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Clinical Trial Results:
A Study of the Safety, Tolerability, and Pharmacokinetics of Intravenous (IV) and Powder for Oral Suspension Formulations of Posaconazole (POS) in Immunocompromised Pediatric Subjects with Neutropenia

Summary
EudraCT number	2014-002807-10
Trial protocol	DE NO SE DK CZ ES BE IT Outside EU/EEA
Global end of trial date	03 Sep 2018

Results information
Results version number	v1
This version publication date	09 Mar 2019
First version publication date	09 Mar 2019
Other versions	v2

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

5592-097

ISRCTN number

US NCT number

NCT02452034

WHO universal trial number (UTN)

Sponsor organisation name

Merck Sharp & Dohme Corp.

Sponsor organisation address

2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033

Public contact

Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com

Scientific contact

Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com

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

Yes

EMA paediatric investigation plan number(s)

EMEA-000468-PIP02-12

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?

Yes

Analysis stage

Final

Date of interim/final analysis

03 Sep 2018

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

03 Sep 2018

Was the trial ended prematurely?

Main objective of the trial

This study aims to evaluate the pharmacokinetics (PK) of posaconazole (POS) administered intravenously (IV) or orally to immunocompromised pediatric participants.

Protection of trial subjects

This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research

Background therapy

Evidence for comparator

Actual start date of recruitment

07 Sep 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Belgium: 13

Country: Number of subjects enrolled

Czech Republic: 19

Country: Number of subjects enrolled

Denmark: 3

Country: Number of subjects enrolled

Germany: 27

Country: Number of subjects enrolled

Guatemala: 4

Country: Number of subjects enrolled

Italy: 8

Country: Number of subjects enrolled

Norway: 7

Country: Number of subjects enrolled

Spain: 5

Country: Number of subjects enrolled

Sweden: 4

Country: Number of subjects enrolled

Thailand: 5

Country: Number of subjects enrolled

United States: 23

Worldwide total number of subjects

118

EEA total number of subjects

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)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

Immunocompromised participants aged 2 to 17 years old, with neutropenia expected to last for at least 7 days following start of study treatment, were enrolled in this study.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

3.5 mg/kg POS (2-7 years old)

Arm description

Children 2 to less than 7 years of age received posaconazole (POS) at 3.5 mg/kg by intravenous (IV) solution twice on Day 1, then once daily on Days 2-10. This was followed by treatment with 3.5 mg/kg POS once daily by powder for oral suspension (PFS) for a minimum of 10 days; or, if they were unwilling or unable to tolerate POS PFS, continued treatment with POS IV.

Arm type

Experimental

Investigational medicinal product name

Posaconazole

Investigational medicinal product code

Other name

Noxafil

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Posaconazole at 3.5 mg/kg by IV solution twice on Day 1, then once daily on Days 2-10.

Investigational medicinal product name

Posaconazole

Investigational medicinal product code

Other name

Noxafil

Pharmaceutical forms

Powder and solvent for oral suspension

Routes of administration

Oral use

Dosage and administration details

Posaconazole at 3.5 mg/kg once daily by PFS for a minimum of 10 days

3.5 mg/kg POS (7-17 years old)

Arm description

Children 7 to 17 years of age received POS at 3.5 mg/kg by IV solution twice on Day 1, then once daily on Days 2-10. This was followed by treatment with 3.5 mg/kg POS once daily by PFS for a minimum of 10 days; or, if they were unwilling or unable to tolerate POS PFS, continued treatment with POS IV.

Arm type

Experimental

Investigational medicinal product name

Posaconazole

Investigational medicinal product code

Other name

Noxafil

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Posaconazole at 3.5 mg/kg by IV solution twice on Day 1, then once daily on Days 2-10.

Investigational medicinal product name

Posaconazole

Investigational medicinal product code

Other name

Noxafil

Pharmaceutical forms

Powder and solvent for oral suspension

Routes of administration

Oral use

Dosage and administration details

Posaconazole at 3.5 mg/kg once daily by PFS for a minimum of 10 days

4.5 mg/kg POS (2-7 years old)

Arm description

Children 2 to less than 7 years of age received POS at 4.5 mg/kg by IV solution twice on Day 1, then once daily on Days 2-10. This was followed by treatment with 4.5 mg/kg POS once daily by PFS for a minimum of 10 days; or, if they were unwilling or unable to tolerate POS PFS, continued treatment with POS IV.

Arm type

Experimental

Investigational medicinal product name

Posaconazole

Investigational medicinal product code

Other name

Noxafil

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Posaconazole at 4.5 mg/kg by IV solution twice on Day 1, then once daily on Days 2-10.

Investigational medicinal product name

Posaconazole

Investigational medicinal product code

Other name

Noxafil

Pharmaceutical forms

Powder and solvent for oral suspension

Routes of administration

Oral use

Dosage and administration details

Posaconazole at 4.5 mg/kg once daily by PFS for a minimum of 10 days

4.5 mg/kg POS (7-17 years old)

Arm description

Children 7 to 17 years of age received POS at 4.5 mg/kg by IV solution twice on Day 1, then once daily on Days 2-10. This was followed by treatment with 4.5 mg/kg POS once daily by PFS for a minimum of 10 days; or, if they were unwilling or unable to tolerate POS PFS, continued treatment with POS IV.

Arm type

Experimental

Investigational medicinal product name

Posaconazole

Investigational medicinal product code

Other name

Noxafil

Pharmaceutical forms

Powder and solvent for oral suspension

Routes of administration

Oral use

Dosage and administration details

Posaconazole at 4.5 mg/kg once daily by PFS for a minimum of 10 days

Investigational medicinal product name

Posaconazole

Investigational medicinal product code

Other name

Noxafil

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Posaconazole at 4.5 mg/kg by IV solution twice on Day 1, then once daily on Days 2-10.

6 mg/kg POS (2-7 years old)

Arm description

Children 2 to less than 7 years of age received POS at 6 mg/kg by IV solution twice on Day 1, then once daily on Days 2-10. This was followed by treatment with 6 mg/kg POS once daily by PFS for a minimum of 10 days; or, if they were unwilling or unable to tolerate POS PFS, continued treatment with POS IV.

Arm type

Experimental

Investigational medicinal product name

Posaconazole

Investigational medicinal product code

Other name

Noxafil

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Posaconazole at 6 mg/kg by IV solution twice on Day 1, then once daily on Days 2-10.

Investigational medicinal product name

Posaconazole

Investigational medicinal product code

Other name

Noxafil

Pharmaceutical forms

Powder and solvent for oral suspension

Routes of administration

Oral use

Dosage and administration details

Posaconazole at 6 mg/kg once daily by PFS for a minimum of 10 days

6 mg/kg POS (7-17 years old)

Arm description

Children 7 to 17 years of age received POS at 6 mg/kg by IV solution twice on Day 1, then once daily on Days 2-10. This was followed by treatment with 6 mg/kg POS once daily by PFS for a minimum of 10 days; or, if they were unwilling or unable to tolerate POS PFS, continued treatment with POS IV.

Arm type

Experimental

Investigational medicinal product name

Posaconazole

Investigational medicinal product code

Other name

Noxafil

Pharmaceutical forms

Powder and solvent for oral suspension

Routes of administration

Oral use

Dosage and administration details

Posaconazole at 6 mg/kg once daily by PFS for a minimum of 10 days

Investigational medicinal product name

Posaconazole

Investigational medicinal product code

Other name

Noxafil

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Posaconazole at 6 mg/kg by IV solution twice on Day 1, then once daily on Days 2-10.

