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Clinical Trial Results:
An open-label, intravenous to oral switch, multiple dose, multi-centre study to investigate the pharmacokinetics, safety and tolerability of Voriconazole in hospitalized children aged 2 to <12 years who require treatment for the prevention of systemic fungal infection

Summary
EudraCT number	2014-004184-21
Trial protocol	Outside EU/EEA
Global end of trial date	30 Jun 2004

Results information
Results version number	v1(current)
This version publication date	13 Jun 2016
First version publication date	29 Jul 2015
Other versions

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

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Trial information

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Sponsor protocol code

A1501037

ISRCTN number

US NCT number

NCT00174473

WHO universal trial number (UTN)

Sponsor organisation name

Pfizer Inc.

Sponsor organisation address

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

Public contact

ClinicalTrials.gov Call Center, Pfizer Inc. , 001 8007181021, ClinicalTrials.govCallCenter@pfizer.com

Scientific contact

ClinicalTrials.gov Call Center, Pfizer Inc. , 001 8007181021, ClinicalTrials.govCallCenter@pfizer.com

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

Yes

EMA paediatric investigation plan number(s)

EMEA-000191-PIP01-08

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

Yes

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

Analysis stage

Final

Date of interim/final analysis

29 Oct 2004

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

30 Jun 2004

Was the trial ended prematurely?

Main objective of the trial

To investigate the pharmacokinetics of voriconazole following intravenous to oral switch in children aged 2 to less than (<) 12 years.

Protection of trial subjects

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

Background therapy

Evidence for comparator

Actual start date of recruitment

11 Jun 2003

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

1 Months

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Germany: 10

Country: Number of subjects enrolled

United States: 32

Country: Number of subjects enrolled

United Kingdom: 6

Worldwide total number of subjects

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

The study was conducted in 3 countries and total 48 subjects were assigned to receive treatment. The study was started on 11 June 2003 and completed on 30 June 2004.

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

Cohort I: Voriconazole 4mg/kg Intravenous

Arm description

Voriconazole 4 milligram per kilogram (mg/kg) intravenous infusion administered over 80 minutes every 12 hours up to and including Day 4 in pharmacokinetic period of cohort I.

Arm type

Experimental

Investigational medicinal product name

Voriconazole

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Voriconazole 4 mg/kg intravenous infusion administered at a rate of 3 mg/kg per hour (mg/kg/hr) over 80 minutes every 12 hours. The 12-hour dosing intervals may vary up to ± 30min.

Cohort I: Voriconazole 6mg/kg Intravenous

Arm description

Voriconazole 6mg/kg intravenous infusion administered over 120 minutes in the morning, and again 12 hours later on Day 1. Voriconazole 6 mg/kg intravenous infusion administered over the time period of 120 minutes at 12-hour intervals starting from Day 5 to Day 8 in pharmacokinetic period of cohort I. Subjects, if unable to take oral dose, continued to receive 6 mg/kg intravenous infusion, but could switch, if able, any morning between Days 10 and 20.

Arm type

Experimental

Investigational medicinal product name

Voriconazole

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Voriconazole 6 mg/kg intravenous infusion administered at a rate of 3 mg/kg/hr over 120 minutes every 12 hours. The 12-hour dosing intervals may vary up to ±30min.

Cohort I: Voriconazole 4mg/kg Oral Suspension

Arm description

Voriconazole oral suspension 4 mg/kg twice daily at 12-hour intervals was given either one hour before or one hour after meals starting from Day 9 up to Day 12 in the pharmacokinetic period of cohort I.

Arm type

Experimental

Investigational medicinal product name

Voriconazole

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for oral suspension

Routes of administration

Oral use

Dosage and administration details

Voriconazole oral suspension 4 mg/kg at 12 hour intervals was administered at least one hour before or one hour following a meal.

Cohort I: Voriconazole non–pharmacokinetic period

Arm description

Subjects who continued to receive voriconazole after the pharmacokinetic period from Day 12 up to Day 30 as per clinician’s discretion due to medical need such as persistent neutropenia (absolute neutrophil count [ANC <500/microliter [mcL]) were included in the non-pharmacokinetic period of cohort 1 and were assessed for safety.

Arm type

Experimental

Investigational medicinal product name

Voriconazole

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for oral suspension

Routes of administration

Oral use

Dosage and administration details

Voriconazole oral suspension 4 mg/kg at 12 hour intervals was administered at least one hour before or one hour following a meal on the discretion of medical need.

Investigational medicinal product name

Voriconazole

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Voriconazole 6 mg/kg intravenous infusion administered at a rate of 3 mg/kg/hr over 120 minutes every 12 hours. The 12-hour dosing intervals may vary up to ±30min.

Cohort II: Voriconazole 6mg/kg Intravenous

Arm description

Voriconazole 6mg/kg intravenous infusion administered over 120 minutes in the morning, and again 12 hours later up to and including Day 4 in pharmacokinetic period of cohort II.

Arm type

Experimental

Investigational medicinal product name

Voriconazole

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Voriconazole 6 mg/kg intravenous infusion administered at a rate of 3 mg/kg/hr over 120 minutes every 12 hours. The 12-hour dosing intervals may vary up to ±30min.

Cohort II: Voriconazole 8mg/kg Intravenous

Arm description

Voriconazole 8 mg/kg intravenous infusion administered at 12-hour intervals over 160 minutes starting from Day 5 up to Day 8 in pharmacokinetic period of cohort II. Subjects if unable to take oral dose, continued to receive 8 mg/kg intravenous infusion up to Day 12.

Arm type

Experimental

Investigational medicinal product name

Voriconazole

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Voriconazole 8 mg/kg intravenous infusion administered at a rate of 3 mg/kg/hr over 120 minutes every 12 hours. The 12-hour dosing intervals may vary up to ±30min.

Cohort II: Voriconazole 6mg/kg Oral Suspension

Arm description

Voriconazole oral suspension 6 mg/kg twice daily at 12-hour intervals was given either one hour before or one hour after meals starting from Day 9 up to Day 12 in the pharmacokinetic period of cohort II. Subjects, if unable to take oral dose, continued to receive 8 mg/kg intravenous infusion, but could switch, if able, any morning between Days 10 and 20.

Arm type

Experimental

Investigational medicinal product name

Voriconazole

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for oral suspension

Routes of administration

Oral use

Dosage and administration details

Voriconazole oral suspension 6 mg/kg at 12 hour intervals was administered at least one hour before or one hour following a meal.

