0	8	1	2
Neck pain
subjects affected / exposed	19 / 477 (3.98%)	1 / 55 (1.82%)	1 / 42 (2.38%)	1 / 32 (3.13%)	3 / 64 (4.69%)	11 / 365 (3.01%)	1 / 10 (10.00%)	4 / 62 (6.45%)
occurrences all number	20	1	1	1	4	11	1	4
Pain in jaw
subjects affected / exposed	2 / 477 (0.42%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	1 / 10 (10.00%)	0 / 62 (0.00%)
occurrences all number	2	0	0	0	0	1	1	0
Infections and infestations
Nasopharyngitis
subjects affected / exposed	51 / 477 (10.69%)	1 / 55 (1.82%)	6 / 42 (14.29%)	4 / 32 (12.50%)	7 / 64 (10.94%)	29 / 365 (7.95%)	2 / 10 (20.00%)	10 / 62 (16.13%)
occurrences all number	69	1	11	5	9	39	4	13
Conjunctivitis
subjects affected / exposed	17 / 477 (3.56%)	1 / 55 (1.82%)	3 / 42 (7.14%)	1 / 32 (3.13%)	2 / 64 (3.13%)	12 / 365 (3.29%)	0 / 10 (0.00%)	3 / 62 (4.84%)
occurrences all number	18	1	4	1	2	13	0	3
Infection
subjects affected / exposed	3 / 477 (0.63%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	2 / 365 (0.55%)	1 / 10 (10.00%)	0 / 62 (0.00%)
occurrences all number	4	0	0	0	0	3	1	0
Influenza
subjects affected / exposed	12 / 477 (2.52%)	0 / 55 (0.00%)	3 / 42 (7.14%)	2 / 32 (6.25%)	0 / 64 (0.00%)	8 / 365 (2.19%)	1 / 10 (10.00%)	1 / 62 (1.61%)
occurrences all number	12	0	3	2	0	8	1	1
Oral candidiasis
subjects affected / exposed	21 / 477 (4.40%)	2 / 55 (3.64%)	3 / 42 (7.14%)	1 / 32 (3.13%)	1 / 64 (1.56%)	18 / 365 (4.93%)	0 / 10 (0.00%)	3 / 62 (4.84%)
occurrences all number	21	2	3	1	1	18	0	3
Oral fungal infection
subjects affected / exposed	3 / 477 (0.63%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	2 / 365 (0.55%)	1 / 10 (10.00%)	0 / 62 (0.00%)
occurrences all number	3	0	0	0	0	2	1	0
Oral herpes
subjects affected / exposed	13 / 477 (2.73%)	1 / 55 (1.82%)	0 / 42 (0.00%)	0 / 32 (0.00%)	1 / 64 (1.56%)	11 / 365 (3.01%)	1 / 10 (10.00%)	1 / 62 (1.61%)
occurrences all number	13	1	0	0	1	11	1	1
Paronychia
subjects affected / exposed	5 / 477 (1.05%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	4 / 365 (1.10%)	1 / 10 (10.00%)	0 / 62 (0.00%)
occurrences all number	6	0	0	0	0	5	1	0
Post procedural cellulitis
subjects affected / exposed	1 / 477 (0.21%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	0 / 365 (0.00%)	1 / 10 (10.00%)	0 / 62 (0.00%)
occurrences all number	3	0	0	0	0	0	3	0
Tongue fungal infection
subjects affected / exposed	2 / 477 (0.42%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	1 / 365 (0.27%)	1 / 10 (10.00%)	0 / 62 (0.00%)
occurrences all number	2	0	0	0	0	1	1	0
Tooth abscess
subjects affected / exposed	3 / 477 (0.63%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	0 / 64 (0.00%)	2 / 365 (0.55%)	1 / 10 (10.00%)	0 / 62 (0.00%)
occurrences all number	4	0	0	0	0	2	2	0
Upper respiratory tract infection
subjects affected / exposed	25 / 477 (5.24%)	1 / 55 (1.82%)	2 / 42 (4.76%)	2 / 32 (6.25%)	3 / 64 (4.69%)	19 / 365 (5.21%)	0 / 10 (0.00%)	2 / 62 (3.23%)
occurrences all number	29	1	3	2	3	23	0	2
Urinary tract infection
subjects affected / exposed	24 / 477 (5.03%)	3 / 55 (5.45%)	2 / 42 (4.76%)	3 / 32 (9.38%)	2 / 64 (3.13%)	20 / 365 (5.48%)	0 / 10 (0.00%)	2 / 62 (3.23%)
occurrences all number	27	3	2	3	2	23	0	2
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	113 / 477 (23.69%)	7 / 55 (12.73%)	12 / 42 (28.57%)	7 / 32 (21.88%)	12 / 64 (18.75%)	87 / 365 (23.84%)	1 / 10 (10.00%)	13 / 62 (20.97%)
occurrences all number	142	8	19	13	17	105	1	14
Hypokalaemia
subjects affected / exposed	43 / 477 (9.01%)	4 / 55 (7.27%)	6 / 42 (14.29%)	2 / 32 (6.25%)	9 / 64 (14.06%)	32 / 365 (8.77%)	1 / 10 (10.00%)	3 / 62 (4.84%)
occurrences all number	59	5	7	2	12	43	1	6
Diabetes mellitus
subjects affected / exposed	8 / 477 (1.68%)	1 / 55 (1.82%)	1 / 42 (2.38%)	0 / 32 (0.00%)	2 / 64 (3.13%)	4 / 365 (1.10%)	1 / 10 (10.00%)	2 / 62 (3.23%)
occurrences all number	9	1	1	0	2	4	1	3
Hyperglycaemia
subjects affected / exposed	17 / 477 (3.56%)	2 / 55 (3.64%)	5 / 42 (11.90%)	0 / 32 (0.00%)	2 / 64 (3.13%)	17 / 365 (4.66%)	0 / 10 (0.00%)	0 / 62 (0.00%)
occurrences all number	20	2	6	0	2	20	0	0
Hypocalcaemia
subjects affected / exposed	10 / 477 (2.10%)	2 / 55 (3.64%)	1 / 42 (2.38%)	0 / 32 (0.00%)	1 / 64 (1.56%)	8 / 365 (2.19%)	1 / 10 (10.00%)	2 / 62 (3.23%)
occurrences all number	12	3	2	0	1	11	1	2
Hyponatraemia
subjects affected / exposed	19 / 477 (3.98%)	2 / 55 (3.64%)	2 / 42 (4.76%)	2 / 32 (6.25%)	1 / 64 (1.56%)	15 / 365 (4.11%)	0 / 10 (0.00%)	3 / 62 (4.84%)
occurrences all number	23	2	3	2	1	17	0	5
Hypophosphataemia
subjects affected / exposed	12 / 477 (2.52%)	0 / 55 (0.00%)	0 / 42 (0.00%)	0 / 32 (0.00%)	3 / 64 (4.69%)	6 / 365 (1.64%)	1 / 10 (10.00%)	2 / 62 (3.23%)
occurrences all number	16	0	0	0	3	10	1	2