Number of subjects in period 1	3.5 mg/kg POS (2-7 years old)	3.5 mg/kg POS (7-17 years old)	4.5 mg/kg POS (2-7 years old)	4.5 mg/kg POS (7-17 years old)	6 mg/kg POS (2-7 years old)	6 mg/kg POS (7-17 years old)
Started	16	21	15	17	20	29
Treated	14	21	15	16	20	29
Completed	14	20	14	16	19	26
Not completed	2	1	1	1	1	3
Physician decision	-	1	1	-	-	-
Screen Failure	1	-	-	1	-	-
Adverse event, non-fatal	-	-	-	-	-	1
Death	-	-	-	-	1	1
Withdrawn by Parent/Guardian	1	-	-	-	-	-
Protocol deviation	-	-	-	-	-	1

Baseline characteristics

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Reporting group title

3.5 mg/kg POS (2-7 years old)

Reporting group description

Reporting group title

3.5 mg/kg POS (7-17 years old)

Reporting group description

Reporting group title

4.5 mg/kg POS (2-7 years old)

Reporting group description

Reporting group title

4.5 mg/kg POS (7-17 years old)

Reporting group description

Reporting group title

6 mg/kg POS (2-7 years old)

Reporting group description

Reporting group title

6 mg/kg POS (7-17 years old)

Reporting group description

Reporting group values	3.5 mg/kg POS (2-7 years old)	3.5 mg/kg POS (7-17 years old)	4.5 mg/kg POS (2-7 years old)	4.5 mg/kg POS (7-17 years old)	6 mg/kg POS (2-7 years old)	6 mg/kg POS (7-17 years old)	Total
Number of subjects	16	21	15	17	20	29	118
Age Categorical
Units: Subjects
In utero	0	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0	0
Children (2-11 years)	16	4	15	5	20	13	73
Adolescents (12-17 years)	0	17	0	12	0	16	45
Adults (18-64 years)	0	0	0	0	0	0	0
From 65-84 years	0	0	0	0	0	0	0
85 years and over	0	0	0	0	0	0	0
Age Continuous
Units: years
arithmetic mean (standard deviation)	3.9 ± 1.5	13.9 ± 2.1	4.1 ± 1.4	12.5 ± 2.7	3.9 ± 1.6	12.0 ± 3.5	-
Gender Categorical
Units: Subjects
Female	3	11	8	8	10	10	50
Male	13	10	7	9	10	19	68
Race
Units: Subjects
Asian	4	1	2	2	1	1	11
Black Or African American	0	0	0	0	1	2	3
Multiple	0	2	0	2	0	0	4
Native Hawaiian Or Other Pacific Islander	0	0	1	0	0	0	1
White	12	18	12	13	18	26	99
Ethnicity
Units: Subjects
Hispanic Or Latino	1	2	2	4	1	2	12
Not Hispanic Or Latino	15	19	12	12	18	27	103
Not Reported	0	0	1	1	0	0	2
Unknown	0	0	0	0	1	0	1

End points

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Reporting group title

3.5 mg/kg POS (2-7 years old)

Reporting group description

Reporting group title

3.5 mg/kg POS (7-17 years old)

Reporting group description

Reporting group title

4.5 mg/kg POS (2-7 years old)

Reporting group description

Reporting group title

4.5 mg/kg POS (7-17 years old)

Reporting group description

Reporting group title

6 mg/kg POS (2-7 years old)

Reporting group description

Reporting group title

6 mg/kg POS (7-17 years old)

Reporting group description

Primary: Area under the plasma concentration versus time curve (AUC) from time 0 to 24 hours post-dose for POS

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End point title

Area under the plasma concentration versus time curve (AUC) from time 0 to 24 hours post-dose for POS ^[1]

End point description

Blood was collected from pre-dose up to 24 hours post-dose in order to determine the plasma AUC from time 0-24 hours post-dose (AUC0- 24hr) of posaconazole. A non-compartmental analysis of posaconazole plasma concentrations was performed. Results are reported for each treatment arm according to the formulation that participants received (IV or PFS). Participants receiving both formulations were counted once for each formulation. The population analyzed was all treated participants who received at least 7 days of POS dosing (IV and PFS), completed the full POS PK sampling, and met pre-specified acceptability criteria.

End point type

Primary

End point timeframe

Any day from Day 7 to Day 10 of therapy for each formulation (up to 28 days) at pre-dose, within 15 minutes after end of infusion (up to 2 hours), and 4, 6, 8, 12, 24 hours post-infusion

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: Statistical comparisons between treatment groups were neither planned nor performed for this primary endpoint.

End point values	3.5 mg/kg POS (2-7 years old)	3.5 mg/kg POS (7-17 years old)	4.5 mg/kg POS (2-7 years old)	4.5 mg/kg POS (7-17 years old)	6 mg/kg POS (2-7 years old)	6 mg/kg POS (7-17 years old)
Number of subjects analysed	11 ^[2]	19 ^[3]	14 ^[4]	15 ^[5]	17 ^[6]	24 ^[7]
Units: hr*ng/mL
geometric mean (geometric coefficient of variation)
IV	17800 ± 55.0	27300 ± 49.7	25600 ± 30.0	29800 ± 42.9	31100 ± 48.9	44200 ± 41.5
PFS	12200 ± 36.0	20700 ± 33.8	21600 ± 64.5	28700 ± 33.7	23000 ± 47.3	25000 ± 184.3

Notes
[2] - IV n= 11; PFS n= 5
[3] - IV n= 19; PFS n= 10
[4] - IV n= 14; PFS n= 8
[5] - IV n= 15; PFS n= 8
[6] - IV n= 17; PFS n= 7
[7] - IV n= 24; PFS n= 12

No statistical analyses for this end point

Primary: Maximum plasma concentration (Cmax) for POS

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End point title

Maximum plasma concentration (Cmax) for POS ^[8]

End point description

Blood was collected from pre-dose up to 24 hours post-dose in order to determine the plasma Cmax of posaconazole. A noncompartmental analysis of posaconazole plasma concentrations was performed. Results are reported for each treatment arm according to the formulation that participants received (IV or PFS). Participants receiving both formulations were counted once for each formulation. The population analyzed was all treated participants who received at least 7 days of POS dosing (IV and PFS), completed the full POS PK sampling, and met pre-specified acceptability criteria.

End point type

Primary

End point timeframe

Any day from Day 7 to Day 10 of therapy for each formulation (up to 28 days) at pre-dose, within 15 minutes after end of infusion (up to 2 hours), and 4, 6, 8, 12, 24 hours post-infusion

Notes
[8] - 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: Statistical comparisons between treatment groups were neither planned nor performed for this primary endpoint.

End point values	3.5 mg/kg POS (2-7 years old)	3.5 mg/kg POS (7-17 years old)	4.5 mg/kg POS (2-7 years old)	4.5 mg/kg POS (7-17 years old)	6 mg/kg POS (2-7 years old)	6 mg/kg POS (7-17 years old)
Number of subjects analysed	11 ^[9]	19 ^[10]	14 ^[11]	15 ^[12]	17 ^[13]	24 ^[14]
Units: ng/mL
geometric mean (geometric coefficient of variation)
IV	1590 ± 43.1	2450 ± 72.7	2320 ± 39.8	2310 ± 40.3	3060 ± 54.1	3340 ± 39.4
PFS	884 ± 44.4	1340 ± 30.8	1550 ± 40.8	1670 ± 28.5	1510 ± 43.4	1370 ± 178.5

Notes
[9] - IV n=11; PFS n=5
[10] - IV n=19; PFS n=10
[11] - IV n=14; PFS n=8
[12] - IV n=15; PFS n=8
[13] - IV n=17; PFS n=7
[14] - IV n=24; PFS n=12

No statistical analyses for this end point

Primary: Minimum plasma concentration (Cmin) for POS

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End point title

Minimum plasma concentration (Cmin) for POS ^[15]

End point description

Blood was collected from pre-dose up to 24 hours post-dose in order to determine the plasma Cmin of posaconazole. A non-compartmental analysis of posaconazole plasma concentrations was performed. Results are reported for each treatment arm according to the formulation that participants received (IV or PFS). Participants receiving both formulations were counted once for each formulation. The population analyzed was all treated participants who received at least 7 days of POS dosing (IV and PFS), completed the full POS PK sampling, and met pre-specified acceptability criteria.

End point type

Primary

End point timeframe

Any day from Day 7 to Day 10 of therapy for each formulation (up to 28 days) at pre-dose, within 15 minutes after end of infusion (up to 2 hours), and 4, 6, 8, 12, 24 hours post-infusion

Notes
[15] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Statistical comparisons between treatment groups were neither planned nor performed for this primary endpoint.

