Public Disclosure Synopsis
Protocol A1501096-2014 December 17-Final

PFIZER INC.
These results are supplied for informational purposes only.
Prescribing decisions should be made based on the approved package insert.
PROPRIETARY DRUG NAME®/GENERIC DRUG NAME: Vfend®/Voriconazole
PROTOCOL NO.: A1501096
PROTOCOL TITLE: A multicenter, open-label, non-controlled, intravenous to oral
switch, phase 2 study to evaluate the pharmacokinetics, safety and tolerability ofvoriconazole in immunocompromised children aged 2 to <15 years who are at high risk forsystemic fungal infection
Study Center(s): 6 centers in Japan
Study Initiation Date and Primary Completion or Final Completion Dates:
20 September 2011 to 11 May 2013
Phase of Development: Phase 2
Study Objective(s): Primary: To characterize the pharmacokinetics, safety, and tolerabilityof voriconazole following an intravenous (IV) to oral switch regimen in
immunocompromised children aged 2 to <15 years who are at high risk for systemic fungal
infection.
Secondary: To explore the effect of potential covariates (eg, cytochrome P450 [CYP] 2C19
genotype status, age, body weight, gender) on the systemic exposure of voriconazole.
METHODS
Study Design: This was a multi-center, open-label, non-controlled Phase 2 study to evaluate
the pharmacokinetics, safety, and tolerability of voriconazole following an IV to oral switch
regimen in immunocompromised children aged 2 to <15 years who were at high risk forsystemic fungal infection.
The study consisted of the pharmacokinetic period (IV and oral treatments),
post-pharmacokinetic period, and follow-up period (Figure 1).
Pharmacokinetic period: a period from the start of IV treatment through the 7th day of oral
treatment (7-day IV treatment and 6.5-day oral treatment with the powder for oral suspension[Day14, only the morning dose]; however, if the subject was unable to take oral medicationon the 1st day of oral treatment [Day 8], IV treatment could be continued for a maximum of
20 days [up to Day 20] before switching to the oral treatment).
Post-pharmacokinetic period: an optional period based on a clinical need (if neutropenia[absolute neutrophil count <500 cells/µL] persisted and the risk for development of systemic
Template version 1.1

Page 1

Public Disclosure Synopsis
Protocol A1501096-2014 December 17-Final

fungal infections was still high) to continue treatment (a treatment period which lasted
beyond the end of the pharmacokinetic period [up to the 7th day of IV or oral treatment] for a
total of up to 30 days [up to Day 30] including the pharmacokinetic period).
Follow-up period: 30 days (±7 days) after the last dose of voriconazole.
Figure 1. Overview of Study Design and Pharmacokinetic Blood Sampling Points

2-20

Voriconazole was administered according to the dosing regimens listed in Table 1.
Table 1.

Voriconazole Dosing Schedule

Administration timing
 Patients aged 2 to <12 years
 Patients aged 12 to <15 years(weighing <50 kg)
 Patients aged 12 to <15 years(weighing ≥50 kg)

Loading dose
IV doseDay 1
9 mg/kg IV q12 h(for the first 24 hoursof treatment)
6 mg/kg IV q12 h(for the first 24 hoursof treatment)

Maintenance dose
IV doseOral dosea
Day 2-7
Day 8b-14c
8 mg/kg IV q12 h
9 mg/kg PO q12 h(up to a maximum of
350 mg PO q12 h)
4 mg/kg IV q12 h
200 mg PO q12 h

q12h = twice daily at 12-hour intervals; IV = intravenous/intravenous dose, PO = powder for oral suspension/oral dosea. The oral regimen was administered at least 1 hour before or 1 hour following a meal. An allowance time for twice
daily dosing at 12-hour intervals was ±1 hour.
b. If subjects were unable to switch to the oral regimen on the 1st day of oral treatment (Day 8), the IV regimen could becontinued up to 20 days (Day 20) before switching to the oral regimen.
c. On the 7th day of oral treatment (Day 14), only the morning oral dose was given. If clinically indicated, voriconazole
treatment could be continued for a total of up to 30 days (Day 30) including the pharmacokinetic period.