Cohort II: Voriconazole non–pharmacokinectic period

Arm description

Subjects who continued to receive voriconazole after the pharmacokinetic period from Day 12 up to Day 30 as per clinician’s discretion due to medical need such as persistent neutropenia (ANC < 500/mcL) were included in the non-pharmacokinetic period of cohort II and were assessed for safety.

Arm type

Experimental

Investigational medicinal product name

Voriconazole

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Voriconazole 6 mg/kg intravenous infusion administered at a rate of 3 mg/kg/hr over 160 minutes every 12 ours. The 12-hour dosing intervals may vary up to ± 30min.

Investigational medicinal product name

Voriconazole

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for oral suspension

Routes of administration

Oral use

Dosage and administration details

Voriconazole oral suspension 6 mg/kg at 12 hour interval was administered at least one hour before or one hour following a meal on the discretion of medical need.

Number of subjects in period 1	Cohort I: Voriconazole 4mg/kg Intravenous	Cohort I: Voriconazole 6mg/kg Intravenous	Cohort I: Voriconazole 4mg/kg Oral Suspension	Cohort I: Voriconazole non–pharmacokinetic period	Cohort II: Voriconazole 6mg/kg Intravenous	Cohort II: Voriconazole 8mg/kg Intravenous	Cohort II: Voriconazole 6mg/kg Oral Suspension	Cohort II: Voriconazole non–pharmacokinectic period
Started	24	23	22	19	24	22	20	12
Completed	23	21	22	18	22	21	18	11
Not completed	1	2	0	1	2	1	2	1
Consent withdrawn by subject	1	1	-	-	2	-	1	-
Adverse Event	-	1	-	1	-	1	1	-
Unspecified	-	-	-	-	-	-	-	1

Baseline characteristics

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Reporting group title

Overall Study

Reporting group description

Reporting group values	Overall Study	Total
Number of subjects	48	48
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	5.8 ( 3 )	-
Gender categorical
Units: Subjects
Female	19	19
Male	29	29

End points

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Reporting group title

Cohort I: Voriconazole 4mg/kg Intravenous

Reporting group description

Voriconazole 4 milligram per kilogram (mg/kg) intravenous infusion administered over 80 minutes every 12 hours up to and including Day 4 in pharmacokinetic period of cohort I.

Reporting group title

Cohort I: Voriconazole 6mg/kg Intravenous

Reporting group description

Reporting group title

Cohort I: Voriconazole 4mg/kg Oral Suspension

Reporting group description

Reporting group title

Cohort I: Voriconazole non–pharmacokinetic period

Reporting group description

Reporting group title

Cohort II: Voriconazole 6mg/kg Intravenous

Reporting group description

Voriconazole 6mg/kg intravenous infusion administered over 120 minutes in the morning, and again 12 hours later up to and including Day 4 in pharmacokinetic period of cohort II.

Reporting group title

Cohort II: Voriconazole 8mg/kg Intravenous

Reporting group description

Reporting group title

Cohort II: Voriconazole 6mg/kg Oral Suspension

Reporting group description

Reporting group title

Cohort II: Voriconazole non–pharmacokinectic period

Reporting group description

Subjects who continued to receive voriconazole after the pharmacokinetic period from Day 12 up to Day 30 as per clinician’s discretion due to medical need such as persistent neutropenia (ANC < 500/mcL) were included in the non-pharmacokinetic period of cohort II and were assessed for safety.

Subject analysis set title

Voriconazole: Cohort I

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects received voriconazole 6mg/kg infusion on Day 1, followed by 4 mg/kg infusion every 12 hour from Day 2 to 4, then 6 mg/kg infusion from Day 5 to 8. Subjects either received 4mg/kg oral suspension every 12 hour or 6mg/kg intravenous (if unable to take oral suspension) from Day 9 up to Day 12 during the pharmacokinetic period.

Subject analysis set title

Voriconazole: Cohort II

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects received voriconazole 6mg/kg infusion on every 12 hour up to Day 4, then 8 mg/kg infusion from Day 5 to 8. Subjects either received 6 mg/kg oral suspension every 12 hour or 8 mg/kg intravenous (if unable to take oral suspension) from Day 9 up to Day 12 during the pharmacokinetic period.

Primary: Area Under the Curve from Time Zero to End of Dosing Interval (AUCtau)

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End point title

Area Under the Curve from Time Zero to End of Dosing Interval (AUCtau) ^[1] ^[2]

End point description

AUCtau was calculated by the linear trapezoidal method. Pharmacokinetic population included those subjects who had complete dosing for at least 1 dosing phase of the cohort and had at least 1 pharmacokinetic parameter derived on Day 4 of that dosing phase.

End point type

Primary

End point timeframe

2 minute pre-infusion end (on Day 1, 4, 8, 12), 2, 4, 6, 8, 12 hour post-infusion start on Day 4, 8 for intravenous dosing; pre-dose, 0.5,1, 2, 4, 6, 8, 12 hour post-dose on Day 12 for oral dosing

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 descriptive data was planned to be reported for this endpoint.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to report only pharmacokinetic data.

End point values	Cohort I: Voriconazole 4mg/kg Intravenous	Cohort I: Voriconazole 6mg/kg Intravenous	Cohort I: Voriconazole 4mg/kg Oral Suspension	Cohort II: Voriconazole 6mg/kg Intravenous	Cohort II: Voriconazole 8mg/kg Intravenous	Cohort II: Voriconazole 6mg/kg Oral Suspension
Number of subjects analysed	22 ^[3]	21 ^[4]	19 ^[5]	19 ^[6]	20 ^[7]	18 ^[8]
Units: nanogramhour per milliliter (nghr/mL)
geometric mean (standard deviation)	11826.5 ( 11354.1 )	22914.2 ( 45327.14 )	5183.8 ( 5036.65 )	17248.7 ( 19636.41 )	29776.4 ( 34089.15 )	8373.4 ( 9225.43 )

Notes
[3] - Subjects who were evaluable for this measure.
[4] - Subjects who were evaluable for this measure.
[5] - Subjects who were evaluable for this measure.
[6] - Subjects who were evaluable for this measure.
[7] - Subjects who were evaluable for this measure.
[8] - Subjects who were evaluable for this measure.