End point values	3.5 mg/kg POS (2-7 years old)	3.5 mg/kg POS (7-17 years old)	4.5 mg/kg POS (2-7 years old)	4.5 mg/kg POS (7-17 years old)	6 mg/kg POS (2-7 years old)	6 mg/kg POS (7-17 years old)
Number of subjects analysed	11 ^[16]	19 ^[17]	14 ^[18]	15 ^[19]	17 ^[20]	24 ^[21]
Units: ng/mL
geometric mean (geometric coefficient of variation)
IV	400 ± 81.3	670 ± 65.1	501 ± 56.8	737 ± 66.0	626 ± 104.8	1160 ± 60.4
PFS	254 ± 45.6	579 ± 44.9	476 ± 164.6	790 ± 48.2	542 ± 68.8	713 ± 300.6

Notes
[16] - IV n=11; PFS n=5
[17] - IV n=19; PFS n=10
[18] - IV n=14; PFS n=8
[19] - IV n=15; PFS n=8
[20] - IV n=17; PFS n=7
[21] - IV n=24; PFS n=12

No statistical analyses for this end point

Primary: Average steady-state plasma concentration (Cavg) for POS

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End point title

Average steady-state plasma concentration (Cavg) for POS ^[22]

End point description

Blood was collected from pre-dose up to 24 hours post-dose in order to determine the plasma Cavg of posaconazole. A non-compartmental analysis of posaconazole plasma concentrations was performed. Results are reported for each treatment arm according to the formulation that participants received (IV or PFS). Participants receiving both formulations were counted once for each formulation. The population analyzed was all treated participants who received at least 7 days of POS dosing (IV and PFS), completed the full POS PK sampling, and met pre-specified acceptability criteria.

End point type

Primary

End point timeframe

Any day from Day 7 to Day 10 of therapy for each formulation (up to 28 days) at pre-dose, within 15 minutes after end of infusion (up to 2 hours), and 4, 6, 8, 12, 24 hours post-infusion

Notes
[22] - 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: Statistical comparisons between treatment groups were neither planned nor performed for this primary endpoint.

End point values	3.5 mg/kg POS (2-7 years old)	3.5 mg/kg POS (7-17 years old)	4.5 mg/kg POS (2-7 years old)	4.5 mg/kg POS (7-17 years old)	6 mg/kg POS (2-7 years old)	6 mg/kg POS (7-17 years old)
Number of subjects analysed	11 ^[23]	19 ^[24]	14 ^[25]	15 ^[26]	17 ^[27]	24 ^[28]
Units: ng/mL
geometric mean (geometric coefficient of variation)
IV	743 ± 55.0	1140 ± 49.7	1070 ± 30.0	1240 ± 42.9	1300 ± 48.9	1840 ± 41.5
PFS	510 ± 36.0	861 ± 33.8	901 ± 64.5	1200 ± 33.7	960 ± 47.3	1040 ± 184.3

Notes
[23] - IV n=11; PFS n=5
[24] - IV n=19; PFS n=10
[25] - IV n=14; PFS n=8
[26] - IV n=15; PFS n=8
[27] - IV n=17; PFS n=7
[28] - IV n=24; PFS n=12

No statistical analyses for this end point

Primary: Time of maximum plasma concentration (Tmax) for POS

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End point title

Time of maximum plasma concentration (Tmax) for POS ^[29]

End point description

Blood was collected from pre-dose up to 24 hours post-dose in order to determine the plasma Tmax of posaconazole. A non-compartmental analysis of posaconazole plasma concentrations was performed. Results are reported for each treatment arm according to the formulation that participants received (IV or PFS). Participants receiving both formulations were counted once for each formulation. The population analyzed was all treated participants who received at least 7 days of POS dosing (IV and PFS), completed the full POS PK sampling, and met pre-specified acceptability criteria.

End point type

Primary

End point timeframe

Any day from Day 7 to Day 10 of therapy for each formulation (up to 28 days) at pre-dose, within 15 minutes after end of infusion (up to 2 hours), and 4, 6, 8, 12, 24 hours post-infusion

Notes
[29] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Statistical comparisons between treatment groups were neither planned nor performed for this primary endpoint.

End point values	3.5 mg/kg POS (2-7 years old)	3.5 mg/kg POS (7-17 years old)	4.5 mg/kg POS (2-7 years old)	4.5 mg/kg POS (7-17 years old)	6 mg/kg POS (2-7 years old)	6 mg/kg POS (7-17 years old)
Number of subjects analysed	11 ^[30]	19 ^[31]	14 ^[32]	15 ^[33]	17 ^[34]	24 ^[35]
Units: Hours
median (full range (min-max))
IV	1.78 (1.67 to 5.53)	1.77 (0.00 to 3.50)	1.78 (1.42 to 5.90)	1.75 (1.52 to 1.80)	1.75 (1.57 to 1.83)	1.77 (1.33 to 6.00)
PFS	3.83 (1.92 to 4.25)	2.20 (1.92 to 6.03)	3.82 (1.88 to 5.92)	6.14 (1.98 to 7.98)	4.00 (2.17 to 7.92)	2.78 (0.00 to 4.00)

Notes
[30] - IV n=11; PFS n=5
[31] - IV n=19; PFS n=10
[32] - IV n=14; PFS n=8
[33] - IV n=15; PFS n=8
[34] - IV n=17; PFS n=7
[35] - IV n=24; PFS n=12

No statistical analyses for this end point

Primary: Total body clearance (CL) for POS administered by IV

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End point title

Total body clearance (CL) for POS administered by IV ^[36]

End point description

Blood was collected from pre-dose up to 24 hours post-dose in order to determine the plasma CL of posaconazole administered by IV. A non-compartmental analysis of posaconazole plasma concentrations was performed. Results are reported for participants that received IV treatment. The population analyzed was all treated participants who received at least 7 days of POS IV solution therapy, completed the full POS PK sampling while on POS IV solution, and met pre-specified acceptability criteria.

End point type

Primary

End point timeframe

Any day from Day 7 to Day 10 of therapy at pre-dose, within 15 minutes after end of infusion (up to 2 hours), and 4, 6, 8, 12, 24 hours post-infusion

Notes
[36] - 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: Statistical comparisons between treatment groups were neither planned nor performed for this primary endpoint.

End point values	3.5 mg/kg POS (2-7 years old)	3.5 mg/kg POS (7-17 years old)	4.5 mg/kg POS (2-7 years old)	4.5 mg/kg POS (7-17 years old)	6 mg/kg POS (2-7 years old)	6 mg/kg POS (7-17 years old)
Number of subjects analysed	11	19	14	15	17	24
Units: L/hr
geometric mean (geometric coefficient of variation)	3.39 ± 52.8	6.64 ± 38.6	2.97 ± 36.2	6.69 ± 37.3	3.27 ± 49.3	4.76 ± 55.7

No statistical analyses for this end point

Primary: Apparent total body clearance (CL/F) for POS administered by PFS

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End point title

Apparent total body clearance (CL/F) for POS administered by PFS ^[37]

End point description

Blood was collected from pre-dose up to 24 hours post-dose in order to determine the plasma CL/F of posaconazole administered by PFS. A non-compartmental analysis of posaconazole plasma concentrations was performed. Results are reported for participants that received PFS treatment. The population analyzed was all treated participants who received at least 7 days of POS PFS therapy, completed the full POS PK sampling while on POS PFS, and met pre-specified acceptability criteria.

End point type

Primary

End point timeframe

Any day from Day 7 to Day 10 of therapy (up to 28 days) at pre-dose, within 15 minutes after end of infusion (up to 2 hours), and 4, 6, 8, 12, 24 hours post-infusion

Notes
[37] - 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: Statistical comparisons between treatment groups were neither planned nor performed for this primary endpoint.

End point values	3.5 mg/kg POS (2-7 years old)	3.5 mg/kg POS (7-17 years old)	4.5 mg/kg POS (2-7 years old)	4.5 mg/kg POS (7-17 years old)	6 mg/kg POS (2-7 years old)	6 mg/kg POS (7-17 years old)
Number of subjects analysed	5	10	8	8	7	12
Units: L/hr
geometric mean (geometric coefficient of variation)	4.97 ± 29.1	7.67 ± 39.9	3.49 ± 59.1	7.84 ± 49.4	4.60 ± 35.2	8.39 ± 190.3

No statistical analyses for this end point

Secondary: Number of participants with an Adverse Event (AE)

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End point title

Number of participants with an Adverse Event (AE)

End point description

An adverse event (AE) is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol - specified procedure, whether or not considered related to the medicinal product or protocol - specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor’s product, is also an AE. The population analyzed was all participants who received at least one dose of study drug.