Number of Subjects (Planned and Analyzed): 20 subjects were planned as targeted
number of subjects and 21 subjects were analyzed.
Diagnosis and Main Criteria for Inclusion: Male or female subjects, 2 to <15 years of age,
who required treatment for the prevention of systemic fungal infection, who was expected todevelop neutropenia (absolute neutrophil count <500 cells/µL) lasting more than 10 days,
and who could tolerate being switched to oral therapy after 7 to 20 days of voriconazole IVtherapy.
Study Treatment: All voriconazole IV doses were administered at an infusion rate of
3 mg/kg/h, ie, the 9, 8, 6, or 4 mg/kg dose was administered intravenously over 180, 160, 120,
or 80 minutes, respectively. If another drug was administered at the same time of
Template version 1.1

Page 2

Public Disclosure Synopsis
Protocol A1501096-2014 December 17-Finalvoriconazole infusion, a different line was used. Voriconazole oral doses were taken
between meals, at least 1 hour before or 1 hour following a meal. An allowance time fortwice daily dosing at 12-hour intervals was ± 1 hour.
Pharmacokinetic and Pharmacogenomic Endpoints: The primary endpoints of thepharmacokinetic evaluations were as follows:•

Steady-state pharmacokinetic parameters of voriconazole following IV or oral
administration: area under the curve over dosing interval at steady state (AUC12,ss), peakplasma concentration at steady state (Cmax,ss), and time to reach Cmax (Tmax)•

Plasma voriconazole concentrations (The 2nd day of IV treatment [Day 2]: just prior to
the start of morning dosing; The 7th day of IV treatment [Day 7]: just prior to the start ofmorning dosing, 1 hour after the start of infusion, 2-20 minutes after the end of infusion,and 4, 6, 8, and 12 hours after the start of infusion; The 7th day of oral treatment[Day 14]: just prior to the start of morning dosing, and 1, 2, 4, 6, 8, and 12 hours after
dosing)

The secondary endpoints were as follows:•

The ratio of AUC12,ss following oral treatment relative to AUC12,ss following IV treatment•

Steady-state pharmacokinetic parameters of the major metabolite UK-121,265(N-oxide-voriconazole) following IV and oral treatment: AUC12,ss, Cmax,ss, and Tmax
(if plasma concentration data allowing to calculate the parameters were obtained)

Plasma voriconazole and UK-121,265 concentrations were analyzed using a validated liquid
chromatography/tandem mass spectrometry method.
In the pharmacogenomic evaluation, CYP2C19 genotyping was performed in all subjects.
Safety Evaluations: Adverse events were recorded on the case report form from the time of
the first IV treatment (Day 1) through the last subject visit of the 30-day follow-up period.
Serious adverse events were reported from the time that the signed informed consent wasprovided through and including 28 calendar days after the last administration of theinvestigational product or the last visit day during the 30-day follow-up period (the latest
allowance date being 37 days) whichever the latest date. However, serious treatment-related
adverse events were to be reported promptly even after completion of the reporting period.
The clinical laboratory tests, near-distance visual acuity test, color vision test, and assessmentof visual symptoms were performed once each at screening, on the 7th day of IV treatment(Day 7), on the 1st day of oral treatment (Day 8, near-distance visual acuity test, color vision
test, and assessment of visual symptoms only), on the 7th day (Day 14) of oral treatment, andat the 30-day follow-up visit. The body temperature, pulse rate, blood pressure, and 12-leadelectrocardiograms were measured once each at screening, on the 1st day of IV treatment(Day 1) just prior to the morning dose, on the 7th day of IV treatment (Day 7) at 15 minutes
before the end of morning dosing, on the 1st day (Day 8) and the 7th day (Day 14) of oral
treatment at 2 hours post morning dosing, and at the 30-day follow-up visit.
Template version 1.1

