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Clinical Trial Results:
Phase 1B Study of the Safety, Tolerance, and Pharmacokinetics of Oral Posaconazole in Immunocompromised Children With Neutropenia

Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.

Summary
EudraCT number	2007-004645-15
Trial protocol	IT DE NL GR Outside EU/EEA
Global end of trial date	01 Apr 2015

Results information
Results version number	v1
This version publication date	29 Jan 2016
First version publication date	29 Jan 2016
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

MK-5592-032

ISRCTN number

US NCT number

NCT01716234

WHO universal trial number (UTN)

Other trial identifiers

Merck Protocol Code: P03579

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., +1 800-672-6372, ClinicalTrialsDisclosure@merck.com

Scientific contact

Clinical Trials Disclosure, Merck Sharp & Dohme Corp., +1 800-672-6372, 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

01 Apr 2015

Is this the analysis of the primary completion data?

Yes

Primary completion date

01 Apr 2015

Global end of trial reached?

Yes

Global end of trial date

01 Apr 2015

Was the trial ended prematurely?

Yes

Main objective of the trial

The purpose of this dose-escalation study was to evaluate the pharmacokinetics, safety, and tolerability of oral posaconazole (POS) in immunocompromised children with neutropenia or expected neutropenia.

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. The following additional measures defined for this individual study were in place for the protection of trial subjects: 1) for any subject who meets institutional criteria to start standard empirical or pre-emptive antifungal therapy or who has a proven breakthrough fungal infection, posaconazole will be discontinued and pre-emptive or empirical therapy with standard of care will be initiated, 2) study drug will not be administered to the higher dosage group in a given age group until after safety data obtained in at least 6 completed subjects in the lower dosage group in a corresponding age group are reviewed independently by the external Data Monitoring Committee and the Sponsor, and 3) the subjects in the youngest age group (3 months to <2 years of age) will not be enrolled until all safety and pharmacokinetics data obtained from the two older age groups in the first two dosage levels are reviewed independently by the Sponsor and external Data Monitoring Committee.

Background therapy

Evidence for comparator

Actual start date of recruitment

17 Apr 2008

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Canada: 22

Country: Number of subjects enrolled

Greece: 9

Country: Number of subjects enrolled

Netherlands: 15

Country: Number of subjects enrolled

United States: 52

Country: Number of subjects enrolled

Germany: 44

Worldwide total number of subjects

142

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

Within a given age group, escalation to the next higher dosage level will be permitted only after mutual agreement by the sponsor and the external Data Monitoring Committee.

Screening details

The study enrolled immunocompromised children with neutropenia or expected neutropenia aged 3 months to <18 years. A total of 160 participants were screened, 142 were randomized / enrolled, and 136 were treated. An arm aged 3 months to <2 years planned to receive posaconazole 18 mg/kg/day TID enrolled no participants.

Period 1 title

Treatment (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

POS 12 BID 2 to <7 Years

Arm description

Participants aged 2 to <7 years received posaconazole oral suspension 12 mg/kg/day divided into 2 doses (BID) until recovery from neutropenia or up to 28 days.

Arm type

Experimental

Investigational medicinal product name

Posaconazole

Investigational medicinal product code

Other name

MK-5592, SCH 56592, Noxafil®

Pharmaceutical forms

Oral suspension

Routes of administration

Oral use

Dosage and administration details

Posaconazole oral suspension 12 mg/kg/day divided into 2 doses (BID) (maximum 800 mg/day)

POS 12 BID 7 to <18 Years

Arm description

Participants aged 7 to <18 years received posaconazole oral suspension 12 mg/kg/day divided into 2 doses (BID) until recovery from neutropenia or up to 28 days.

Arm type

Experimental

Investigational medicinal product name

Posaconazole

Investigational medicinal product code

Other name

MK-5592, SCH 56592, Noxafil®

Pharmaceutical forms

Oral suspension

Routes of administration

Oral use

Dosage and administration details

Posaconazole oral suspension 12 mg/kg/day divided into 2 doses (BID) (maximum 800 mg/day)

POS 18 BID 2 to <7 Years

Arm description

Participants aged 2 to <7 years received posaconazole oral suspension 18 mg/kg/day divided into 2 doses (BID) until recovery from neutropenia or up to 28 days.

Arm type

Experimental

Investigational medicinal product name

Posaconazole

Investigational medicinal product code

Other name

MK-5592, SCH 56592, Noxafil®

Pharmaceutical forms

Oral suspension

Routes of administration

Oral use

Dosage and administration details

Posaconazole oral suspension 18 mg/kg/day divided into 2 doses (BID) (maximum 1200 mg/day)

POS 18 BID 7 to <18 Years

Arm description

Participants aged 7 to <18 years received posaconazole oral suspension 18 mg/kg/day divided into 2 doses (BID) until recovery from neutropenia or up to 28 days.

Arm type

Experimental

Investigational medicinal product name

Posaconazole

Investigational medicinal product code

Other name

MK-5592, SCH 56592, Noxafil®

Pharmaceutical forms

Oral suspension

Routes of administration

Oral use

Dosage and administration details

Posaconazole oral suspension 18 mg/kg/day divided into 2 doses (BID) (maximum 1200 mg/day)

POS 18 TID 2 to <7 Years

Arm description

Participants aged 2 to <7 years received posaconazole oral suspension 18 mg/kg/day divided into 3 doses (TID) until recovery from neutropenia or up to 28 days.

Arm type

Experimental

Investigational medicinal product name

Posaconazole

Investigational medicinal product code

Other name

MK-5592, SCH 56592, Noxafil®

Pharmaceutical forms

Oral suspension

Routes of administration

Oral use

Dosage and administration details

Posaconazole oral suspension 18 mg/kg/day divided into 3 doses (TID) (maximum 1200 mg/day)

POS 18 TID 7 to <18 Years

Arm description

Participants aged 7 to <18 years received posaconazole oral suspension 18 mg/kg/day divided into 3 doses (TID) until recovery from neutropenia or up to 28 days.

Arm type

Experimental

Investigational medicinal product name

Posaconazole

Investigational medicinal product code

Other name

MK-5592, SCH 56592, Noxafil®

Pharmaceutical forms

Oral suspension

Routes of administration

Oral use

Dosage and administration details

Posaconazole oral suspension 18 mg/kg/day divided into 3 doses (TID) (maximum 1200 mg/day)

POS 12 TID 3 months to <2 Years

Arm description

Participants aged 3 months to <2 years received posaconazole oral suspension 12 mg/kg/day divided into 3 doses (TID) until recovery from neutropenia or up to 28 days.