End point type

Secondary

End point timeframe

14 days after end of treatment (Up to 42 days)

End point values	3.5 mg/kg POS (2-7 years old)	3.5 mg/kg POS (7-17 years old)	4.5 mg/kg POS (2-7 years old)	4.5 mg/kg POS (7-17 years old)	6 mg/kg POS (2-7 years old)	6 mg/kg POS (7-17 years old)
Number of subjects analysed	14	21	15	16	20	29
Units: Participants	13	21	15	16	19	29

No statistical analyses for this end point

Secondary: Number of participants who discontinued treatment of study drug due to an Adverse Event (AE)

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End point title

Number of participants who discontinued treatment of study drug due to an Adverse Event (AE)

End point description

An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol - specified procedure, whether or not considered related to the medicinal product or protocol - specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor’s product, is also an AE. The population analyzed was all participants who received at least one dose of study drug.

End point type

Secondary

End point timeframe

Up to 28 days

End point values	3.5 mg/kg POS (2-7 years old)	3.5 mg/kg POS (7-17 years old)	4.5 mg/kg POS (2-7 years old)	4.5 mg/kg POS (7-17 years old)	6 mg/kg POS (2-7 years old)	6 mg/kg POS (7-17 years old)
Number of subjects analysed	14	21	15	16	20	29
Units: Participants	3	3	0	2	4	6

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

14 days after end of treatment (up to day 42)

Adverse event reporting additional description

All participants who received at least one dose of study drug. Participants were followed for survival up to 110 days; and deaths that occurred outside of the timeframe for adverse event reporting were recorded in the Disposition

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

21.0

Reporting group title

3.5 mg/kg posaconazole (2-<7 years old)

Reporting group description

Reporting group title

3.5 mg/kg posaconazole (7-17 years old)

Reporting group description

Reporting group title

4.5 mg/kg posaconazole (2-<7 years old)

Reporting group description

Children 2 to less than 7 years of age received posaconazole (POS) at 4.5 mg/kg by intravenous (IV) solution twice on Day 1, then once daily on Days 2-10. This was followed by treatment with 4.5 mg/kg POS once daily by powder for oral suspension (PFS) for a minimum of 10 days; or, if they were unwilling or unable to tolerate POS PFS, continued treatment with POS IV.

Reporting group title

4.5 mg/kg posaconazole (7-17 years old)

Reporting group description

Reporting group title

6.0 mg/kg posaconazole (2-<7 years old)

Reporting group description

Children 2 to less than 7 years of age received posaconazole (POS) at 6 mg/kg by intravenous (IV) solution twice on Day 1, then once daily on Days 2-10. This was followed by treatment with 6 mg/kg POS once daily by powder for oral suspension (PFS) for a minimum of 10 days; or, if they were unwilling or unable to tolerate POS PFS, continued treatment with POS IV.

Reporting group title

6.0 mg/kg posaconazole (7-17 years old)