Page 3

Public Disclosure Synopsis
Protocol A1501096-2014 December 17-Final

Statistical Methods: The pharmacokinetic concentration analysis was performed on all
subjects treated who had at least 1 concentration in either IV or oral treatment period.
Descriptive statistics of plasma concentrations of voriconazole and the major metabolite
UK-121,265 (N-oxide-voriconazole) were calculated by specified sampling timepoints after
the administration.
The pharmacokinetic parameter analysis was performed on all subjects treated who had atleast 1 of the pharmacokinetic parameters of interest. Descriptive statistics of AUC12,ss,
Cmax,ss and Tmax on the 7th day of IV and oral treatments were calculated. Descriptive
statistics of the ratio of AUC12,ss following oral treatment relative to AUC12,ss following IV
treatment were calculated.
The safety analysis was performed on all subjects who received at least 1 dose of study
medication.
The safety endpoints were summarized in accordance with the Pfizer Data Standards, which
specifies Pfizer’s standard methods for reporting clinical study data. Adverse events werecoded to the system organ class and preferred term using Medical Dictionary for Regulatory
Activities (MedDRA) version 16.0.
RESULTS
Subject Disposition and Demography: Subject disposition is summarized in Table 2. A
total of 21 subjects were assigned to and received study treatment in this study. A total of 16
subjects completed and 5 subjects discontinued the study. Two of the 5 subjects
discontinued before switching to the oral treatment. The reasons for discontinuations weretreatment related adverse event in 2 subjects (hepatic function abnormal and liver function
test abnormal), other (because a treatment with commercial voriconazole was required during
the follow-up) in 2 subjects, and no longer willing to participate in study in 1 subject.
All the 21 subjects who received study treatment were analyzed for safety andpharmacokinetic concentration. One subject (aged 11 years and extensive metabolizer [EM])was excluded from the pharmacokinetic parameter analysis because the subject discontinued
the study on Day 7 and blood sampling for drug concentration was performed at only 1
timepoint on Day 7. Consequently, 20 subjects were analyzed for pharmacokinetic
parameter.

Template version 1.1

Page 4

Public Disclosure Synopsis
Protocol A1501096-2014 December 17-Final

Table 2.

Subject Disposition

Number (%) of Subjects
Assigned to study treatment
TreatedCompleted
Discontinued
Treatment related adverse event
No longer willing to participate in study
Other
Analyzed for pharmacokinetics
Pharmacokinetic concentration
Pharmacokinetic parameter
Analyzed for safety
Adverse events
Laboratory data

All
21
21
16 (76.2)
5 (23.8)2 (9.5)1 (4.8)2 (9.5)a21 (100.0)
20 (95.2)
21 (100.0)
21 (100.0)

a. Because a treatment with commercial voriconazole was required during the follow-up.

Of the 21 subjects, 9 subjects (42.9%) were male and 12 subjects (57.1%) were female. The
mean age was 9.2 years (range: 3 to 14 years), the mean weight was 30.4 kg (range: 11.5 to55.2 kg), and the mean Body Mass Index was 16.6 kg/m2 (range: 11.9 to 22.9 kg/m2)(Table 3).
Table 3.

Demographic Characteristics

Number (%) of Subjects
GenderMale
FemaleRace
AsianAge (years)
2～6
7～11
12～14
Mean ± Standard Deviation
Range
Weight (kg)
Mean ± Standard Deviation
Range
BMI (kg/m2)
Mean ± Standard Deviation
Range
Height (cm)Mean ± Standard Deviation
Range
BMI = Body Mass Index
BMI = Weight / (Height × 0.01)2

N=21
9 (42.9)
12 (57.1)
21 (100.0)
5 (23.8)
10 (47.6)
6 (28.6)
9.2±3.43～1430.4±12.7
11.5～55.2
16.6±3.0
11.9～22.9
132.3±22.6
89.0～166.1

The diseases or procedures that caused immunocompromised status were acute lymphocytic
leukaemia in 8 subjects, acute myeloid leukaemia in 7 subjects, Ewing’s sarcoma in 2
Template version 1.1

Page 5

Public Disclosure Synopsis
Protocol A1501096-2014 December 17-Final

subjects, and neuroblastoma, osteosarcoma, bone marrow transplant, and stem cell transplantin 1 subject each.
Pharmacokinetic and Pharmacogenomic Results: Voriconazole pharmacokinetic
parameters are summarized descriptively for all subjects and by age-weight group in Table 4.
Cmax,ss were generally observed at the end of IV administration and about 1 hour postdose
following oral administration. Individual Tmax values of 1 to 4 hours were observed for bothIV and oral dosing. For all subjects included in the pharmacokinetic parameter analysis, themean AUC12,ss following IV administration was 51.13 µg•hr/mL and the mean AUC12,ss
following oral administration was 45.76 µg•hr/mL. The largest group of subjects (N=14)
was the younger age group of 2 to <12 years. The mean AUC12,ss for this age group was
51.92 µg•hr/mL following IV administration, and 48.23 µg•hr/mL following oral dosing.
The 4 subjects in the older age group with lower body weight (12 to <15 years and <50 kg)
had higher average exposure than the younger subjects with the same dosing regimen,
especially following IV administration. These average values reflect 1 of the 4 subjects who
had the highest AUC12,ss value (for IV dosing, 177 µg•hr/mL; for oral dosing,
117 µg•hr/mL); the values of the 3 other subjects were comparable with the younger age
group. The 2 subjects in the 12 to <15 years age group with ≥50 kg body weight, with lower
voriconazole doses (the same regimen as for adults), both had a lower AUC12,ss than othergroups for both IV dosing and oral dosing. The results for voriconazole Cmax,ss wereconsistent with those observed for AUC12,ss.