No statistical analyses for this end point

Primary: Maximum Observed Plasma Concentration (Cmax)

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End point title

Maximum Observed Plasma Concentration (Cmax) ^[9] ^[10]

End point description

Maximum Observed Plasma Concentration (Cmax) calculated by the recorded plasma concentration-time data. Pharmacokinetic population included those subjects who had complete dosing for at least 1 dosing phase of the cohort and had at least 1 pharmacokinetic parameter derived on Day 4 of that dosing phase.

End point type

Primary

End point timeframe

2 minute pre-infusion end (on Day 1, 4, 8, 12), 2, 4, 6, 8, 12 hour post-infusion start on Day 4, 8 for intravenous dosing; pre-dose, 0.5,1, 2, 4, 6, 8, 12 hour post-dose on Day 12 for oral dosing

Notes
[9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was planned to be reported for this endpoint.
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to report only pharmacokinetic data.

End point values	Cohort I: Voriconazole 4mg/kg Intravenous	Cohort I: Voriconazole 6mg/kg Intravenous	Cohort I: Voriconazole 4mg/kg Oral Suspension	Cohort II: Voriconazole 6mg/kg Intravenous	Cohort II: Voriconazole 8mg/kg Intravenous	Cohort II: Voriconazole 6mg/kg Oral Suspension
Number of subjects analysed	23 ^[11]	21 ^[12]	21 ^[13]	20 ^[14]	20 ^[15]	19 ^[16]
Units: ng/mL
geometric mean (standard deviation)	3212.4 ( 2546.68 )	4352.6 ( 6027.41 )	1177.8 ( 1123.67 )	4286.1 ( 4758.73 )	5767.3 ( 10683.32 )	1760.7 ( 1271.65 )

Notes
[11] - Subjects who were evaluable for this measure.
[12] - Subjects who were evaluable for this measure.
[13] - Subjects who were evaluable for this measure.
[14] - Subjects who were evaluable for this measure.
[15] - Subjects who were evaluable for this measure.
[16] - Subjects who were evaluable for this measure.

No statistical analyses for this end point

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

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End point title

Time to Reach Maximum Observed Plasma Concentration (Tmax) ^[17] ^[18]

End point description

Time to Reach Maximum Observed Plasma Concentration (Tmax) calculated by the recorded plasma concentration-time data. Pharmacokinetic population included those subjects who had complete dosing for at least 1 dosing phase of the cohortand had at least 1 pharmacokinetic parameter derived on Day 4 of that dosing phase.

End point type

Primary

End point timeframe

2 minute pre-infusion end (on Day 1, 4, 8, 12), 2, 4, 6, 8, 12 hour post-infusion start on Day 4, 8 for intravenous dosing; pre-dose, 0.5,1, 2, 4, 6, 8, 12 hour post-dose on Day 12 for oral dosing

Notes
[17] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was planned to be reported for this endpoint.
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to report only pharmacokinetic data.

End point values	Cohort I: Voriconazole 4mg/kg Intravenous	Cohort I: Voriconazole 6mg/kg Intravenous	Cohort I: Voriconazole 4mg/kg Oral Suspension	Cohort II: Voriconazole 6mg/kg Intravenous	Cohort II: Voriconazole 8mg/kg Intravenous	Cohort II: Voriconazole 6mg/kg Oral Suspension
Number of subjects analysed	23 ^[19]	21 ^[20]	21 ^[21]	20 ^[22]	20 ^[23]	19 ^[24]
Units: hr
arithmetic mean (standard deviation)	1.361 ( 0.2017 )	1.97 ( 0 )	1.429 ( 1.7485 )	2.072 ( 0.4539 )	2.836 ( 0.5019 )	1.342 ( 1.2478 )

Notes
[19] - Subjects who were evaluable for this measure.
[20] - Subjects who were evaluable for this measure.
[21] - Subjects who were evaluable for this measure.
[22] - Subjects who were evaluable for this measure.
[23] - Subjects who were evaluable for this measure.
[24] - Subjects who were evaluable for this measure.

No statistical analyses for this end point

Primary: Bioavailability (F)

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End point title

Bioavailability (F) ^[25]

End point description

Bioavailability is a measurement of the rate and extent to which a drug reaches the systemic circulation. Bioavailability was calculated as ratio of (AUC oral dosing*intravenous dose)/(AUC intravenous dosing*oral dose). Evaluable subjects for the pharmacokinetic bioavailability were those who had AUCtau data from both the intravenous and oral phases of the study.

End point type

Primary

End point timeframe

2 minute pre-infusion end (on Day 1, 4, 8, 12), 2, 4, 6, 8, 12 hour post-infusion start on Day 4, 8 for intravenous dosing; pre-dose, 0.5,1, 2, 4, 6, 8, 12 hour post-dose on Day 12 for oral dosing

Notes
[25] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was planned to be reported for this endpoint.

End point values	Voriconazole: Cohort I	Voriconazole: Cohort II
Number of subjects analysed	19 ^[26]	15 ^[27]
Units: ratio
arithmetic mean (standard deviation)	0.66 ( 0.6368 )	0.651 ( 0.4581 )

Notes
[26] - Subjects who were evaluable for this measure.
[27] - Subjects who were evaluable for this measure.

No statistical analyses for this end point

Secondary: Number of Subjects with Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

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End point title

Number of Subjects with Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

End point description

An AE was any untoward medical occurrence attributed to study drug in a subject who received study drug. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state. All subjects who received study treatment were included in safety population. AEs included both SAEs and non-SAEs.

End point type

Secondary

End point timeframe

Baseline up to 30 Days after the last dose of study drug

End point values	Cohort I: Voriconazole 4mg/kg Intravenous	Cohort I: Voriconazole 6mg/kg Intravenous	Cohort I: Voriconazole 4mg/kg Oral Suspension	Cohort I: Voriconazole non–pharmacokinetic period	Cohort II: Voriconazole 6mg/kg Intravenous	Cohort II: Voriconazole 8mg/kg Intravenous	Cohort II: Voriconazole 6mg/kg Oral Suspension	Cohort II: Voriconazole non–pharmacokinectic period
Number of subjects analysed	24	23	22	19	24	22	20	12
Units: Subjects
AEs	22	21	21	17	19	22	20	12
SAEs	0	2	2	2	0	4	3	4

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

AEs: Baseline up to 7 Days after last dose of study drug. SAEs: Baseline up to 30 Days after the last dose of study drug

Adverse event reporting additional description

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

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

17.1

Reporting group title

Cohort I: Voriconazole 4mg/kg Intravenous

Reporting group description

Voriconazole 4mg/kg intravenous infusion administered over 80 minutes every 12 hours up to and including Day 4 in pharmacokinetic period of cohort I.