Reporting group description

Serious adverse events	3.5 mg/kg posaconazole (2-<7 years old)	3.5 mg/kg posaconazole (7-17 years old)	4.5 mg/kg posaconazole (2-<7 years old)	4.5 mg/kg posaconazole (7-17 years old)	6.0 mg/kg posaconazole (2-<7 years old)	6.0 mg/kg posaconazole (7-17 years old)
Total subjects affected by serious adverse events
subjects affected / exposed	3 / 14 (21.43%)	8 / 21 (38.10%)	4 / 15 (26.67%)	5 / 16 (31.25%)	3 / 20 (15.00%)	8 / 29 (27.59%)
number of deaths (all causes)	0	0	0	0	0	2
number of deaths resulting from adverse events	0	0	0	0	0	0
Vascular disorders
Capillary leak syndrome
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences causally related to treatment / all	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
Hypertension
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences causally related to treatment / all	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
Thrombophlebitis superficial
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	1 / 16 (6.25%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Venoocclusive disease
subjects affected / exposed	1 / 14 (7.14%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences causally related to treatment / all	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 / 1
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	0 / 14 (0.00%)	2 / 21 (9.52%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Drug hypersensitivity
subjects affected / exposed	1 / 14 (7.14%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Engraftment syndrome
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Transplant rejection
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences causally related to treatment / all	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
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Hypoxia
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	1 / 16 (6.25%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Respiratory failure
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences causally related to treatment / all	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 / 1
Cardiac disorders
Cardiac failure
subjects affected / exposed	1 / 14 (7.14%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiomyopathy
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Nervous system disorders
Posterior reversible encephalopathy syndrome
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	1 / 20 (5.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Presyncope
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	1 / 16 (6.25%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Blood and lymphatic system disorders
Febrile neutropenia
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	1 / 20 (5.00%)	1 / 29 (3.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	1 / 20 (5.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Stomatitis
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences causally related to treatment / all	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
Vomiting
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	1 / 20 (5.00%)	1 / 29 (3.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Hepatic lesion
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Venoocclusive liver disease
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences causally related to treatment / all	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
Renal failure
subjects affected / exposed	1 / 14 (7.14%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Chest wall haematoma
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	1 / 16 (6.25%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Infections and infestations
Adenovirus infection
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Clostridium difficile colitis
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Cystitis
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Device related infection
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences causally related to treatment / all	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
Enterobacter infection
subjects affected / exposed	1 / 14 (7.14%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fungal infection
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	1 / 16 (6.25%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Herpes zoster
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Parainfluenzae virus infection
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences causally related to treatment / all	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
Pneumonia
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Pneumonia viral
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Streptococcal sepsis
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	1 / 16 (6.25%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Systemic mycosis
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	1 / 16 (6.25%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Upper respiratory tract infection
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Urinary tract infection viral
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences causally related to treatment / all	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
Metabolism and nutrition disorders
Hyponatraemia
subjects affected / exposed	1 / 14 (7.14%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	3.5 mg/kg posaconazole (2-<7 years old)	3.5 mg/kg posaconazole (7-17 years old)	4.5 mg/kg posaconazole (2-<7 years old)	4.5 mg/kg posaconazole (7-17 years old)	6.0 mg/kg posaconazole (2-<7 years old)	6.0 mg/kg posaconazole (7-17 years old)
Total subjects affected by non serious adverse events
subjects affected / exposed	13 / 14 (92.86%)	20 / 21 (95.24%)	15 / 15 (100.00%)	16 / 16 (100.00%)	19 / 20 (95.00%)	29 / 29 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	1
Vascular disorders
Capillary leak syndrome
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	1
Flushing
subjects affected / exposed	1 / 14 (7.14%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	1	1	0	0	0	0
Haematoma
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	1	0	0	0	0
Hyperaemia
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	1 / 20 (5.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	1	1
Hypertension
subjects affected / exposed	5 / 14 (35.71%)	2 / 21 (9.52%)	2 / 15 (13.33%)	1 / 16 (6.25%)	6 / 20 (30.00%)	4 / 29 (13.79%)
occurrences all number	5	2	2	1	6	4
Hypotension
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	2 / 16 (12.50%)	1 / 20 (5.00%)	2 / 29 (6.90%)
occurrences all number	0	0	0	2	1	2
Pallor
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	2	0	0	0
Phlebitis
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	1 / 16 (6.25%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	1	0	0
Venoocclusive disease
subjects affected / exposed	2 / 14 (14.29%)	0 / 21 (0.00%)	1 / 15 (6.67%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	2	0	1	0	0	2
General disorders and administration site conditions
Axillary pain
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	1	0	0	1
Catheter site erythema
subjects affected / exposed	1 / 14 (7.14%)	0 / 21 (0.00%)	1 / 15 (6.67%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	1	0	1	0	0	0
Catheter site haemorrhage
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	1	0	0	0	0
Catheter site oedema
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	2
Catheter site pain
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	1	0	0	2
Catheter site swelling
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	1	0	0	0
Chills
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	1	0	0	0	0
Face oedema
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	2 / 29 (6.90%)
occurrences all number	0	0	0	0	0	2
Fatigue
subjects affected / exposed	1 / 14 (7.14%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	1	1	0	0	0	1
General physical health deterioration
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	2 / 29 (6.90%)
occurrences all number	0	0	0	0	0	3
Generalised oedema
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	1
Granuloma
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	1 / 16 (6.25%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	1	0	0
Infusion site erythema
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	1	0	0	0
Malaise
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	2
Mucosal inflammation
subjects affected / exposed	3 / 14 (21.43%)	9 / 21 (42.86%)	5 / 15 (33.33%)	4 / 16 (25.00%)	5 / 20 (25.00%)	6 / 29 (20.69%)
occurrences all number	3	10	5	4	5	6
Oedema
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	1 / 20 (5.00%)	0 / 29 (0.00%)
occurrences all number	0	1	0	0	1	0
Oedema peripheral
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	1 / 20 (5.00%)	2 / 29 (6.90%)
occurrences all number	0	1	0	0	1	2
Pain
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	1 / 16 (6.25%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	1	0	0
Pyrexia
subjects affected / exposed	8 / 14 (57.14%)	9 / 21 (42.86%)	6 / 15 (40.00%)	10 / 16 (62.50%)	8 / 20 (40.00%)	8 / 29 (27.59%)
occurrences all number	13	11	9	13	8	12
Systemic inflammatory response syndrome
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	1	0	0	0	0
Immune system disorders
Drug hypersensitivity
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	2 / 20 (10.00%)	2 / 29 (6.90%)
occurrences all number	0	0	0	0	2	3
Engraftment syndrome
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	2 / 29 (6.90%)
occurrences all number	0	0	0	0	0	2
Graft versus host disease
subjects affected / exposed	2 / 14 (14.29%)	2 / 21 (9.52%)	0 / 15 (0.00%)	1 / 16 (6.25%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	2	2	0	1	0	1
Graft versus host disease in gastrointestinal tract
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	1 / 16 (6.25%)	0 / 20 (0.00%)	2 / 29 (6.90%)
occurrences all number	0	0	0	1	0	2
Graft versus host disease in liver
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	1 / 20 (5.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	0	1	0
Graft versus host disease in skin
subjects affected / exposed	0 / 14 (0.00%)	2 / 21 (9.52%)	0 / 15 (0.00%)	1 / 16 (6.25%)	2 / 20 (10.00%)	1 / 29 (3.45%)
occurrences all number	0	2	0	1	2	1
Hypogammaglobulinaemia
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	2 / 20 (10.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	0	2	0
Immunodeficiency
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	1
Immunodeficiency common variable
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	1 / 16 (6.25%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	1	0	0
Serum sickness
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	1	0	0	0
Reproductive system and breast disorders
Menorrhagia
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	1
Metrorrhagia
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	1 / 16 (6.25%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	1	0	0
Perineal erythema
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	1 / 20 (5.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	0	1	0
Perineal pain
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	1 / 20 (5.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	0	1	0
Scrotal oedema
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	1
Testicular oedema
subjects affected / exposed	1 / 14 (7.14%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	1	0	0	0	0	0
Vulvovaginal inflammation
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	1	0	0	0	0
Vulvovaginal pruritus
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	1 / 20 (5.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	0	1	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	2 / 14 (14.29%)	0 / 21 (0.00%)	4 / 15 (26.67%)	1 / 16 (6.25%)	0 / 20 (0.00%)	3 / 29 (10.34%)
occurrences all number	2	0	4	1	0	3
Dysphonia
subjects affected / exposed	1 / 14 (7.14%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	1	0	0	0	0	0
Dyspnoea
subjects affected / exposed	0 / 14 (0.00%)	2 / 21 (9.52%)	0 / 15 (0.00%)	1 / 16 (6.25%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	2	0	1	0	1
Epistaxis
subjects affected / exposed	2 / 14 (14.29%)	1 / 21 (4.76%)	1 / 15 (6.67%)	5 / 16 (31.25%)	1 / 20 (5.00%)	3 / 29 (10.34%)
occurrences all number	4	1	1	8	1	4
Haemoptysis
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	1 / 16 (6.25%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	1	0	0
Hypoxia
subjects affected / exposed	0 / 14 (0.00%)	2 / 21 (9.52%)	0 / 15 (0.00%)	1 / 16 (6.25%)	1 / 20 (5.00%)	1 / 29 (3.45%)
occurrences all number	0	2	0	1	1	1
Increased viscosity of bronchial secretion
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	1 / 16 (6.25%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	1	0	0
Lung infiltration
subjects affected / exposed	1 / 14 (7.14%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	1	0	0	0	0	0
Nasal congestion
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	1
Oropharyngeal pain
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	1 / 15 (6.67%)	0 / 16 (0.00%)	0 / 20 (0.00%)	3 / 29 (10.34%)
occurrences all number	0	1	1	0	0	3
Pharyngeal inflammation
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	1
Pleural effusion
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	1 / 20 (5.00%)	0 / 29 (0.00%)
occurrences all number	0	1	0	0	1	0
Pleuritic pain
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	1	0	0	0	0
Productive cough
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	1
Pulmonary oedema
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	1
Rales
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	1	0	0	0
Rhinitis allergic
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	1	0	0	0
Rhinorrhoea
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	1
Tachypnoea
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	1	0	0	0
Tonsillar exudate
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	1	0	0	0
Psychiatric disorders
Agitation
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	1
Anxiety
subjects affected / exposed	1 / 14 (7.14%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	2 / 29 (6.90%)
occurrences all number	1	0	0	0	0	2
Depressed mood
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	1
Depression
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	1	0	0	0	0
Insomnia
subjects affected / exposed	1 / 14 (7.14%)	0 / 21 (0.00%)	0 / 15 (0.00%)	1 / 16 (6.25%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	1	0	0	1	0	0
Irritability
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	1 / 20 (5.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	0	1	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	1 / 15 (6.67%)	0 / 16 (0.00%)	1 / 20 (5.00%)	5 / 29 (17.24%)