Arm type

Experimental

Investigational medicinal product name

Posaconazole

Investigational medicinal product code

Other name

MK-5592, SCH 56592, Noxafil®

Pharmaceutical forms

Oral suspension

Routes of administration

Oral use

Dosage and administration details

Posaconazole oral suspension 12 mg/kg/day divided into 3 doses (TID) (maximum 800 mg/day)

Number of subjects in period 1	POS 12 BID 2 to <7 Years	POS 12 BID 7 to <18 Years	POS 18 BID 2 to <7 Years	POS 18 BID 7 to <18 Years	POS 18 TID 2 to <7 Years	POS 18 TID 7 to <18 Years	POS 12 TID 3 months to <2 Years
Started	24	22	20	28	15	32	1
Treated	22	21	19	28	15	30	1
Completed	14	12	15	16	10	18	1
Not completed	10	10	5	12	5	14	0
Did not meet protocol eligibility	-	-	1	-	-	4	-
Consent withdrawn by subject	3	-	2	2	1	3	-
Adverse event, non-fatal	7	10	2	8	3	6	-
Protocol deviation	-	-	-	1	1	1	-
Lack of efficacy	-	-	-	1	-	-	-

Baseline characteristics

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Reporting group title

POS 12 BID 2 to <7 Years

Reporting group description

Participants aged 2 to <7 years received posaconazole oral suspension 12 mg/kg/day divided into 2 doses (BID) until recovery from neutropenia or up to 28 days.

Reporting group title

POS 12 BID 7 to <18 Years

Reporting group description

Participants aged 7 to <18 years received posaconazole oral suspension 12 mg/kg/day divided into 2 doses (BID) until recovery from neutropenia or up to 28 days.

Reporting group title

POS 18 BID 2 to <7 Years

Reporting group description

Participants aged 2 to <7 years received posaconazole oral suspension 18 mg/kg/day divided into 2 doses (BID) until recovery from neutropenia or up to 28 days.

Reporting group title

POS 18 BID 7 to <18 Years

Reporting group description

Participants aged 7 to <18 years received posaconazole oral suspension 18 mg/kg/day divided into 2 doses (BID) until recovery from neutropenia or up to 28 days.

Reporting group title

POS 18 TID 2 to <7 Years

Reporting group description

Participants aged 2 to <7 years received posaconazole oral suspension 18 mg/kg/day divided into 3 doses (TID) until recovery from neutropenia or up to 28 days.

Reporting group title

POS 18 TID 7 to <18 Years

Reporting group description

Participants aged 7 to <18 years received posaconazole oral suspension 18 mg/kg/day divided into 3 doses (TID) until recovery from neutropenia or up to 28 days.

Reporting group title

POS 12 TID 3 months to <2 Years

Reporting group description

Participants aged 3 months to <2 years received posaconazole oral suspension 12 mg/kg/day divided into 3 doses (TID) until recovery from neutropenia or up to 28 days.

Reporting group values	POS 12 BID 2 to <7 Years	POS 12 BID 7 to <18 Years	POS 18 BID 2 to <7 Years	POS 18 BID 7 to <18 Years	POS 18 TID 2 to <7 Years	POS 18 TID 7 to <18 Years	POS 12 TID 3 months to <2 Years	Total
Number of subjects	24	22	20	28	15	32	1	142
Age Categorical
Units: Subjects
Age Continuous
Units: years
arithmetic mean (standard deviation)	4 ± 1.3	11.9 ± 3.5	4.4 ± 1.5	12.2 ± 3.2	4.1 ± 1.3	13.1 ± 3	0.9 ± 0	-
Gender Categorical
Units: Subjects
Female	10	12	8	9	6	14	0	59
Male	14	10	12	19	9	18	1	83

End points

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Reporting group title

POS 12 BID 2 to <7 Years

Reporting group description

Participants aged 2 to <7 years received posaconazole oral suspension 12 mg/kg/day divided into 2 doses (BID) until recovery from neutropenia or up to 28 days.

Reporting group title

POS 12 BID 7 to <18 Years

Reporting group description

Participants aged 7 to <18 years received posaconazole oral suspension 12 mg/kg/day divided into 2 doses (BID) until recovery from neutropenia or up to 28 days.

Reporting group title

POS 18 BID 2 to <7 Years

Reporting group description

Participants aged 2 to <7 years received posaconazole oral suspension 18 mg/kg/day divided into 2 doses (BID) until recovery from neutropenia or up to 28 days.

Reporting group title

POS 18 BID 7 to <18 Years

Reporting group description

Participants aged 7 to <18 years received posaconazole oral suspension 18 mg/kg/day divided into 2 doses (BID) until recovery from neutropenia or up to 28 days.

Reporting group title

POS 18 TID 2 to <7 Years

Reporting group description

Participants aged 2 to <7 years received posaconazole oral suspension 18 mg/kg/day divided into 3 doses (TID) until recovery from neutropenia or up to 28 days.

Reporting group title

POS 18 TID 7 to <18 Years

Reporting group description

Participants aged 7 to <18 years received posaconazole oral suspension 18 mg/kg/day divided into 3 doses (TID) until recovery from neutropenia or up to 28 days.

Reporting group title

POS 12 TID 3 months to <2 Years

Reporting group description

Participants aged 3 months to <2 years received posaconazole oral suspension 12 mg/kg/day divided into 3 doses (TID) until recovery from neutropenia or up to 28 days.

Primary: Average Concentration of Posaconazole (Cavg) on Day 1 (Single Dose)

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End point title

Average Concentration of Posaconazole (Cavg) on Day 1 (Single Dose) ^[1]

End point description

Blood samples for determination of plasma posaconazole concentration were collected predose and approximately 3, 5, 8, and 12 hours after the first dose on Day 1. The 12-hour sample was not obtained for the TID dose groups. Day 1 pharmacokinetic samples were not collected for participants 3 months to <2 years of age weighing <6.5 kg. The pharmacokinetic evaluable population included all treated participants with evaluable samples applicable to the endpoint.

End point type

Primary

End point timeframe

Up to 12 hours after the first dose (BID dose groups) or up to 8 hours after the first dose (TID dose (TID dose groups)

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only summary statistics were planned for Average Concentration of Posaconazole (Cavg) on Day 1 (Single Dose), including means and standard deviations.

End point values	POS 12 BID 2 to <7 Years	POS 12 BID 7 to <18 Years	POS 18 BID 2 to <7 Years	POS 18 BID 7 to <18 Years	POS 18 TID 2 to <7 Years	POS 18 TID 7 to <18 Years	POS 12 TID 3 months to <2 Years
Number of subjects analysed	22	19	12	12	5	10	1
Units: ng/mL
arithmetic mean (standard deviation)	122 ± 101	107 ± 92.5	112 ± 86.9	113 ± 100	68.4 ± 40.4	57.9 ± 30.2	68.5 ± 0

No statistical analyses for this end point

Primary: Average Concentration of Posaconazole (Cavg) on Day 7 (Steady State)

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End point title

Average Concentration of Posaconazole (Cavg) on Day 7 (Steady State) ^[2]

End point description

Blood samples for determination of plasma posaconazole concentration were collected predose and approximately 3, 5, 8, and 12 hours after the first dose on Day 7 (steady state). The 12-hour sample was not obtained for the TID dose groups. The pharmacokinetic evaluable population included alltreated participants with evaluable samples applicable to the endpoint. The target Cavg range was 500to <2500 ng/mL.