Reporting group title

Cohort I: Voriconazole 6mg/kg Intravenous

Reporting group description

Voriconazole 6mg/kg intravenous infusion administered over 120 minutes in the morning, and again 12 hours later on Day 1. Voriconazole 6mg/kg intravenous infusion administered over the time period of 120 minutes at 12-hour intervals starting from Day 5 to Day 8 in pharmacokinetic period of cohort I. Subjects, if unable to take oral dose, continued to receive 6mg/kg intravenous infusion, but could switch, if able, any morning between Days 10 and 20.

Reporting group title

Cohort I: Voriconazole 4mg/kg Oral Suspension

Reporting group description

Voriconazole oral suspension 4mg/kg twice daily at 12-hour intervals was given either one hour before or one hour after meals starting from Day 9 up to Day 12 in the pharmacokinetic period of cohort I.

Reporting group title

Cohort I: Voriconazole non-pharmacokinetic period

Reporting group description

Subjects who continued to receive voriconazole after the pharmacokinetic period from Day 12 up to Day 30 as per clinician’s discretion due to medical need such as persistent neutropenia (ANC<500/mcL) were included in the non-pharmacokinetic period of cohort II and were assessed for safety.

Reporting group title

Cohort II: Voriconazole 6mg/kg Intravenous

Reporting group description

Voriconazole 6mg/kg intravenous infusion administered over 120 minutes in the morning, and again 12 hours later up to and including Day 4 in pharmacokinetic period of cohort II.

Reporting group title

Cohort II: Voriconazole 8mg/kg Intravenous

Reporting group description

Voriconazole 8mg/kg intravenous infusion administered at 12-hour intervals over 160 minutes starting from Day 5 up to Day 8 in pharmacokinetic period of cohort II. Subjects if unable to take oral dose, continued to receive 8mg/kg intravenous infusion up to Day 12.

Reporting group title

Cohort II: Voriconazole 6mg/kg Oral Suspension

Reporting group description

Voriconazole oral suspension 6mg/kg twice daily at 12-hour intervals was given either one hour before or one hour after meals starting from Day 9 up to Day 12 in the pharmacokinetic period of cohort II. Subjects, if unable to take oral dose, continued to receive 8mg/kg intravenous infusion, but could switch, if able, any morning between Days 10 and 20.

Reporting group title

Cohort II: Voriconazole non-pharmacokinetic period

Reporting group description

Subjects who continued to receive voriconazole after the pharmacokinetic period from Day 12 up to Day 30 as per clinician’s discretion due to medical need such as persistent neutropenia (absolute neutrophil count [ANC<500/mcL]) were included in the non-pharmacokinetic period of cohort 1 and were assessed for safety.