occurrences all number	0	1	1	0	1	5
Aspartate aminotransferase increased
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	1 / 15 (6.67%)	1 / 16 (6.25%)	0 / 20 (0.00%)	5 / 29 (17.24%)
occurrences all number	0	1	1	1	0	6
BK polyomavirus test positive
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	1 / 20 (5.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	0	1	0
Bacterial test positive
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	1 / 16 (6.25%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	1	0	0
Blood albumin decreased
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	1 / 16 (6.25%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	1	0	1
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	1	0	0	0
Blood bilirubin increased
subjects affected / exposed	1 / 14 (7.14%)	1 / 21 (4.76%)	0 / 15 (0.00%)	2 / 16 (12.50%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	1	1	0	2	0	0
Blood calcium decreased
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	1	0	0	0	0
Blood creatinine increased
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	1 / 16 (6.25%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	1	0	1	0	0
Blood culture positive
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	1	0	0	0	0
Blood immunoglobulin G decreased
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	1
Blood lactate dehydrogenase increased
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	1
Blood magnesium decreased
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	1
Blood phosphorus decreased
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	1 / 15 (6.67%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	1	1	0	0	0
Blood potassium decreased
subjects affected / exposed	1 / 14 (7.14%)	2 / 21 (9.52%)	0 / 15 (0.00%)	1 / 16 (6.25%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	1	2	0	1	0	0
Blood potassium increased
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	1 / 16 (6.25%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	2	0	0
Blood urea increased
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	1 / 16 (6.25%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	1	0	0
Blood uric acid decreased
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	1 / 16 (6.25%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	1	0	0
Blood uric acid increased
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	1 / 16 (6.25%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	1	0	0
Breath sounds abnormal
subjects affected / exposed	1 / 14 (7.14%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	1	0	0	0	0	0
C-reactive protein increased
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	1	0	0	0
Cytomegalovirus test positive
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	1 / 16 (6.25%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	1	0	0
Drug level increased
subjects affected / exposed	0 / 14 (0.00%)	2 / 21 (9.52%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	2	0	0	0	0
Electrocardiogram QT prolonged
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	1 / 16 (6.25%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	1	0	1
Fibrin D dimer increased
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	1
Fluid balance positive
subjects affected / exposed	1 / 14 (7.14%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	1	0	0	0	0	0
Neutrophil count decreased
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	1
Oxygen saturation decreased
subjects affected / exposed	1 / 14 (7.14%)	0 / 21 (0.00%)	1 / 15 (6.67%)	1 / 16 (6.25%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	1	0	1	1	0	2
Platelet count decreased
subjects affected / exposed	1 / 14 (7.14%)	0 / 21 (0.00%)	0 / 15 (0.00%)	1 / 16 (6.25%)	1 / 20 (5.00%)	2 / 29 (6.90%)
occurrences all number	2	0	0	2	1	2
Pulmonary arterial pressure increased
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	1 / 16 (6.25%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	1	0	0
Red blood cells urine positive
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	1
Transaminases increased
subjects affected / exposed	2 / 14 (14.29%)	1 / 21 (4.76%)	1 / 15 (6.67%)	3 / 16 (18.75%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	2	1	1	3	0	0
Viral test positive
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	1	0	0	0
Vitamin D decreased
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	1 / 20 (5.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	0	1	0
Weight increased
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	2 / 29 (6.90%)
occurrences all number	0	0	0	0	0	2
White blood cell count decreased
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	1
Injury, poisoning and procedural complications
Accidental overdose
subjects affected / exposed	1 / 14 (7.14%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	1	0	0	0	0	0
Allergic transfusion reaction
subjects affected / exposed	1 / 14 (7.14%)	0 / 21 (0.00%)	0 / 15 (0.00%)	1 / 16 (6.25%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	1	0	0	1	0	0
Buttock injury
subjects affected / exposed	1 / 14 (7.14%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	1	0	0	0	0	0
Eye contusion
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	1	0	0	0
Head injury
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	1	0	0	0
Infusion related reaction
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	1 / 16 (6.25%)	1 / 20 (5.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	1	1	0
Procedural pain
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	1	0	0	0	1
Scratch
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	1
Transfusion reaction
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	1 / 16 (6.25%)	1 / 20 (5.00%)	1 / 29 (3.45%)
occurrences all number	0	1	0	1	1	1
Cardiac disorders
Bradycardia
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	1	0	0	1
Pericardial effusion
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	1
Sinus bradycardia
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	1
Sinus tachycardia
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	1 / 16 (6.25%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	1	0	0
Tachycardia
subjects affected / exposed	1 / 14 (7.14%)	2 / 21 (9.52%)	1 / 15 (6.67%)	0 / 16 (0.00%)	1 / 20 (5.00%)	1 / 29 (3.45%)
occurrences all number	1	2	1	0	1	1
Nervous system disorders
Dizziness
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	1	0	0	0	1
Headache
subjects affected / exposed	1 / 14 (7.14%)	4 / 21 (19.05%)	0 / 15 (0.00%)	5 / 16 (31.25%)	1 / 20 (5.00%)	5 / 29 (17.24%)
occurrences all number	1	4	0	6	1	7
Hypoaesthesia
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	2
Hypotonia
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	1	0	0	0	0
Intention tremor
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	1
Myoclonus
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	2	0	0	0	0
Opisthotonus
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	1 / 20 (5.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	0	1	0
Paraesthesia
subjects affected / exposed	1 / 14 (7.14%)	0 / 21 (0.00%)	0 / 15 (0.00%)	1 / 16 (6.25%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	1	0	0	1	0	1
Posterior reversible encephalopathy syndrome
subjects affected / exposed	1 / 14 (7.14%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	1	0	0	0	0	0
Somnolence
subjects affected / exposed	1 / 14 (7.14%)	0 / 21 (0.00%)	0 / 15 (0.00%)	2 / 16 (12.50%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	1	0	0	2	0	0
Blood and lymphatic system disorders
Agranulocytosis
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	1	0	0	0
Anaemia
subjects affected / exposed	1 / 14 (7.14%)	1 / 21 (4.76%)	1 / 15 (6.67%)	3 / 16 (18.75%)	2 / 20 (10.00%)	2 / 29 (6.90%)
occurrences all number	4	1	2	4	2	3
Disseminated intravascular coagulation
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	1
Febrile neutropenia
subjects affected / exposed	2 / 14 (14.29%)	3 / 21 (14.29%)	2 / 15 (13.33%)	2 / 16 (12.50%)	7 / 20 (35.00%)	7 / 29 (24.14%)
occurrences all number	2	3	2	2	7	8
Leukopenia
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	1	0	0	0
Neutropenia
subjects affected / exposed	0 / 14 (0.00%)	2 / 21 (9.52%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	2 / 29 (6.90%)
occurrences all number	0	2	0	0	0	2
Pancytopenia
subjects affected / exposed	1 / 14 (7.14%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	1	1	0	0	0	0
Splenomegaly
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	1	0	0	0	0
Thrombocytopenia
subjects affected / exposed	0 / 14 (0.00%)	2 / 21 (9.52%)	0 / 15 (0.00%)	2 / 16 (12.50%)	1 / 20 (5.00%)	2 / 29 (6.90%)
occurrences all number	0	2	0	2	3	4
Ear and labyrinth disorders
Ear haemorrhage
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	1	0	0	0	0
Ear pain
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)	1 / 16 (6.25%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	1	1	0	0
Tinnitus
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	1 / 16 (6.25%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	1	0	0
Vertigo
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	1 / 20 (5.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	0	1	0
Eye disorders
Conjunctival haemorrhage
subjects affected / exposed	1 / 14 (7.14%)	0 / 21 (0.00%)	1 / 15 (6.67%)	0 / 16 (0.00%)	0 / 20 (0.00%)	2 / 29 (6.90%)
occurrences all number	1	0	1	0	0	2
Dry eye
subjects affected / exposed	1 / 14 (7.14%)	0 / 21 (0.00%)	0 / 15 (0.00%)	1 / 16 (6.25%)	1 / 20 (5.00%)	2 / 29 (6.90%)
occurrences all number	1	0	0	1	1	2
Eye haemorrhage
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	1
Eye irritation
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	1
Eye pain
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	1 / 16 (6.25%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	1	0	1
Eyelid oedema
subjects affected / exposed	2 / 14 (14.29%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	2 / 29 (6.90%)
occurrences all number	2	0	0	0	0	2
Ocular hyperaemia
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	1	0	0	0	1
Periorbital oedema
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	1
Photophobia
subjects affected / exposed	1 / 14 (7.14%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	1	1	0	0	0	0
Vision blurred
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	2
Visual impairment
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	1	0	0	0	0
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	1
Abdominal distension
subjects affected / exposed	2 / 14 (14.29%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	2	0	0	0	0	0
Abdominal pain
subjects affected / exposed	2 / 14 (14.29%)	2 / 21 (9.52%)	2 / 15 (13.33%)	6 / 16 (37.50%)	2 / 20 (10.00%)	5 / 29 (17.24%)
occurrences all number	2	2	2	8	2	7
Abdominal pain upper
subjects affected / exposed	1 / 14 (7.14%)	2 / 21 (9.52%)	2 / 15 (13.33%)	0 / 16 (0.00%)	2 / 20 (10.00%)	2 / 29 (6.90%)
occurrences all number	1	2	2	0	2	2
Anal fissure
subjects affected / exposed	0 / 14 (0.00%)	2 / 21 (9.52%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	2	0	0	0	0
Anal inflammation
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	1
Anorectal discomfort
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	1
Anorectal disorder
subjects affected / exposed	1 / 14 (7.14%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	1	0	0	0	0	0
Aphthous ulcer
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	1 / 20 (5.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	0	1	0
Ascites
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	1 / 20 (5.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	0	1	0
Colitis
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	1 / 20 (5.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	1	1
Constipation
subjects affected / exposed	3 / 14 (21.43%)	2 / 21 (9.52%)	2 / 15 (13.33%)	1 / 16 (6.25%)	0 / 20 (0.00%)	4 / 29 (13.79%)
occurrences all number	3	2	2	1	0	4
Diarrhoea
subjects affected / exposed	5 / 14 (35.71%)	2 / 21 (9.52%)	5 / 15 (33.33%)	4 / 16 (25.00%)	5 / 20 (25.00%)	4 / 29 (13.79%)
occurrences all number	5	2	5	4	6	5
Dyspepsia
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	1	0	0	1
Dysphagia
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	1	0	0	0	0
Faeces hard
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	1
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	1 / 16 (6.25%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	1	0	0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	1	0	0	0	0
Gingival bleeding
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	1 / 20 (5.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	0	1	0
Gingival pain
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	1	0	0	0	0
Glossodynia
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	1	0	0	0	0
Haematemesis
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	1	0	0	0	0
Haematochezia
subjects affected / exposed	1 / 14 (7.14%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	1	0	0	0	0	0
Haemorrhoids
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	1 / 20 (5.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	0	1	0
Lip dry
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	1	0	0	0	1
Lip pruritus
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	1
Loose tooth
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	1
Mouth ulceration
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	1
Nausea
subjects affected / exposed	1 / 14 (7.14%)	4 / 21 (19.05%)	1 / 15 (6.67%)	3 / 16 (18.75%)	2 / 20 (10.00%)	7 / 29 (24.14%)
occurrences all number	1	5	1	5	2	9
Odynophagia
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	1	0	0	0	0
Oesophagitis
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	1 / 16 (6.25%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	1	0	1
Oral disorder
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	1	0	0	0
Oral mucosal blistering
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	2 / 29 (6.90%)
occurrences all number	0	0	0	0	0	2
Oral mucosal exfoliation
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	1	0	0	0
Oral pain
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	1
Rectal haemorrhage
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	1	0	0	0	0
Scalloped tongue
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	1	0	0	0
Stomatitis
subjects affected / exposed	0 / 14 (0.00%)	2 / 21 (9.52%)	0 / 15 (0.00%)	1 / 16 (6.25%)	3 / 20 (15.00%)	6 / 29 (20.69%)
occurrences all number	0	2	0	1	3	6
Subileus
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	1 / 20 (5.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	0	1	0
Tongue haemorrhage
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	1	0	0	0