End point type

Primary

End point timeframe

Up to 12 hours after the first dose on Day 7 (BID dose groups) or up to 8 hours after the first dose on Day 7 (TID dose groups)

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only summary statistics were planned for Average Concentration of Posaconazole (Cavg) on Day 7 (Steady State), including means and standard deviations.

End point values	POS 12 BID 2 to <7 Years	POS 12 BID 7 to <18 Years	POS 18 BID 2 to <7 Years	POS 18 BID 7 to <18 Years	POS 18 TID 2 to <7 Years	POS 18 TID 7 to <18 Years	POS 12 TID 3 months to <2 Years
Number of subjects analysed	16	14	12	12	5	10	1
Units: ng/mL
arithmetic mean (standard deviation)	604 ± 779	1050 ± 798	485 ± 306	1240 ± 1400	620 ± 411	1150 ± 750	453 ± 0

No statistical analyses for this end point

Secondary: Number of Participants with an Adverse Event

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End point title

Number of Participants with an Adverse Event

End point description

An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product, biologic (at any dose), or medical device, which does not necessarily have a causal relationship with the treatment. Adverse events may include the onset of new illness and the exacerbation of preexisting conditions. The population analyzed was all treated participants.

End point type

Secondary

End point timeframe

Up to Day 58

End point values	POS 12 BID 2 to <7 Years	POS 12 BID 7 to <18 Years	POS 18 BID 2 to <7 Years	POS 18 BID 7 to <18 Years	POS 18 TID 2 to <7 Years	POS 18 TID 7 to <18 Years	POS 12 TID 3 months to <2 Years
Number of subjects analysed	22	21	19	28	15	30	1
Units: Participants	21	21	16	26	13	30	1

No statistical analyses for this end point

Secondary: Number of Participants with an Adverse Event Leading to Study Drug Discontinuation

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End point title

Number of Participants with an Adverse Event Leading to Study Drug Discontinuation

End point description

End point type

Secondary

End point timeframe

Up to Day 28

End point values	POS 12 BID 2 to <7 Years	POS 12 BID 7 to <18 Years	POS 18 BID 2 to <7 Years	POS 18 BID 7 to <18 Years	POS 18 TID 2 to <7 Years	POS 18 TID 7 to <18 Years	POS 12 TID 3 months to <2 Years
Number of subjects analysed	22	21	19	28	15	30	1
Units: Participants	7	9	2	9	3	6	0

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

All AEs: from Day 1 up to Day 39; SAEs: up to Day 58

Adverse event reporting additional description

The population analyzed is all treated participants.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

18.0

Reporting group title

POS 12 BID 2 to <7 yrs

Reporting group description

Participants aged 2 to <7 years received posaconazole oral suspension 12 mg/kg/day divided into 2 doses (BID) until recovery from neutropenia or up to 28 days.

Reporting group title

POS 12 BID 7 to <18 yrs

Reporting group description

Participants aged 7 to <18 years received posaconazole oral suspension 12 mg/kg/day divided into 2 doses (BID) until recovery from neutropenia or up to 28 days.

Reporting group title

POS 18 BID 2 to <7 yrs

Reporting group description

Participants aged 2 to <7 years received posaconazole oral suspension 18 mg/kg/day divided into 2 doses (BID) until recovery from neutropenia or up to 28 days.

Reporting group title

POS 18 BID 7 to <18 yrs

Reporting group description

Participants aged 7 to <18 years received posaconazole oral suspension 18 mg/kg/day divided into 2 doses (BID) until recovery from neutropenia or up to 28 days.

Reporting group title

POS 18 TID 2 to <7 yrs

Reporting group description

Participants aged 2 to <7 years received posaconazole oral suspension 18 mg/kg/day divided into 3 doses (TID) until recovery from neutropenia or up to 28 days.

Reporting group title

POS 18 TID 7 to <18 yrs

Reporting group description

Participants aged 7 to <18 years received posaconazole oral suspension 18 mg/kg/day divided into 3 doses (TID) until recovery from neutropenia or up to 28 days.

Reporting group title

POS 12 TID 3 months to <2 yrs

Reporting group description

Participants aged 3 months to <2 years received posaconazole oral suspension 12 mg/kg/day divided into 3 doses (TID) until recovery from neutropenia or up to 28 days.