Serious adverse events	Cohort I: Voriconazole 4mg/kg Intravenous	Cohort I: Voriconazole 6mg/kg Intravenous	Cohort I: Voriconazole 4mg/kg Oral Suspension	Cohort I: Voriconazole non-pharmacokinetic period	Cohort II: Voriconazole 6mg/kg Intravenous	Cohort II: Voriconazole 8mg/kg Intravenous	Cohort II: Voriconazole 6mg/kg Oral Suspension	Cohort II: Voriconazole non-pharmacokinetic period
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 24 (0.00%)	2 / 23 (8.70%)	2 / 22 (9.09%)	2 / 19 (10.53%)	0 / 24 (0.00%)	4 / 22 (18.18%)	3 / 20 (15.00%)	4 / 12 (33.33%)
number of deaths (all causes)	0	0	0	0	0	0	0	0
number of deaths resulting from adverse events
Investigations
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	1 / 22 (4.55%)	1 / 20 (5.00%)	1 / 12 (8.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Infusion related reaction
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	1 / 12 (8.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Cardiac failure congestive
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	1 / 20 (5.00%)	1 / 12 (8.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Tonic convulsion
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	1 / 22 (4.55%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	1 / 22 (4.55%)	1 / 20 (5.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Bone marrow transplant rejection
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	1 / 12 (8.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Graft versus host disease in skin
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	1 / 22 (4.55%)	1 / 19 (5.26%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	1 / 20 (5.00%)	1 / 12 (8.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	1 / 12 (8.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	1 / 19 (5.26%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Escherichia bacteraemia
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	1 / 22 (4.55%)	1 / 19 (5.26%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis adenovirus
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	1 / 12 (8.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 24 (0.00%)	2 / 23 (8.70%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Fluid overload
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	1 / 22 (4.55%)	1 / 20 (5.00%)	1 / 12 (8.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Cohort I: Voriconazole 4mg/kg Intravenous	Cohort I: Voriconazole 6mg/kg Intravenous	Cohort I: Voriconazole 4mg/kg Oral Suspension	Cohort I: Voriconazole non-pharmacokinetic period	Cohort II: Voriconazole 6mg/kg Intravenous	Cohort II: Voriconazole 8mg/kg Intravenous	Cohort II: Voriconazole 6mg/kg Oral Suspension	Cohort II: Voriconazole non-pharmacokinetic period
Total subjects affected by non serious adverse events
subjects affected / exposed	22 / 24 (91.67%)	21 / 23 (91.30%)	21 / 22 (95.45%)	17 / 19 (89.47%)	19 / 24 (79.17%)	22 / 22 (100.00%)	20 / 20 (100.00%)	12 / 12 (100.00%)
Vascular disorders
Haematoma
subjects affected / exposed	1 / 24 (4.17%)	1 / 23 (4.35%)	1 / 22 (4.55%)	1 / 19 (5.26%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	1	1	1	0	0	0	0
Haemorrhage
subjects affected / exposed	1 / 24 (4.17%)	1 / 23 (4.35%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	1	0	0	0	0	0	0
Hypertension
subjects affected / exposed	1 / 24 (4.17%)	0 / 23 (0.00%)	1 / 22 (4.55%)	3 / 19 (15.79%)	4 / 24 (16.67%)	7 / 22 (31.82%)	8 / 20 (40.00%)	5 / 12 (41.67%)
occurrences all number	1	0	1	3	4	7	9	5
Hypotension
subjects affected / exposed	1 / 24 (4.17%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	2 / 22 (9.09%)	0 / 20 (0.00%)	1 / 12 (8.33%)
occurrences all number	1	0	0	0	0	2	0	1
Venoocclusive disease
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	1 / 22 (4.55%)	1 / 20 (5.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	1	1	1
General disorders and administration site conditions
Catheter site inflammation
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	1 / 22 (4.55%)	1 / 19 (5.26%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	1	1	0	0	0	0
Catheter site pain
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	1 / 19 (5.26%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Chest pain
subjects affected / exposed	1 / 24 (4.17%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Chills
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Device occlusion
subjects affected / exposed	1 / 24 (4.17%)	1 / 23 (4.35%)	2 / 22 (9.09%)	3 / 19 (15.79%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	1	2	3	0	0	0	0
Generalised oedema
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Infusion site pain
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0
Mucosal inflammation
subjects affected / exposed	7 / 24 (29.17%)	12 / 23 (52.17%)	9 / 22 (40.91%)	4 / 19 (21.05%)	3 / 24 (12.50%)	7 / 22 (31.82%)	4 / 20 (20.00%)	2 / 12 (16.67%)
occurrences all number	7	12	9	4	4	7	4	2
Mucosal pain
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	1 / 24 (4.17%)	1 / 22 (4.55%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	1	1	0	0
Oedema
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	1 / 22 (4.55%)	1 / 19 (5.26%)	1 / 24 (4.17%)	1 / 22 (4.55%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	1	1	1	0	0
Oedema peripheral
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	1 / 22 (4.55%)	1 / 20 (5.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	1	1	0
Performance status decreased
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	1 / 22 (4.55%)	1 / 19 (5.26%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	1	1	0	0	0	0
Pyrexia
subjects affected / exposed	4 / 24 (16.67%)	5 / 23 (21.74%)	2 / 22 (9.09%)	3 / 19 (15.79%)	2 / 24 (8.33%)	5 / 22 (22.73%)	1 / 20 (5.00%)	2 / 12 (16.67%)
occurrences all number	4	6	4	4	3	8	1	2
Immune system disorders
Drug hypersensitivity
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	1
Graft versus host disease
subjects affected / exposed	0 / 24 (0.00%)	3 / 23 (13.04%)	5 / 22 (22.73%)	5 / 19 (26.32%)	0 / 24 (0.00%)	1 / 22 (4.55%)	0 / 20 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	3	5	5	0	1	0	1
Graft versus host disease in skin
subjects affected / exposed	1 / 24 (4.17%)	1 / 23 (4.35%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	1 / 22 (4.55%)	1 / 20 (5.00%)	1 / 12 (8.33%)
occurrences all number	1	1	0	0	0	1	1	1
Serum sickness
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	1 / 22 (4.55%)	1 / 20 (5.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	1	1	0
Reproductive system and breast disorders
Genital erythema
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	1 / 24 (4.17%)	1 / 22 (4.55%)	1 / 20 (5.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	1	1	1	1
Perineal erythema
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	1 / 24 (4.17%)	1 / 22 (4.55%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	1	1	0	0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	1 / 22 (4.55%)	1 / 20 (5.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	2	1	0
Atelectasis
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	1 / 22 (4.55%)	1 / 19 (5.26%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	1	1	0	0	0	0
Cough
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	2 / 22 (9.09%)	1 / 19 (5.26%)	1 / 24 (4.17%)	3 / 22 (13.64%)	1 / 20 (5.00%)	1 / 12 (8.33%)
occurrences all number	0	1	2	1	1	3	1	1
Dyspnoea
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	1 / 24 (4.17%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Epistaxis
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	0 / 22 (0.00%)	0 / 19 (0.00%)	1 / 24 (4.17%)	3 / 22 (13.64%)	1 / 20 (5.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0	1	4	1	0
Laryngospasm
subjects affected / exposed	1 / 24 (4.17%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Nasal congestion
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	1 / 24 (4.17%)	0 / 22 (0.00%)	0 / 20 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	1	0	0	1
Oropharyngeal pain
subjects affected / exposed	1 / 24 (4.17%)	1 / 23 (4.35%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	1	0	0	0	0	0	0
Pleural effusion
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	1 / 22 (4.55%)	1 / 19 (5.26%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	1	1	1	0	0	0	1
Pulmonary oedema
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	0 / 22 (0.00%)	1 / 19 (5.26%)	1 / 24 (4.17%)	1 / 22 (4.55%)	1 / 20 (5.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	1	1	1	1	0
Respiratory distress
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	1 / 22 (4.55%)	1 / 20 (5.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	1	1	0
Rhinorrhoea
subjects affected / exposed	0 / 24 (0.00%)	2 / 23 (8.70%)	3 / 22 (13.64%)	2 / 19 (10.53%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	2	3	2	0	0	0	0
Tachypnoea
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	1 / 22 (4.55%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	1	0	0	0	0	0
Psychiatric disorders
Agitation
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	1 / 22 (4.55%)	1 / 19 (5.26%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	1	1	1	0	0	0	1
Confusional state
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	1 / 20 (5.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Hallucination
subjects affected / exposed	0 / 24 (0.00%)	2 / 23 (8.70%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0
Nightmare
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	1 / 22 (4.55%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	1 / 19 (5.26%)	1 / 24 (4.17%)	1 / 22 (4.55%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	1	1	0	0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	1 / 19 (5.26%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Bacterial test positive