Tooth loss
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	1
Toothache
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	1 / 20 (5.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	0	1	0
Vomiting
subjects affected / exposed	4 / 14 (28.57%)	6 / 21 (28.57%)	2 / 15 (13.33%)	6 / 16 (37.50%)	6 / 20 (30.00%)	6 / 29 (20.69%)
occurrences all number	6	9	3	8	8	13
Hepatobiliary disorders
Hepatomegaly
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	1 / 16 (6.25%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	1	0	0
Hyperbilirubinaemia
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)	1 / 16 (6.25%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	1	1	0	0
Jaundice
subjects affected / exposed	1 / 14 (7.14%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	1	0	0	0	0	0
Skin and subcutaneous tissue disorders
Acne
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	1	0	0	0	0
Alopecia
subjects affected / exposed	2 / 14 (14.29%)	0 / 21 (0.00%)	0 / 15 (0.00%)	1 / 16 (6.25%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	2	0	0	1	0	0
Blister
subjects affected / exposed	1 / 14 (7.14%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	1	0	0	0	0	0
Dermatitis
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	1 / 20 (5.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	0	1	0
Dermatitis atopic
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	1 / 16 (6.25%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	1	0	0
Dermatitis bullous
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	1 / 16 (6.25%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	1	0	0
Dermatitis contact
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	1	0	0	0	0
Dermatitis diaper
subjects affected / exposed	1 / 14 (7.14%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	1	0	0	0	0	0
Drug eruption
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	2
Dry skin
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	1	0	0	0	1
Erythema
subjects affected / exposed	1 / 14 (7.14%)	0 / 21 (0.00%)	1 / 15 (6.67%)	1 / 16 (6.25%)	3 / 20 (15.00%)	1 / 29 (3.45%)
occurrences all number	1	0	1	1	4	1
Erythema multiforme
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	1 / 20 (5.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	0	2	0
Macule
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	1 / 20 (5.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	0	1	0
Night sweats
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	1
Palmar erythema
subjects affected / exposed	1 / 14 (7.14%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	1	0	0	0	0	0
Papule
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	1	0	0	0	0
Petechiae
subjects affected / exposed	1 / 14 (7.14%)	1 / 21 (4.76%)	1 / 15 (6.67%)	2 / 16 (12.50%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	1	1	1	2	0	1
Pruritus
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	1 / 15 (6.67%)	5 / 16 (31.25%)	4 / 20 (20.00%)	7 / 29 (24.14%)
occurrences all number	0	1	1	5	5	7
Pruritus allergic
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	1 / 20 (5.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	0	1	0
Rash
subjects affected / exposed	2 / 14 (14.29%)	4 / 21 (19.05%)	3 / 15 (20.00%)	2 / 16 (12.50%)	4 / 20 (20.00%)	3 / 29 (10.34%)
occurrences all number	3	4	4	2	6	3
Rash generalised
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	2 / 20 (10.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	0	2	0
Rash macular
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	1	0	0	0	0
Rash maculo-papular
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	1
Rash pruritic
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	1
Skin burning sensation
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	1	0	0	0
Skin exfoliation
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	1	0	0	0
Skin hyperpigmentation
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	1	0	0	0	0
Skin lesion
subjects affected / exposed	1 / 14 (7.14%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	1	1	0	0	0	0
Skin mass
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	1 / 16 (6.25%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	1	0	0
Skin ulcer
subjects affected / exposed	1 / 14 (7.14%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	1	0	0	0	0	0
Swelling face
subjects affected / exposed	1 / 14 (7.14%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	1	1	0	0	0	0
Urticaria
subjects affected / exposed	1 / 14 (7.14%)	0 / 21 (0.00%)	1 / 15 (6.67%)	1 / 16 (6.25%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	1	0	1	1	0	0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	1 / 14 (7.14%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	1	0	0	0	0	0
Cystitis haemorrhagic
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	1 / 16 (6.25%)	1 / 20 (5.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	1	1	1
Dysuria
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	1	0	0	0	1
Glycosuria
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	1 / 16 (6.25%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	1	0	0
Haematuria
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	1	0	0	0
Micturition urgency
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	1
Nephropathy toxic
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	1	0	0	0	0
Proteinuria
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	1	0	0	0	0
Tubulointerstitial nephritis
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	1 / 20 (5.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	0	1	0
Urinary retention
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	1
Endocrine disorders
Cushingoid
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	1
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	1	0	0	0	1
Back pain
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	3 / 16 (18.75%)	1 / 20 (5.00%)	3 / 29 (10.34%)
occurrences all number	0	1	0	4	1	3
Bone pain
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)	1 / 16 (6.25%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	1	1	0	0
Flank pain
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	1	0	0	0	0
Joint range of motion decreased
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	1 / 16 (6.25%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	1	0	0
Muscle spasms
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	1 / 20 (5.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	0	1	0
Muscle tightness
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	1	0	0	0	0
Musculoskeletal chest pain
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	1
Musculoskeletal pain
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	1	0	0	0	1
Myalgia
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	1 / 16 (6.25%)	0 / 20 (0.00%)	3 / 29 (10.34%)
occurrences all number	0	1	0	1	0	3
Pain in extremity
subjects affected / exposed	2 / 14 (14.29%)	1 / 21 (4.76%)	1 / 15 (6.67%)	3 / 16 (18.75%)	1 / 20 (5.00%)	0 / 29 (0.00%)
occurrences all number	2	1	2	5	1	0
Pain in jaw
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	1 / 16 (6.25%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	1	0	0
Soft tissue swelling
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	1	0	0	0
Infections and infestations
Adenovirus infection
subjects affected / exposed	1 / 14 (7.14%)	0 / 21 (0.00%)	1 / 15 (6.67%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	1	0	1	0	0	0
BK virus infection
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	1	0	0	0	0
Bacteraemia
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	2 / 29 (6.90%)
occurrences all number	0	0	0	0	0	2
Bacterial infection
subjects affected / exposed	1 / 14 (7.14%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	1	0	0	0	0	0
Bronchitis
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	1 / 20 (5.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	0	1	0
Clostridial infection
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	1	0	0	0
Clostridium difficile colitis
subjects affected / exposed	1 / 14 (7.14%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	1	0	0	0	0	0
Clostridium difficile infection
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	1 / 16 (6.25%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	1	0	0
Conjunctivitis
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	1	0	0	1
Corona virus infection
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	1
Cystitis
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	1	0	0	0	1
Cytomegalovirus infection
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	3 / 15 (20.00%)	1 / 16 (6.25%)	1 / 20 (5.00%)	2 / 29 (6.90%)
occurrences all number	0	0	3	1	1	2
Device related infection
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	1 / 20 (5.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	0	1	0
Ear infection
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	1	0	0	0	0
Endocarditis
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	1
Enterobacter bacteraemia
subjects affected / exposed	1 / 14 (7.14%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	1	0	0	0	0	0
Epstein-Barr virus infection
subjects affected / exposed	1 / 14 (7.14%)	1 / 21 (4.76%)	1 / 15 (6.67%)	0 / 16 (0.00%)	1 / 20 (5.00%)	2 / 29 (6.90%)
occurrences all number	1	1	1	0	1	2
Escherichia sepsis
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	1	0	0	1
Gingivitis
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	1	0	0	0
Hepatitis E
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	1
Human bocavirus infection
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	1
Infection
subjects affected / exposed	1 / 14 (7.14%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	1	0	0	0	0	2
Klebsiella bacteraemia
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	1
Klebsiella infection
subjects affected / exposed	1 / 14 (7.14%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	1	0	0	0	0	0
Localised infection
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	1	0	0	0	0
Lung infection
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	2
Mucosal infection
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	1
Nasopharyngitis
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	1	0	0	0
Oral herpes
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	1
Paronychia
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	1	0	0	0	0
Pneumonia
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	1 / 16 (6.25%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	1	0	1
Pneumonia parainfluenzae viral
subjects affected / exposed	1 / 14 (7.14%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	1	0	0	0	0	0
Proctitis herpes
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	1 / 16 (6.25%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	1	0	0
Respiratory tract infection
subjects affected / exposed	1 / 14 (7.14%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	1	0	0	0	0	1
Rhinitis
subjects affected / exposed	1 / 14 (7.14%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	1	0	0	0	0	1
Rhinovirus infection
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	1
Sepsis
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	1	0	0	0	1
Staphylococcal bacteraemia
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	0	1
Staphylococcal infection
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)	0 / 16 (0.00%)	0 / 20 (0.00%)	2 / 29 (6.90%)
occurrences all number	0	0	1	0	0	2
Staphylococcal sepsis
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	1	0	0	0
Upper respiratory tract infection
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	1 / 20 (5.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	0	1	0
Viraemia
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	1	0	0	0
Viral infection
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	1	0	0	0
Viral upper respiratory tract infection
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	1	0	0	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	2 / 14 (14.29%)	4 / 21 (19.05%)	3 / 15 (20.00%)	1 / 16 (6.25%)	3 / 20 (15.00%)	4 / 29 (13.79%)
occurrences all number	2	4	3	1	3	4
Fluid intake reduced
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	1	0	0	0
Fluid retention
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	1 / 16 (6.25%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	1	0	0
Hyperglycaemia
subjects affected / exposed	2 / 14 (14.29%)	0 / 21 (0.00%)	0 / 15 (0.00%)	1 / 16 (6.25%)	1 / 20 (5.00%)	0 / 29 (0.00%)
occurrences all number	2	0	0	1	1	0
Hyperkalaemia
subjects affected / exposed	1 / 14 (7.14%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	1	0	0	0	0	0
Hypernatraemia
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	0	1	0	0	0
Hypertriglyceridaemia
subjects affected / exposed	1 / 14 (7.14%)	0 / 21 (0.00%)	0 / 15 (0.00%)	1 / 16 (6.25%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	1	0	0	1	0	0
Hypoalbuminaemia
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	2 / 20 (10.00%)	2 / 29 (6.90%)
occurrences all number	0	0	0	0	2	2
Hypocalcaemia
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	1 / 20 (5.00%)	1 / 29 (3.45%)
occurrences all number	0	0	0	0	1	1
Hypochloraemia
subjects affected / exposed	1 / 14 (7.14%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	3	0	0	0	0	0
Hypoglycaemia
subjects affected / exposed	1 / 14 (7.14%)	0 / 21 (0.00%)	1 / 15 (6.67%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	3	0	1	0	0	0
Hypokalaemia
subjects affected / exposed	2 / 14 (14.29%)	0 / 21 (0.00%)	1 / 15 (6.67%)	3 / 16 (18.75%)	3 / 20 (15.00%)	7 / 29 (24.14%)
occurrences all number	2	0	1	3	3	8
Hypomagnesaemia
subjects affected / exposed	2 / 14 (14.29%)	1 / 21 (4.76%)	2 / 15 (13.33%)	1 / 16 (6.25%)	0 / 20 (0.00%)	4 / 29 (13.79%)
occurrences all number	2	1	3	1	0	5
Hyponatraemia
subjects affected / exposed	2 / 14 (14.29%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	1 / 20 (5.00%)	0 / 29 (0.00%)
occurrences all number	2	0	0	0	1	0
Hypophagia
subjects affected / exposed	1 / 14 (7.14%)	0 / 21 (0.00%)	1 / 15 (6.67%)	0 / 16 (0.00%)	1 / 20 (5.00%)	0 / 29 (0.00%)
occurrences all number	1	0	1	0	1	0
Hypophosphataemia
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	1 / 15 (6.67%)	0 / 16 (0.00%)	3 / 20 (15.00%)	1 / 29 (3.45%)
occurrences all number	0	0	1	0	3	1
Magnesium deficiency
subjects affected / exposed	0 / 14 (0.00%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	1 / 20 (5.00%)	0 / 29 (0.00%)
occurrences all number	0	0	0	0	1	0
Metabolic acidosis
subjects affected / exposed	0 / 14 (0.00%)	1 / 21 (4.76%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	1	0	0	0	0
Vitamin D deficiency
subjects affected / exposed	1 / 14 (7.14%)	0 / 21 (0.00%)	0 / 15 (0.00%)	0 / 16 (0.00%)	0 / 20 (0.00%)	0 / 29 (0.00%)
occurrences all number	1	0	0	0	0	0