Serious adverse events	POS 12 BID 2 to <7 yrs	POS 12 BID 7 to <18 yrs	POS 18 BID 2 to <7 yrs	POS 18 BID 7 to <18 yrs	POS 18 TID 2 to <7 yrs	POS 18 TID 7 to <18 yrs	POS 12 TID 3 months to <2 yrs
Total subjects affected by serious adverse events
subjects affected / exposed	5 / 22 (22.73%)	3 / 21 (14.29%)	1 / 19 (5.26%)	7 / 28 (25.00%)	7 / 15 (46.67%)	11 / 30 (36.67%)	1 / 1 (100.00%)
number of deaths (all causes)	0	0	0	1	1	1	0
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Burkitt's Lymphoma Recurrent
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	0 / 15 (0.00%)	1 / 30 (3.33%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Vascular disorders
Hypotension
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	1 / 28 (3.57%)	0 / 15 (0.00%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Hypothermia
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	0 / 15 (0.00%)	1 / 30 (3.33%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mucosal Inflammation
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	1 / 28 (3.57%)	0 / 15 (0.00%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Multi-Organ Failure
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	1 / 28 (3.57%)	1 / 15 (6.67%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	1 / 22 (4.55%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	0 / 15 (0.00%)	1 / 30 (3.33%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Anaphylactic Reaction
subjects affected / exposed	0 / 22 (0.00%)	1 / 21 (4.76%)	0 / 19 (0.00%)	0 / 28 (0.00%)	0 / 15 (0.00%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Menorrhagia
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	0 / 15 (0.00%)	1 / 30 (3.33%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute Respiratory Distress Syndrome
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	1 / 28 (3.57%)	0 / 15 (0.00%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Epistaxis
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	0 / 15 (0.00%)	1 / 30 (3.33%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory Failure
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 19 (5.26%)	0 / 28 (0.00%)	0 / 15 (0.00%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Alanine Aminotransferase Increased
subjects affected / exposed	1 / 22 (4.55%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	0 / 15 (0.00%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aspartate Aminotransferase Increased
subjects affected / exposed	1 / 22 (4.55%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	0 / 15 (0.00%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chemotherapeutic Drug Level Increased
subjects affected / exposed	1 / 22 (4.55%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	0 / 15 (0.00%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Electrocardiogram T Wave Inversion
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	0 / 15 (0.00%)	1 / 30 (3.33%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Transaminases Increased
subjects affected / exposed	1 / 22 (4.55%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	0 / 15 (0.00%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Bradycardia
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	0 / 15 (0.00%)	1 / 30 (3.33%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Headache
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	0 / 15 (0.00%)	2 / 30 (6.67%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	0 / 22 (0.00%)	1 / 21 (4.76%)	0 / 19 (0.00%)	0 / 28 (0.00%)	0 / 15 (0.00%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 22 (4.55%)	1 / 21 (4.76%)	0 / 19 (0.00%)	0 / 28 (0.00%)	0 / 15 (0.00%)	1 / 30 (3.33%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Febrile Neutropenia
subjects affected / exposed	1 / 22 (4.55%)	0 / 21 (0.00%)	0 / 19 (0.00%)	3 / 28 (10.71%)	5 / 15 (33.33%)	5 / 30 (16.67%)	1 / 1 (100.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 3	0 / 7	0 / 5	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	0 / 15 (0.00%)	1 / 30 (3.33%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	1 / 28 (3.57%)	0 / 15 (0.00%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Nausea
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	0 / 15 (0.00%)	1 / 30 (3.33%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Hepatic Haemorrhage
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	1 / 15 (6.67%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic Vein Occlusion
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	1 / 28 (3.57%)	0 / 15 (0.00%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary Disease
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 19 (5.26%)	0 / 28 (0.00%)	0 / 15 (0.00%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Venoocclusive Liver Disease
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 19 (5.26%)	0 / 28 (0.00%)	0 / 15 (0.00%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Skin Lesion
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	0 / 15 (0.00%)	1 / 30 (3.33%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute Kidney Injury
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	1 / 28 (3.57%)	0 / 15 (0.00%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal Failure
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 19 (5.26%)	0 / 28 (0.00%)	0 / 15 (0.00%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Catheter Site Cellulitis
subjects affected / exposed	1 / 22 (4.55%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	0 / 15 (0.00%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia Klebsiella
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	1 / 28 (3.57%)	0 / 15 (0.00%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Puncture Site Infection
subjects affected / exposed	1 / 22 (4.55%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	0 / 15 (0.00%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	1 / 28 (3.57%)	0 / 15 (0.00%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Streptococcal Bacteraemia
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	1 / 15 (6.67%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	POS 12 BID 2 to <7 yrs	POS 12 BID 7 to <18 yrs	POS 18 BID 2 to <7 yrs	POS 18 BID 7 to <18 yrs	POS 18 TID 2 to <7 yrs	POS 18 TID 7 to <18 yrs	POS 12 TID 3 months to <2 yrs
Total subjects affected by non serious adverse events
subjects affected / exposed	21 / 22 (95.45%)	20 / 21 (95.24%)	16 / 19 (84.21%)	26 / 28 (92.86%)	13 / 15 (86.67%)	28 / 30 (93.33%)	1 / 1 (100.00%)
Vascular disorders
Flushing
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	1 / 15 (6.67%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Hypertension
subjects affected / exposed	4 / 22 (18.18%)	1 / 21 (4.76%)	1 / 19 (5.26%)	3 / 28 (10.71%)	2 / 15 (13.33%)	2 / 30 (6.67%)	0 / 1 (0.00%)
occurrences all number	5	1	1	3	3	2	0
Hypotension
subjects affected / exposed	1 / 22 (4.55%)	3 / 21 (14.29%)	0 / 19 (0.00%)	3 / 28 (10.71%)	2 / 15 (13.33%)	2 / 30 (6.67%)	0 / 1 (0.00%)
occurrences all number	1	3	0	3	2	2	0
Pallor
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 19 (5.26%)	0 / 28 (0.00%)	0 / 15 (0.00%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Venoocclusive Disease
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	1 / 15 (6.67%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Surgical and medical procedures
Central Venous Catheter Removal
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	1 / 15 (6.67%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Central Venous Catheterisation
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	1 / 15 (6.67%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0	0
General disorders and administration site conditions
Catheter Site Erythema
subjects affected / exposed	2 / 22 (9.09%)	1 / 21 (4.76%)	0 / 19 (0.00%)	1 / 28 (3.57%)	0 / 15 (0.00%)	1 / 30 (3.33%)	0 / 1 (0.00%)