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	1 / 20 (5.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	1	3
Blood bilirubin increased
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	1 / 22 (4.55%)	1 / 19 (5.26%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	1	1	0	0	0	0
Blood lactate dehydrogenase increased
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	1 / 22 (4.55%)	1 / 19 (5.26%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	1	1	0	0	0	0
Blood magnesium decreased
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	2 / 22 (9.09%)	2 / 19 (10.53%)	0 / 24 (0.00%)	1 / 22 (4.55%)	1 / 20 (5.00%)	1 / 12 (8.33%)
occurrences all number	0	1	2	2	0	1	1	1
Blood phosphorus decreased
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	1 / 22 (4.55%)	1 / 19 (5.26%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	1	1	0	0	0	0
Blood potassium decreased
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	1 / 22 (4.55%)	1 / 19 (5.26%)	1 / 24 (4.17%)	1 / 22 (4.55%)	1 / 20 (5.00%)	1 / 12 (8.33%)
occurrences all number	0	1	1	1	1	1	1	1
Blood pressure increased
subjects affected / exposed	2 / 24 (8.33%)	2 / 23 (8.70%)	2 / 22 (9.09%)	2 / 19 (10.53%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	2	2	2	2	0	0	0	0
Blood urea increased
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	1 / 22 (4.55%)	1 / 20 (5.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	1	1	0
Cytomegalovirus test positive
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	1 / 22 (4.55%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Drug level increased
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	1 / 22 (4.55%)	1 / 19 (5.26%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	1	1	0	0	0	0
Gamma-glutamyltransferase increased
subjects affected / exposed	1 / 24 (4.17%)	2 / 23 (8.70%)	2 / 22 (9.09%)	2 / 19 (10.53%)	1 / 24 (4.17%)	1 / 22 (4.55%)	1 / 20 (5.00%)	0 / 12 (0.00%)
occurrences all number	1	2	2	2	1	1	1	0
Hepatic enzyme increased
subjects affected / exposed	1 / 24 (4.17%)	1 / 23 (4.35%)	1 / 22 (4.55%)	1 / 19 (5.26%)	0 / 24 (0.00%)	1 / 22 (4.55%)	1 / 20 (5.00%)	1 / 12 (8.33%)
occurrences all number	1	1	1	1	0	1	1	1
Immunosuppressant drug level decreased
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	1 / 22 (4.55%)	1 / 19 (5.26%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	1	0	0	0	0
Immunosuppressant drug level increased
subjects affected / exposed	1 / 24 (4.17%)	1 / 23 (4.35%)	0 / 22 (0.00%)	1 / 19 (5.26%)	2 / 24 (8.33%)	2 / 22 (9.09%)	2 / 20 (10.00%)	0 / 12 (0.00%)
occurrences all number	1	1	0	1	2	2	2	0
Liver function test abnormal
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	1 / 22 (4.55%)	1 / 20 (5.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	1	1	1
Oxygen saturation decreased
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	1	0	0	0	0	0	1
Transaminases increased
subjects affected / exposed	1 / 24 (4.17%)	1 / 23 (4.35%)	1 / 22 (4.55%)	1 / 19 (5.26%)	0 / 24 (0.00%)	1 / 22 (4.55%)	2 / 20 (10.00%)	1 / 12 (8.33%)
occurrences all number	1	1	1	1	0	1	2	1
Waist circumference increased
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Injury, poisoning and procedural complications
Allergic transfusion reaction
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Incision site pain
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	1 / 19 (5.26%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Incorrect dose administered
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	1 / 22 (4.55%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	1	0	0	0	0	0
Skin abrasion
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	1 / 19 (5.26%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Tongue injury
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Toxicity to various agents
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	1 / 22 (4.55%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	1	0	0	0	0	0
Cardiac disorders
Bradyarrhythmia
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	1 / 22 (4.55%)	1 / 19 (5.26%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	1	0	0	0	0
Pericardial effusion
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	1 / 22 (4.55%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	1	0	0	0	0	1
Tachycardia
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	1 / 22 (4.55%)	0 / 19 (0.00%)	1 / 24 (4.17%)	1 / 22 (4.55%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	1	1	0	0
Nervous system disorders
Benign intracranial hypertension
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	1 / 22 (4.55%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	1	0	0	0	0	0
Convulsion
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	1 / 19 (5.26%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Headache
subjects affected / exposed	1 / 24 (4.17%)	3 / 23 (13.04%)	3 / 22 (13.64%)	1 / 19 (5.26%)	2 / 24 (8.33%)	0 / 22 (0.00%)	0 / 20 (0.00%)	1 / 12 (8.33%)
occurrences all number	1	4	3	1	2	0	0	1
Hemiparesis
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	1 / 22 (4.55%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Lethargy
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	1 / 22 (4.55%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Neuralgia
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	1 / 22 (4.55%)	1 / 19 (5.26%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	1	0	0	0	0
Sedation
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	1 / 24 (4.17%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Somnolence
subjects affected / exposed	1 / 24 (4.17%)	1 / 23 (4.35%)	1 / 22 (4.55%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	1	1	0	0	0	0	0
Blood and lymphatic system disorders
Bone marrow failure
subjects affected / exposed	1 / 24 (4.17%)	1 / 23 (4.35%)	0 / 22 (0.00%)	0 / 19 (0.00%)	1 / 24 (4.17%)	2 / 22 (9.09%)	2 / 20 (10.00%)	2 / 12 (16.67%)
occurrences all number	1	1	0	0	1	2	2	2
Coagulopathy
subjects affected / exposed	1 / 24 (4.17%)	1 / 23 (4.35%)	1 / 22 (4.55%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	1	1	0	0	0	0	0
Disseminated intravascular coagulation
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Febrile neutropenia
subjects affected / exposed	1 / 24 (4.17%)	1 / 23 (4.35%)	1 / 22 (4.55%)	1 / 19 (5.26%)	0 / 24 (0.00%)	1 / 22 (4.55%)	1 / 20 (5.00%)	1 / 12 (8.33%)
occurrences all number	1	1	1	2	0	1	1	1
Granulocytopenia
subjects affected / exposed	1 / 24 (4.17%)	1 / 23 (4.35%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	1	0	0	0	0	0	0
Neutropenia
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	1 / 22 (4.55%)	1 / 19 (5.26%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	1	1	0	0	0	0
Pancytopenia
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	1 / 24 (4.17%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Eye disorders
Conjunctival haemorrhage
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	1 / 22 (4.55%)	1 / 19 (5.26%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	1	1	0	0	0	0
Dry eye
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	1 / 22 (4.55%)	1 / 19 (5.26%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	1	1	0	0	0	0
Eye haemorrhage
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Eye pain
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	1 / 22 (4.55%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	1	0	0	0	0	0
Eye swelling
subjects affected / exposed	0 / 24 (0.00%)	2 / 23 (8.70%)	2 / 22 (9.09%)	1 / 19 (5.26%)	1 / 24 (4.17%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	2	2	1	1	0	0	0
Ocular icterus
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	1 / 20 (5.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Periorbital oedema
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	1 / 20 (5.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Photophobia
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	1 / 22 (4.55%)	1 / 19 (5.26%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	1	1	0	0	0	0
Vision blurred
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	1 / 24 (4.17%)	1 / 22 (4.55%)	1 / 20 (5.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	1	1	1	1
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	1 / 22 (4.55%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Abdominal pain
subjects affected / exposed	1 / 24 (4.17%)	0 / 23 (0.00%)	1 / 22 (4.55%)	1 / 19 (5.26%)	0 / 24 (0.00%)	1 / 22 (4.55%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	1	1	0	2	0	0
Abdominal tenderness
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	1 / 22 (4.55%)	1 / 19 (5.26%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	1	0	0	0	0
Anal fissure
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	1 / 24 (4.17%)	1 / 22 (4.55%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	1	1	0	0
Chapped lips
subjects affected / exposed	1 / 24 (4.17%)	1 / 23 (4.35%)	1 / 22 (4.55%)	1 / 19 (5.26%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	1	1	1	0	0	0	0
Cheilitis
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	1 / 22 (4.55%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Constipation
subjects affected / exposed	0 / 24 (0.00%)	2 / 23 (8.70%)	2 / 22 (9.09%)	2 / 19 (10.53%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	2	2	2	0	0	0	0
Diarrhoea
subjects affected / exposed	2 / 24 (8.33%)	5 / 23 (21.74%)	3 / 22 (13.64%)	2 / 19 (10.53%)	2 / 24 (8.33%)	3 / 22 (13.64%)	1 / 20 (5.00%)	2 / 12 (16.67%)
occurrences all number	2	5	3	2	2	3	1	2
Enteritis
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	0 / 22 (0.00%)	1 / 19 (5.26%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	1	0	0	0	0
Gingival bleeding