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Were there any global substantial amendments to the protocol? Yes

15 May 2015

Amendment 1: The primary reason for the amendment was to note a change in the suspension vehicle used to prepare the oral formulation of the study medication. In the initial protocol the oral formulation was called oral granules for suspension (OGS) and was to be suspended in water. In amendment 1 the suspension vehicle was changed to Oral-Blend and the name of the oral formulation was changed to powder for oral suspension (PFS).

15 May 2017

Amendment 2: The primary reason for this amendment was to add a third dose cohort of 6mg/kg. Based on interim analysis of the first 2 dose cohorts, the primary PK targets were not met in both age groups for both formulations (oral and IV). In addition the number of participants enrolled in a dedicated safety cohort was increased.

Were there any global interruptions to the trial? No

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

None reported

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Clinical trials

Clinical Trial Results:
A Study of the Safety, Tolerability, and Pharmacokinetics of Intravenous (IV) and Powder for Oral Suspension Formulations of Posaconazole (POS) in Immunocompromised Pediatric Subjects with Neutropenia

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Area under the plasma concentration versus time curve (AUC) from time 0 to 24 hours post-dose for POS

Primary: Area under the plasma concentration versus time curve (AUC) from time 0 to 24 hours post-dose for POS

Primary: Maximum plasma concentration (Cmax) for POS

Primary: Maximum plasma concentration (Cmax) for POS

Primary: Minimum plasma concentration (Cmin) for POS

Primary: Minimum plasma concentration (Cmin) for POS

Primary: Average steady-state plasma concentration (Cavg) for POS

Primary: Average steady-state plasma concentration (Cavg) for POS

Primary: Time of maximum plasma concentration (Tmax) for POS

Primary: Time of maximum plasma concentration (Tmax) for POS

Primary: Total body clearance (CL) for POS administered by IV

Primary: Total body clearance (CL) for POS administered by IV

Primary: Apparent total body clearance (CL/F) for POS administered by PFS

Primary: Apparent total body clearance (CL/F) for POS administered by PFS

Secondary: Number of participants with an Adverse Event (AE)

Secondary: Number of participants with an Adverse Event (AE)

Secondary: Number of participants who discontinued treatment of study drug due to an Adverse Event (AE)

Secondary: Number of participants who discontinued treatment of study drug due to an Adverse Event (AE)

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical trials

Clinical Trial Results: A Study of the Safety, Tolerability, and Pharmacokinetics of Intravenous (IV) and Powder for Oral Suspension Formulations of Posaconazole (POS) in Immunocompromised Pediatric Subjects with Neutropenia

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Area under the plasma concentration versus time curve (AUC) from time 0 to 24 hours post-dose for POS

Primary: Area under the plasma concentration versus time curve (AUC) from time 0 to 24 hours post-dose for POS

Primary: Maximum plasma concentration (Cmax) for POS

Primary: Maximum plasma concentration (Cmax) for POS

Primary: Minimum plasma concentration (Cmin) for POS

Primary: Minimum plasma concentration (Cmin) for POS

Primary: Average steady-state plasma concentration (Cavg) for POS

Primary: Average steady-state plasma concentration (Cavg) for POS

Primary: Time of maximum plasma concentration (Tmax) for POS

Primary: Time of maximum plasma concentration (Tmax) for POS

Primary: Total body clearance (CL) for POS administered by IV

Primary: Total body clearance (CL) for POS administered by IV

Primary: Apparent total body clearance (CL/F) for POS administered by PFS

Primary: Apparent total body clearance (CL/F) for POS administered by PFS

Secondary: Number of participants with an Adverse Event (AE)

Secondary: Number of participants with an Adverse Event (AE)

Secondary: Number of participants who discontinued treatment of study drug due to an Adverse Event (AE)

Secondary: Number of participants who discontinued treatment of study drug due to an Adverse Event (AE)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Study of the Safety, Tolerability, and Pharmacokinetics of Intravenous (IV) and Powder for Oral Suspension Formulations of Posaconazole (POS) in Immunocompromised Pediatric Subjects with Neutropenia