occurrences all number	2	1	0	1	0	1	0
Catheter Site Pruritus
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	0 / 15 (0.00%)	2 / 30 (6.67%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	2	0
Chills
subjects affected / exposed	1 / 22 (4.55%)	1 / 21 (4.76%)	0 / 19 (0.00%)	1 / 28 (3.57%)	0 / 15 (0.00%)	3 / 30 (10.00%)	0 / 1 (0.00%)
occurrences all number	1	1	0	1	0	3	0
Device Occlusion
subjects affected / exposed	0 / 22 (0.00%)	1 / 21 (4.76%)	0 / 19 (0.00%)	2 / 28 (7.14%)	0 / 15 (0.00%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	3	0	0	0
Fatigue
subjects affected / exposed	1 / 22 (4.55%)	0 / 21 (0.00%)	0 / 19 (0.00%)	3 / 28 (10.71%)	0 / 15 (0.00%)	6 / 30 (20.00%)	0 / 1 (0.00%)
occurrences all number	1	0	0	3	0	7	0
Local Swelling
subjects affected / exposed	1 / 22 (4.55%)	0 / 21 (0.00%)	1 / 19 (5.26%)	0 / 28 (0.00%)	0 / 15 (0.00%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	1	0	0	0	0
Mucosal Inflammation
subjects affected / exposed	9 / 22 (40.91%)	3 / 21 (14.29%)	2 / 19 (10.53%)	7 / 28 (25.00%)	1 / 15 (6.67%)	4 / 30 (13.33%)	0 / 1 (0.00%)
occurrences all number	9	3	5	7	1	4	0
Oedema
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	2 / 28 (7.14%)	0 / 15 (0.00%)	1 / 30 (3.33%)	0 / 1 (0.00%)
occurrences all number	0	0	0	2	0	1	0
Oedema Peripheral
subjects affected / exposed	1 / 22 (4.55%)	0 / 21 (0.00%)	1 / 19 (5.26%)	1 / 28 (3.57%)	0 / 15 (0.00%)	1 / 30 (3.33%)	0 / 1 (0.00%)
occurrences all number	1	0	1	1	0	1	0
Pain
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	2 / 19 (10.53%)	1 / 28 (3.57%)	0 / 15 (0.00%)	1 / 30 (3.33%)	0 / 1 (0.00%)
occurrences all number	0	0	3	1	0	1	0
Pyrexia
subjects affected / exposed	13 / 22 (59.09%)	8 / 21 (38.10%)	3 / 19 (15.79%)	8 / 28 (28.57%)	2 / 15 (13.33%)	6 / 30 (20.00%)	0 / 1 (0.00%)
occurrences all number	14	9	3	10	4	7	0
Vessel Puncture Site Pain
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	1 / 15 (6.67%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Immune system disorders
Engraftment Syndrome
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	1 / 15 (6.67%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Graft Versus Host Disease In* Skin
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	1 / 15 (6.67%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Reproductive system and breast disorders
Genital Pain
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	1 / 15 (6.67%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Genital Rash
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	1 / 15 (6.67%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Genital Ulceration
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 19 (5.26%)	0 / 28 (0.00%)	0 / 15 (0.00%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Penile Oedema
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 19 (5.26%)	0 / 28 (0.00%)	0 / 15 (0.00%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Pruritus Genital
subjects affected / exposed	2 / 22 (9.09%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	0 / 15 (0.00%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	2	0	0	0	0	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	2 / 22 (9.09%)	3 / 21 (14.29%)	3 / 19 (15.79%)	1 / 28 (3.57%)	2 / 15 (13.33%)	2 / 30 (6.67%)	0 / 1 (0.00%)
occurrences all number	2	3	3	1	2	2	0
Epistaxis
subjects affected / exposed	1 / 22 (4.55%)	1 / 21 (4.76%)	0 / 19 (0.00%)	2 / 28 (7.14%)	1 / 15 (6.67%)	3 / 30 (10.00%)	0 / 1 (0.00%)
occurrences all number	1	1	0	3	1	4	0
Hypoxia
subjects affected / exposed	1 / 22 (4.55%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	1 / 15 (6.67%)	1 / 30 (3.33%)	0 / 1 (0.00%)
occurrences all number	1	0	0	0	1	1	0
Nasal Congestion
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 19 (5.26%)	0 / 28 (0.00%)	0 / 15 (0.00%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Oropharyngeal Pain
subjects affected / exposed	1 / 22 (4.55%)	0 / 21 (0.00%)	1 / 19 (5.26%)	2 / 28 (7.14%)	1 / 15 (6.67%)	4 / 30 (13.33%)	0 / 1 (0.00%)
occurrences all number	2	0	1	2	1	4	0
Pleural Effusion
subjects affected / exposed	0 / 22 (0.00%)	1 / 21 (4.76%)	1 / 19 (5.26%)	0 / 28 (0.00%)	0 / 15 (0.00%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	1	0	0	0	0
Tachypnoea
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	2 / 28 (7.14%)	1 / 15 (6.67%)	1 / 30 (3.33%)	0 / 1 (0.00%)
occurrences all number	0	0	0	2	1	1	0
Psychiatric disorders
Abnormal Behaviour
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	1 / 15 (6.67%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Agitation
subjects affected / exposed	1 / 22 (4.55%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	1 / 15 (6.67%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	0	0	1	0	0
Hallucination
subjects affected / exposed	1 / 22 (4.55%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	1 / 15 (6.67%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	0	0	1	0	0
Insomnia
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	1 / 15 (6.67%)	1 / 30 (3.33%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	1	0
Investigations
Alanine Aminotransferase Increased
subjects affected / exposed	1 / 22 (4.55%)	1 / 21 (4.76%)	1 / 19 (5.26%)	3 / 28 (10.71%)	2 / 15 (13.33%)	2 / 30 (6.67%)	0 / 1 (0.00%)
occurrences all number	1	1	1	3	5	2	0
Aspartate Aminotransferase Increased
subjects affected / exposed	0 / 22 (0.00%)	1 / 21 (4.76%)	1 / 19 (5.26%)	1 / 28 (3.57%)	2 / 15 (13.33%)	1 / 30 (3.33%)	0 / 1 (0.00%)
occurrences all number	0	1	1	1	5	1	0
Biopsy Skin
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	1 / 15 (6.67%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Blood Bilirubin Increased
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	1 / 15 (6.67%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	4	0	0
Blood Glucose Increased
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 19 (5.26%)	0 / 28 (0.00%)	0 / 15 (0.00%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Electrocardiogram Qt Prolonged
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 19 (5.26%)	2 / 28 (7.14%)	1 / 15 (6.67%)	2 / 30 (6.67%)	0 / 1 (0.00%)
occurrences all number	0	0	1	2	1	3	0
Fluid Balance Positive
subjects affected / exposed	1 / 22 (4.55%)	3 / 21 (14.29%)	0 / 19 (0.00%)	1 / 28 (3.57%)	0 / 15 (0.00%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	5	0	1	0	0	0
Gamma-Glutamyltransferase Increased
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 19 (5.26%)	1 / 28 (3.57%)	0 / 15 (0.00%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	1	0	0	0
International Normalised Ratio Decreased
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	1 / 15 (6.67%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Lymphocyte Count Decreased
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	0 / 15 (0.00%)	2 / 30 (6.67%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	5	0
Neutrophil Count Decreased
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 19 (5.26%)	1 / 28 (3.57%)	1 / 15 (6.67%)	2 / 30 (6.67%)	0 / 1 (0.00%)
occurrences all number	0	0	2	1	3	4	0
Platelet Count Decreased
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	2 / 19 (10.53%)	1 / 28 (3.57%)	2 / 15 (13.33%)	4 / 30 (13.33%)	0 / 1 (0.00%)
occurrences all number	0	0	11	1	5	11	0
Transaminases Increased
subjects affected / exposed	2 / 22 (9.09%)	1 / 21 (4.76%)	0 / 19 (0.00%)	0 / 28 (0.00%)	0 / 15 (0.00%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	2	1	0	0	0	0	0
Weight Increased
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 19 (5.26%)	0 / 28 (0.00%)	0 / 15 (0.00%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	0	0	0
White Blood Cell Count Decreased
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 19 (5.26%)	0 / 28 (0.00%)	1 / 15 (6.67%)	3 / 30 (10.00%)	0 / 1 (0.00%)
occurrences all number	0	0	3	0	3	4	0