subjects affected / exposed	1 / 24 (4.17%)	1 / 23 (4.35%)	1 / 22 (4.55%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	1	1	0	0	0	0	0
Haematochezia
subjects affected / exposed	0 / 24 (0.00%)	2 / 23 (8.70%)	1 / 22 (4.55%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	2	1	0	0	0	0	0
Ileus
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	1 / 22 (4.55%)	1 / 20 (5.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	1	1	1
Lower gastrointestinal haemorrhage
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	1
Mouth ulceration
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	1 / 22 (4.55%)	1 / 19 (5.26%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	1	0	0	0	0
Nausea
subjects affected / exposed	4 / 24 (16.67%)	3 / 23 (13.04%)	2 / 22 (9.09%)	3 / 19 (15.79%)	1 / 24 (4.17%)	1 / 22 (4.55%)	0 / 20 (0.00%)	1 / 12 (8.33%)
occurrences all number	4	3	2	3	1	1	0	1
Neutropenic colitis
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Oral disorder
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	1 / 22 (4.55%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Proctalgia
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	1 / 22 (4.55%)	1 / 19 (5.26%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	1	0	0	0	0
Rectal fissure
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	1 / 22 (4.55%)	1 / 19 (5.26%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	1	0	0	0	0
Stomatitis
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	1 / 24 (4.17%)	1 / 22 (4.55%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	1	1	0	0
Toothache
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	1 / 19 (5.26%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Vomiting
subjects affected / exposed	3 / 24 (12.50%)	3 / 23 (13.04%)	2 / 22 (9.09%)	1 / 19 (5.26%)	2 / 24 (8.33%)	3 / 22 (13.64%)	1 / 20 (5.00%)	1 / 12 (8.33%)
occurrences all number	4	4	3	1	2	6	1	1
Hepatobiliary disorders
Hyperbilirubinaemia
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	1 / 22 (4.55%)	1 / 19 (5.26%)	0 / 24 (0.00%)	2 / 22 (9.09%)	1 / 20 (5.00%)	1 / 12 (8.33%)
occurrences all number	0	1	1	1	0	2	1	1
Jaundice
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	1 / 20 (5.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	2 / 24 (8.33%)	3 / 23 (13.04%)	3 / 22 (13.64%)	3 / 19 (15.79%)	0 / 24 (0.00%)	0 / 22 (0.00%)	1 / 20 (5.00%)	1 / 12 (8.33%)
occurrences all number	2	3	3	3	0	0	1	1
Dermatitis diaper
subjects affected / exposed	1 / 24 (4.17%)	1 / 23 (4.35%)	1 / 22 (4.55%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	1	1	0	0	0	0	0
Erythema
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	1 / 22 (4.55%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	1	0	0	0	0	0
Ingrowing nail
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	1 / 19 (5.26%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Petechiae
subjects affected / exposed	1 / 24 (4.17%)	1 / 23 (4.35%)	0 / 22 (0.00%)	0 / 19 (0.00%)	1 / 24 (4.17%)	1 / 22 (4.55%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	1	0	0	1	1	0	0
Pruritus
subjects affected / exposed	4 / 24 (16.67%)	5 / 23 (21.74%)	1 / 22 (4.55%)	0 / 19 (0.00%)	1 / 24 (4.17%)	2 / 22 (9.09%)	1 / 20 (5.00%)	0 / 12 (0.00%)
occurrences all number	7	5	1	0	1	2	1	0
Rash
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	2 / 22 (9.09%)	4 / 19 (21.05%)	6 / 24 (25.00%)	8 / 22 (36.36%)	5 / 20 (25.00%)	2 / 12 (16.67%)
occurrences all number	0	1	2	4	6	9	5	2
Rash erythematous
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	1 / 22 (4.55%)	1 / 19 (5.26%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	1	1	0	0	0	0
Rash macular
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	1 / 22 (4.55%)	1 / 19 (5.26%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	1	1	0	0	0	0
Rash maculo-papular
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	1 / 22 (4.55%)	1 / 20 (5.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	1	1	1
Rash pruritic
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Urticaria
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	1 / 24 (4.17%)	1 / 22 (4.55%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	1	1	0	0
Renal and urinary disorders
Dysuria
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	2 / 22 (9.09%)	0 / 19 (0.00%)	1 / 24 (4.17%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	2	0	1	0	0	0
Haematuria
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	1 / 24 (4.17%)	0 / 22 (0.00%)	0 / 20 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	1	0	0	1
Renal failure
subjects affected / exposed	1 / 24 (4.17%)	1 / 23 (4.35%)	1 / 22 (4.55%)	2 / 19 (10.53%)	1 / 24 (4.17%)	1 / 22 (4.55%)	2 / 20 (10.00%)	1 / 12 (8.33%)
occurrences all number	1	1	1	2	1	1	2	1
Endocrine disorders
Adrenal insufficiency
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	1 / 20 (5.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	1	1
Musculoskeletal and connective tissue disorders
Arthropathy
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	1
Back pain
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	1 / 22 (4.55%)	2 / 20 (10.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	1	2	1
Bone pain
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	1 / 22 (4.55%)	1 / 19 (5.26%)	0 / 24 (0.00%)	1 / 22 (4.55%)	1 / 20 (5.00%)	1 / 12 (8.33%)
occurrences all number	0	1	1	1	0	1	1	1
Compartment syndrome
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Myalgia
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Pain in extremity
subjects affected / exposed	1 / 24 (4.17%)	2 / 23 (8.70%)	2 / 22 (9.09%)	3 / 19 (15.79%)	1 / 24 (4.17%)	1 / 22 (4.55%)	2 / 20 (10.00%)	1 / 12 (8.33%)
occurrences all number	1	2	2	4	1	1	2	1
Infections and infestations
Bacteraemia
subjects affected / exposed	1 / 24 (4.17%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Bacterial sepsis
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	1 / 22 (4.55%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Bronchitis
subjects affected / exposed	1 / 24 (4.17%)	1 / 23 (4.35%)	1 / 22 (4.55%)	1 / 19 (5.26%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	1	1	1	0	0	0	0
Candida infection
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	1 / 20 (5.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	1	1
Conjunctivitis
subjects affected / exposed	1 / 24 (4.17%)	1 / 23 (4.35%)	3 / 22 (13.64%)	2 / 19 (10.53%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	1	3	2	0	0	0	0
Cytomegalovirus infection
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	1 / 19 (5.26%)	0 / 24 (0.00%)	0 / 22 (0.00%)	2 / 20 (10.00%)	2 / 12 (16.67%)
occurrences all number	0	0	0	1	0	0	2	2
Enterococcal infection
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	1
Gastroenteritis adenovirus
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	1 / 20 (5.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	1	1
Gastroenteritis viral
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	1 / 20 (5.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Human polyomavirus infection
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	1
Paronychia
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	1 / 19 (5.26%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Pneumonia
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	1 / 22 (4.55%)	2 / 20 (10.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	1	2	0
Rhinitis
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	1 / 22 (4.55%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Sinusitis
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	1 / 22 (4.55%)	1 / 19 (5.26%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	1	1	0	0	0	0
Staphylococcal bacteraemia
subjects affected / exposed	2 / 24 (8.33%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	2	0	0	0	0	0	0	0
Upper respiratory tract infection
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	1 / 19 (5.26%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Viral infection
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	1 / 22 (4.55%)	1 / 19 (5.26%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	1	1	0	0	0	0
Viral rash
subjects affected / exposed	1 / 24 (4.17%)	1 / 23 (4.35%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	1	0	0	0	0	0	0
Metabolism and nutrition disorders
Electrolyte imbalance
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Fluid retention
subjects affected / exposed	1 / 24 (4.17%)	2 / 23 (8.70%)	1 / 22 (4.55%)	1 / 19 (5.26%)	3 / 24 (12.50%)	4 / 22 (18.18%)	4 / 20 (20.00%)	2 / 12 (16.67%)
occurrences all number	1	2	1	1	3	4	4	2
Hyperglycaemia
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	1 / 22 (4.55%)	2 / 20 (10.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	1	2	0
Hyperkalaemia
subjects affected / exposed	1 / 24 (4.17%)	0 / 23 (0.00%)	0 / 22 (0.00%)	1 / 19 (5.26%)	0 / 24 (0.00%)	1 / 22 (4.55%)	1 / 20 (5.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	1	0	1	1	0
Hypoalbuminaemia
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	1
Hypokalaemia
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	1 / 22 (4.55%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0	0	1	0	0
Hypomagnesaemia
subjects affected / exposed	1 / 24 (4.17%)	1 / 23 (4.35%)	0 / 22 (0.00%)	1 / 19 (5.26%)	2 / 24 (8.33%)	2 / 22 (9.09%)	1 / 20 (5.00%)	1 / 12 (8.33%)
occurrences all number	1	1	0	1	2	2	1	1
Hyponatraemia
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 22 (0.00%)	1 / 19 (5.26%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	1	0	0	0	1
Type 1 diabetes mellitus
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	0 / 22 (0.00%)	0 / 19 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 20 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0