More information

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Were there any global substantial amendments to the protocol? Yes

06 Jan 2016

Exclusion Criteria Update

05 Feb 2016

Exclusion Criterion Update

25 May 2016

Study Treatment Dose Update

03 Aug 2016

Management Algorithms for Immuno-Oncology Agents Update

19 Aug 2016

Adverse Event Management Algorithms Update

31 Jul 2018

Follow-up Phase Timeline Update

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.

The Nivolumab monotherapy dose in Part II is changed to 240 mg flat dose for those subjects who enrolled after the implementation of Amendment 04

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Clinical trials

Clinical Trial Results: A Single-Arm, Open-Label, Multicenter Clinical Trial of Nivolumab (BMS-936558) Combined with Ipilimumab in Previously Untreated Subjects With Histologically Confirmed Stage III (Unresectable) or Stage IV Melanoma

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Incidence of Participants with High-Grade (CTCAE v4.0 Grade 3-5) Treatment-Related Select Adverse Events

Primary: Incidence of Participants with High-Grade (CTCAE v4.0 Grade 3-5) Treatment-Related Select Adverse Events

Secondary: Incidence of Participants with All High-Grade (Grades 3-5) Select Adverse Events

Secondary: Incidence of Participants with All High-Grade (Grades 3-5) Select Adverse Events

Secondary: Median Time to Onset (Grades 3-4) of Select Adverse Events

Secondary: Median Time to Onset (Grades 3-4) of Select Adverse Events

Secondary: Median Time to Resolution (Grades 3-4) of Select Adverse Events

Secondary: Median Time to Resolution (Grades 3-4) of Select Adverse Events

Secondary: Time to Resolution of an Adverse Event (AE)

Secondary: Time to Resolution of an Adverse Event (AE)

Secondary: Overall Survival (OS)

Secondary: Overall Survival (OS)

Secondary: Incidence of Participants with Adverse Events

Secondary: Incidence of Participants with Adverse Events

Secondary: Incidence of Participants with Select Adverse Events

Secondary: Incidence of Participants with Select Adverse Events

Secondary: Incidence of Participants with Laboratory Abnormalities - Liver

Secondary: Incidence of Participants with Laboratory Abnormalities - Liver

Secondary: Incidence of Participants with Laboratory Abnormalities - Thyroid

Secondary: Incidence of Participants with Laboratory Abnormalities - Thyroid

Secondary: Objective Response Rate (ORR)

Secondary: Objective Response Rate (ORR)

Secondary: Progression Free Survival (PFS)

Secondary: Progression Free Survival (PFS)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Single-Arm, Open-Label, Multicenter Clinical Trial of Nivolumab (BMS-936558) Combined with Ipilimumab in Previously Untreated Subjects With Histologically Confirmed Stage III (Unresectable) or Stage IV Melanoma