Injury, poisoning and procedural complications
Allergic Transfusion Reaction
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 19 (5.26%)	2 / 28 (7.14%)	0 / 15 (0.00%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	2	0	0	0
Contusion
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 19 (5.26%)	0 / 28 (0.00%)	0 / 15 (0.00%)	1 / 30 (3.33%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	0	2	0
Fall
subjects affected / exposed	1 / 22 (4.55%)	0 / 21 (0.00%)	1 / 19 (5.26%)	0 / 28 (0.00%)	0 / 15 (0.00%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	1	0	0	0	0
Infusion Related Reaction
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	1 / 15 (6.67%)	1 / 30 (3.33%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	1	0
Procedural Headache
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	1 / 15 (6.67%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Skin Abrasion
subjects affected / exposed	1 / 22 (4.55%)	0 / 21 (0.00%)	1 / 19 (5.26%)	0 / 28 (0.00%)	0 / 15 (0.00%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	1	0	0	0	0
Transfusion Reaction
subjects affected / exposed	1 / 22 (4.55%)	1 / 21 (4.76%)	0 / 19 (0.00%)	2 / 28 (7.14%)	0 / 15 (0.00%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	1	0	2	0	0	0
Congenital, familial and genetic disorders
Antithrombin Iii Deficiency
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	1 / 15 (6.67%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Cardiac disorders
Bradycardia
subjects affected / exposed	0 / 22 (0.00%)	1 / 21 (4.76%)	0 / 19 (0.00%)	0 / 28 (0.00%)	1 / 15 (6.67%)	1 / 30 (3.33%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0	1	1	0
Sinus Tachycardia
subjects affected / exposed	1 / 22 (4.55%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	2 / 15 (13.33%)	1 / 30 (3.33%)	0 / 1 (0.00%)
occurrences all number	1	0	0	0	2	2	0
Tachycardia
subjects affected / exposed	3 / 22 (13.64%)	2 / 21 (9.52%)	1 / 19 (5.26%)	2 / 28 (7.14%)	1 / 15 (6.67%)	3 / 30 (10.00%)	0 / 1 (0.00%)
occurrences all number	3	2	1	2	1	4	0
Nervous system disorders
Dizziness
subjects affected / exposed	0 / 22 (0.00%)	2 / 21 (9.52%)	0 / 19 (0.00%)	1 / 28 (3.57%)	0 / 15 (0.00%)	4 / 30 (13.33%)	0 / 1 (0.00%)
occurrences all number	0	2	0	1	0	4	0
Dysgeusia
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	0 / 15 (0.00%)	2 / 30 (6.67%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	2	0
Headache
subjects affected / exposed	1 / 22 (4.55%)	2 / 21 (9.52%)	1 / 19 (5.26%)	8 / 28 (28.57%)	1 / 15 (6.67%)	3 / 30 (10.00%)	0 / 1 (0.00%)
occurrences all number	1	2	1	10	1	3	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	4 / 22 (18.18%)	2 / 21 (9.52%)	3 / 19 (15.79%)	8 / 28 (28.57%)	3 / 15 (20.00%)	6 / 30 (20.00%)	0 / 1 (0.00%)
occurrences all number	6	3	6	12	11	12	0
Coagulopathy
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	2 / 28 (7.14%)	0 / 15 (0.00%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	2	0	0	0
Febrile Neutropenia
subjects affected / exposed	1 / 22 (4.55%)	4 / 21 (19.05%)	0 / 19 (0.00%)	4 / 28 (14.29%)	4 / 15 (26.67%)	5 / 30 (16.67%)	0 / 1 (0.00%)
occurrences all number	1	4	0	4	5	5	0
Leukopenia
subjects affected / exposed	5 / 22 (22.73%)	0 / 21 (0.00%)	0 / 19 (0.00%)	1 / 28 (3.57%)	0 / 15 (0.00%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	5	0	0	1	0	0	0
Lymphopenia
subjects affected / exposed	2 / 22 (9.09%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	0 / 15 (0.00%)	1 / 30 (3.33%)	0 / 1 (0.00%)
occurrences all number	2	0	0	0	0	1	0
Neutropenia
subjects affected / exposed	3 / 22 (13.64%)	0 / 21 (0.00%)	1 / 19 (5.26%)	2 / 28 (7.14%)	1 / 15 (6.67%)	2 / 30 (6.67%)	0 / 1 (0.00%)
occurrences all number	3	0	1	2	1	2	0
Thrombocytopenia
subjects affected / exposed	8 / 22 (36.36%)	7 / 21 (33.33%)	3 / 19 (15.79%)	6 / 28 (21.43%)	1 / 15 (6.67%)	5 / 30 (16.67%)	0 / 1 (0.00%)
occurrences all number	19	15	10	22	2	8	0
Ear and labyrinth disorders
Ear Pain
subjects affected / exposed	1 / 22 (4.55%)	1 / 21 (4.76%)	0 / 19 (0.00%)	0 / 28 (0.00%)	1 / 15 (6.67%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	1	0	0	1	0	0
Eye disorders
Conjunctival Hyperaemia
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	1 / 15 (6.67%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Dry Eye
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 19 (5.26%)	0 / 28 (0.00%)	0 / 15 (0.00%)	2 / 30 (6.67%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	0	2	0
Eye Movement Disorder
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	1 / 15 (6.67%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Eye Pruritus
subjects affected / exposed	1 / 22 (4.55%)	0 / 21 (0.00%)	2 / 19 (10.53%)	0 / 28 (0.00%)	0 / 15 (0.00%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	2	0	0	0	0
Eye Swelling
subjects affected / exposed	1 / 22 (4.55%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	1 / 15 (6.67%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	0	0	1	0	0
Eyelid Oedema
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	1 / 15 (6.67%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Photophobia
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 19 (5.26%)	0 / 28 (0.00%)	0 / 15 (0.00%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Gastrointestinal disorders
Abdominal Distension
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 19 (5.26%)	0 / 28 (0.00%)	0 / 15 (0.00%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Abdominal Pain
subjects affected / exposed	7 / 22 (31.82%)	6 / 21 (28.57%)	1 / 19 (5.26%)	2 / 28 (7.14%)	3 / 15 (20.00%)	4 / 30 (13.33%)	0 / 1 (0.00%)
occurrences all number	7	7	1	2	3	5	0
Abdominal Pain Upper
subjects affected / exposed	2 / 22 (9.09%)	0 / 21 (0.00%)	1 / 19 (5.26%)	1 / 28 (3.57%)	0 / 15 (0.00%)	2 / 30 (6.67%)	0 / 1 (0.00%)
occurrences all number	2	0	1	1	0	2	0
Ascites
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	1 / 15 (6.67%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	2	0	0
Constipation
subjects affected / exposed	0 / 22 (0.00%)	4 / 21 (19.05%)	1 / 19 (5.26%)	1 / 28 (3.57%)	1 / 15 (6.67%)	4 / 30 (13.33%)	0 / 1 (0.00%)
occurrences all number	0	4	1	1	1	5	0
Diarrhoea
subjects affected / exposed	5 / 22 (22.73%)	3 / 21 (14.29%)	3 / 19 (15.79%)	7 / 28 (25.00%)	3 / 15 (20.00%)	5 / 30 (16.67%)	0 / 1 (0.00%)
occurrences all number	5	3	5	7	7	5	0
Dyspepsia
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	0 / 15 (0.00%)	2 / 30 (6.67%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	2	0
Enteritis
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 19 (5.26%)	0 / 28 (0.00%)	0 / 15 (0.00%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Frequent Bowel Movements
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 19 (5.26%)	0 / 28 (0.00%)	1 / 15 (6.67%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	1	0	0
Gingival Pain
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	1 / 15 (6.67%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Lip Dry
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 19 (5.26%)	0 / 28 (0.00%)	0 / 15 (0.00%)	3 / 30 (10.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	0	3	0
Loose Tooth
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	1 / 15 (6.67%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Nausea
subjects affected / exposed	5 / 22 (22.73%)	3 / 21 (14.29%)	2 / 19 (10.53%)	9 / 28 (32.14%)	3 / 15 (20.00%)	13 / 30 (43.33%)	0 / 1 (0.00%)
occurrences all number	8	3	5	9	3	21	0
Oral Pain
subjects affected / exposed	0 / 22 (0.00%)	2 / 21 (9.52%)	0 / 19 (0.00%)	0 / 28 (0.00%)	0 / 15 (0.00%)	1 / 30 (3.33%)	0 / 1 (0.00%)
occurrences all number	0	2	0	0	0	2	0
Proctalgia
subjects affected / exposed	1 / 22 (4.55%)	0 / 21 (0.00%)	1 / 19 (5.26%)	0 / 28 (0.00%)	0 / 15 (0.00%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	1	0	0	0	0
Proctitis
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	1 / 15 (6.67%)	1 / 30 (3.33%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	1	0