More information

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Were there any global substantial amendments to the protocol? Yes

04 Apr 2003

If Voriconazole treatment was stopped between Days 12 to Day 30 a physical examination and safety laboratory tests and a serum pregnancy test (for females with child bearing potential only) were to be performed on the last Day of dosing. If abnormalities were observed in any of the laboratory tests, those tests was to be repeated every 5-7 Days until they return to the normal, or until a reason for the abnormality was determined.

08 Jun 2004

Any serious adverse event or death was to be reported immediately independent of the circumstances or suspected cause if it occurred or came to the attention of the investigator at any time during the study through the one month follow-up visit required by the protocol or 30 Days after the last administration of study drug, whichever came later. Any serious adverse event occurring at any other time after completion of the study promptly reported if a causal relationship to study drug was suspected. The only exception to these reporting requirements were serious adverse events that occurred during a prerandomization/washout run-in period, during which either placebo alone was administered, or no active study drug or no protocol-specified background drug was administered.

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:
An open-label, intravenous to oral switch, multiple dose, multi-centre study to investigate the pharmacokinetics, safety and tolerability of Voriconazole in hospitalized children aged 2 to <12 years who require treatment for the prevention of systemic fungal infection

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Area Under the Curve from Time Zero to End of Dosing Interval (AUCtau)

Primary: Area Under the Curve from Time Zero to End of Dosing Interval (AUCtau)

Primary: Maximum Observed Plasma Concentration (Cmax)

Primary: Maximum Observed Plasma Concentration (Cmax)

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

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

Primary: Bioavailability (F)

Primary: Bioavailability (F)

Secondary: Number of Subjects with Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

Secondary: Number of Subjects with Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

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: An open-label, intravenous to oral switch, multiple dose, multi-centre study to investigate the pharmacokinetics, safety and tolerability of Voriconazole in hospitalized children aged 2 to <12 years who require treatment for the prevention of systemic fungal infection

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Area Under the Curve from Time Zero to End of Dosing Interval (AUCtau)

Primary: Area Under the Curve from Time Zero to End of Dosing Interval (AUCtau)

Primary: Maximum Observed Plasma Concentration (Cmax)

Primary: Maximum Observed Plasma Concentration (Cmax)

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

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

Primary: Bioavailability (F)

Primary: Bioavailability (F)

Secondary: Number of Subjects with Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

Secondary: Number of Subjects with Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
An open-label, intravenous to oral switch, multiple dose, multi-centre study to investigate the pharmacokinetics, safety and tolerability of Voriconazole in hospitalized children aged 2 to <12 years who require treatment for the prevention of systemic fungal infection