Retching
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	1 / 15 (6.67%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Stomatitis
subjects affected / exposed	3 / 22 (13.64%)	0 / 21 (0.00%)	2 / 19 (10.53%)	4 / 28 (14.29%)	5 / 15 (33.33%)	6 / 30 (20.00%)	0 / 1 (0.00%)
occurrences all number	4	0	2	5	9	8	0
Tongue Coated
subjects affected / exposed	1 / 22 (4.55%)	1 / 21 (4.76%)	0 / 19 (0.00%)	0 / 28 (0.00%)	1 / 15 (6.67%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	1	0	0	1	0	0
Vomiting
subjects affected / exposed	8 / 22 (36.36%)	3 / 21 (14.29%)	5 / 19 (26.32%)	11 / 28 (39.29%)	7 / 15 (46.67%)	9 / 30 (30.00%)	0 / 1 (0.00%)
occurrences all number	13	5	6	14	11	14	0
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 19 (5.26%)	0 / 28 (0.00%)	1 / 15 (6.67%)	1 / 30 (3.33%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	1	1	0
Dermatitis
subjects affected / exposed	1 / 22 (4.55%)	0 / 21 (0.00%)	1 / 19 (5.26%)	1 / 28 (3.57%)	2 / 15 (13.33%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	3	1	2	0	0
Dermatitis Diaper
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 19 (5.26%)	0 / 28 (0.00%)	0 / 15 (0.00%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Ecchymosis
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	1 / 15 (6.67%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	2	0	0
Erythema
subjects affected / exposed	2 / 22 (9.09%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	1 / 15 (6.67%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	2	0	0	0	2	0	0
Petechiae
subjects affected / exposed	2 / 22 (9.09%)	2 / 21 (9.52%)	2 / 19 (10.53%)	0 / 28 (0.00%)	0 / 15 (0.00%)	2 / 30 (6.67%)	0 / 1 (0.00%)
occurrences all number	2	2	2	0	0	2	0
Pruritus
subjects affected / exposed	3 / 22 (13.64%)	5 / 21 (23.81%)	1 / 19 (5.26%)	3 / 28 (10.71%)	2 / 15 (13.33%)	3 / 30 (10.00%)	0 / 1 (0.00%)
occurrences all number	3	5	1	5	5	3	0
Rash
subjects affected / exposed	4 / 22 (18.18%)	1 / 21 (4.76%)	2 / 19 (10.53%)	4 / 28 (14.29%)	2 / 15 (13.33%)	5 / 30 (16.67%)	0 / 1 (0.00%)
occurrences all number	4	1	3	5	2	5	0
Red Man Syndrome
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	1 / 28 (3.57%)	1 / 15 (6.67%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	1	1	0	0
Renal and urinary disorders
Dysuria
subjects affected / exposed	0 / 22 (0.00%)	1 / 21 (4.76%)	0 / 19 (0.00%)	0 / 28 (0.00%)	1 / 15 (6.67%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	2	0	0	1	0	0
Proteinuria
subjects affected / exposed	1 / 22 (4.55%)	2 / 21 (9.52%)	0 / 19 (0.00%)	0 / 28 (0.00%)	0 / 15 (0.00%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	2	0	0	0	0	0
Musculoskeletal and connective tissue disorders
Back Pain
subjects affected / exposed	1 / 22 (4.55%)	2 / 21 (9.52%)	1 / 19 (5.26%)	1 / 28 (3.57%)	0 / 15 (0.00%)	1 / 30 (3.33%)	0 / 1 (0.00%)
occurrences all number	1	2	1	1	0	1	0
Bone Pain
subjects affected / exposed	1 / 22 (4.55%)	0 / 21 (0.00%)	0 / 19 (0.00%)	1 / 28 (3.57%)	0 / 15 (0.00%)	2 / 30 (6.67%)	0 / 1 (0.00%)
occurrences all number	1	0	0	1	0	2	0
Pain In Extremity
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 19 (5.26%)	0 / 28 (0.00%)	2 / 15 (13.33%)	3 / 30 (10.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	2	4	0
Infections and infestations
Alpha Haemolytic Streptococcal* Infection
subjects affected / exposed	0 / 22 (0.00%)	2 / 21 (9.52%)	0 / 19 (0.00%)	0 / 28 (0.00%)	0 / 15 (0.00%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	2	0	0	0	0	0
Bacteraemia
subjects affected / exposed	0 / 22 (0.00%)	1 / 21 (4.76%)	0 / 19 (0.00%)	1 / 28 (3.57%)	1 / 15 (6.67%)	1 / 30 (3.33%)	0 / 1 (0.00%)
occurrences all number	0	1	0	1	1	1	0
Cellulitis
subjects affected / exposed	1 / 22 (4.55%)	0 / 21 (0.00%)	1 / 19 (5.26%)	0 / 28 (0.00%)	0 / 15 (0.00%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	1	0	0	0	0
Clostridium Difficile Infection
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 19 (5.26%)	0 / 28 (0.00%)	0 / 15 (0.00%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Cystitis
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 19 (5.26%)	0 / 28 (0.00%)	0 / 15 (0.00%)	1 / 30 (3.33%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	0	1	0
Gingivitis
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	2 / 15 (13.33%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	2	0	0
Infection
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	1 / 15 (6.67%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Pseudomonal Bacteraemia
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	1 / 15 (6.67%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Respiratory Tract Infection
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	0 / 15 (0.00%)	0 / 30 (0.00%)	1 / 1 (100.00%)
occurrences all number	0	0	0	0	0	0	1
Rhinitis
subjects affected / exposed	1 / 22 (4.55%)	0 / 21 (0.00%)	2 / 19 (10.53%)	0 / 28 (0.00%)	0 / 15 (0.00%)	1 / 30 (3.33%)	0 / 1 (0.00%)
occurrences all number	1	0	3	0	0	1	0
Sinusitis
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 19 (5.26%)	0 / 28 (0.00%)	0 / 15 (0.00%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Streptococcal Infection
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 19 (5.26%)	1 / 28 (3.57%)	0 / 15 (0.00%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	1	0	0	0
Viraemia
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 19 (5.26%)	0 / 28 (0.00%)	0 / 15 (0.00%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Viral Infection
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	1 / 15 (6.67%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Vulvitis
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	1 / 15 (6.67%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Metabolism and nutrition disorders
Decreased Appetite
subjects affected / exposed	1 / 22 (4.55%)	0 / 21 (0.00%)	0 / 19 (0.00%)	1 / 28 (3.57%)	3 / 15 (20.00%)	8 / 30 (26.67%)	0 / 1 (0.00%)
occurrences all number	1	0	0	1	3	9	0
Fluid Overload
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	1 / 15 (6.67%)	2 / 30 (6.67%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	2	0
Hyperalbuminaemia
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	1 / 15 (6.67%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	2	0	0
Hyperglycaemia
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	1 / 28 (3.57%)	2 / 15 (13.33%)	3 / 30 (10.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	1	4	3	0
Hypertriglyceridaemia
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	1 / 28 (3.57%)	1 / 15 (6.67%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	1	2	0	0
Hypoalbuminaemia
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	2 / 15 (13.33%)	1 / 30 (3.33%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	4	1	0
Hypocalcaemia
subjects affected / exposed	0 / 22 (0.00%)	1 / 21 (4.76%)	0 / 19 (0.00%)	1 / 28 (3.57%)	1 / 15 (6.67%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	2	0	1	3	0	0
Hypoglycaemia
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 28 (0.00%)	1 / 15 (6.67%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Hypokalaemia
subjects affected / exposed	2 / 22 (9.09%)	3 / 21 (14.29%)	1 / 19 (5.26%)	1 / 28 (3.57%)	4 / 15 (26.67%)	2 / 30 (6.67%)	0 / 1 (0.00%)
occurrences all number	2	6	1	2	6	3	0
Hypomagnesaemia
subjects affected / exposed	1 / 22 (4.55%)	4 / 21 (19.05%)	0 / 19 (0.00%)	1 / 28 (3.57%)	0 / 15 (0.00%)	2 / 30 (6.67%)	0 / 1 (0.00%)
occurrences all number	1	4	0	2	0	3	0
Hyponatraemia
subjects affected / exposed	0 / 22 (0.00%)	1 / 21 (4.76%)	0 / 19 (0.00%)	0 / 28 (0.00%)	1 / 15 (6.67%)	1 / 30 (3.33%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0	1	1	0
Hypophosphataemia
subjects affected / exposed	2 / 22 (9.09%)	2 / 21 (9.52%)	0 / 19 (0.00%)	1 / 28 (3.57%)	2 / 15 (13.33%)	0 / 30 (0.00%)	0 / 1 (0.00%)
occurrences all number	2	2	0	1	3	0	0

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Were there any global substantial amendments to the protocol? Yes

23 Jan 2008

Protocol Amendment 1: this amendment documented a switch from central safety lab collection to local safety lab collection, which addressed concerns raised regarding the volume of blood collection.

17 Nov 2008

Protocol Amendment 2: This amendment made the following significant changes to the trial design: 1) clarification of the exclusion criteria related to the prohibited medications, 2) protocol has changed in order to reflect potential discontinuation in cases of any related Grade 3 or Grade 4 adverse events, 3) change in the prohibited medications section.

13 Oct 2010

Protocol Amendment 3: This amendment made the following significant change to the trial design: the following addition was made to the list of clinical situations applicable to inclusion criterion #3: Recipients of allogeneic hematopoietic stem cell transplantation during the pre-engraftment period (neutropenia period).

17 Apr 2013

Protocol Amendment 4: Several key changes were made based on a review of the available clinical pharmacokinetics and safety pediatric data from this ongoing study: 1) enrollment in Age Group 1 Dose Group 2 (7 to <18 years receiving 18 mg/kg/day divided BID) was stopped early, 2) the dosing schedule for Age Group 3 Dose Group 1 (3 months to <2 years) was changed to 12 mg/kg/day divided TID, 3) the dosing schedule for Age Group 3 Dose Group 2 was changed to 18 mg/kg/day divided TID, 4) for Age Group 3 (3 months to <7 years), Dose Group 3 was removed, and 5) an additional pharmacokinetic and safety analysis was added for all available TID data across age groups.

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.

Study was terminated early (10 July 2015) based on preliminary analysis of pharmacokinetic data. Only 1 participant was enrolled in the POS 12 TID 3 months to <2 years group, limiting conclusions that may be drawn for pharmacokinetics or safety.

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Clinical trials

Clinical Trial Results:
Phase 1B Study of the Safety, Tolerance, and Pharmacokinetics of Oral Posaconazole in Immunocompromised Children With Neutropenia

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Trial information

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Subject disposition

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Baseline characteristics

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End points

Primary: Average Concentration of Posaconazole (Cavg) on Day 1 (Single Dose)

Primary: Average Concentration of Posaconazole (Cavg) on Day 1 (Single Dose)

Primary: Average Concentration of Posaconazole (Cavg) on Day 7 (Steady State)

Primary: Average Concentration of Posaconazole (Cavg) on Day 7 (Steady State)

Secondary: Number of Participants with an Adverse Event

Secondary: Number of Participants with an Adverse Event

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Secondary: Number of Participants with an Adverse Event Leading to Study Drug Discontinuation

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Clinical trials

Clinical Trial Results: Phase 1B Study of the Safety, Tolerance, and Pharmacokinetics of Oral Posaconazole in Immunocompromised Children With Neutropenia

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Average Concentration of Posaconazole (Cavg) on Day 1 (Single Dose)

Primary: Average Concentration of Posaconazole (Cavg) on Day 1 (Single Dose)

Primary: Average Concentration of Posaconazole (Cavg) on Day 7 (Steady State)

Primary: Average Concentration of Posaconazole (Cavg) on Day 7 (Steady State)

Secondary: Number of Participants with an Adverse Event

Secondary: Number of Participants with an Adverse Event

Secondary: Number of Participants with an Adverse Event Leading to Study Drug Discontinuation

Secondary: Number of Participants with an Adverse Event Leading to Study Drug Discontinuation

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
Phase 1B Study of the Safety, Tolerance, and Pharmacokinetics of Oral Posaconazole in Immunocompromised Children With Neutropenia