Template version 1.1

Page 6

Public Disclosure Synopsis
Protocol A1501096-2014 December 17-Final

Table 4.

Pharmacokinetic Parameters for Plasma Voriconazole Concentration by
Age-Weight

Route Parameter (Units)IV

PO

Age-WeightN

AUC12,ss (µg•hr/mL) All20
142≤ age (years) <1212≤ age (years) <15 and weight (kg) <50 4
12≤ age (years) <15 and weight (kg) ≥50 2
Cmax,ss (µg/mL)
All
20
14
2≤ age (years) <1212≤ age (years) <15 and weight (kg) <50 4
12≤ age (years) <15 and weight (kg) ≥50 2
Tmax (hr)All20
142≤ age (years) <1212≤ age (years) <15 and weight (kg) <50 4
12≤ age (years) <15 and weight (kg) ≥50 2
AUC12,ss (µg•hr/mL) All18
142≤ age (years) <1212≤ age (years) <15 and weight (kg) <50 3
12≤ age (years) <15 and weight (kg) ≥50 1
Cmax,ss (µg/mL)
All
18
14
2≤ age (years) <1212≤ age (years) <15 and weight (kg) <50 3
12≤ age (years) <15 and weight (kg) ≥50 1
Tmax (hr)All18142≤ age (years) <1212≤ age (years) <15 and weight (kg) <50 3
12≤ age (years) <15 and weight (kg) ≥50 1

Geometric
Mean(Coefficient of
Variation%)
51.13 (68)51.92 (51)83.39 (56)17.27 (28)7.323 (51)7.753 (38)9.233 (55)3.092 (42)
NA
NA
NA
NA
45.76 (90)48.23 (83)59.42 (67)NA
7.222 (59)7.755 (50)
7.910 (45)
NA
NA
NA
NA
NA

Mediana(Range)59.25 (14.2-177)
60.15 (23.0-103)
70.45 (55.7-177)
17.60 (14.2-21.0)
7.715 (2.32-19.6)
8.205 (4.62-12.6)
7.715 (6.24-19.6)
3.220 (2.32-4.12)
2.96 (0.950-4.20)
2.96 (0.950-4.00)
4.00 (2.92-4.20)
1.34 (1.00-1.67)
45.60 (10.0-156)
45.60 (12.4-156)
49.40 (36.3-117)
10.00a6.475 (2.03-18.3)
6.695 (3.58-18.3)
6.210 (6.13-13.0)
2.03a
1.04 (0.917-3.78)
1.09 (0.917-3.78)
1.00 (0.950-2.03)
1.00a

N = number of subjects contributing to the summary statistics. Only median (range) is presented for Tmax. Summary
statistics were not calculated if N=1.
NA = not applicable; IV = intravenous administration; PO = oral administration; AUC12,ss = area under the curve overdosing interval at steady state; Cmax,ss = peak plasma concentration at steady state; Tmax = time to reach Cmax
a. Individual value if N=1

Voriconazole pharmacokinetic results by CYP2C19 genotype are summarized in Table 5.
The CYP2C19 genotype status was categorized as EM in 8 subjects, heterozygous extensive
metabolizer (HEM) in 10 subjects, and poor metabolizer (PM) in 2 subjects. Of the 2 PM
subjects, 1 subject had the highest observed AUC12,ss and Cmax,ss values for IV dosing; andthe other subject had among the highest observed AUC12,ss and Cmax,ss values for both IV andoral dosing.

Template version 1.1

Page 7

Public Disclosure Synopsis
Protocol A1501096-2014 December 17-Final

Table 5.

Pharmacokinetic Parameters for Plasma Voriconazole Concentration by
Genotype of CYP2C19

RouteParameter (Units)IV

AUC12,ss (µg•hr/mL)
Cmax,ss (µg/mL)
Tmax (hr)PO

AUC12,ss (µg•hr/mL)
Cmax,ss (µg/mL)
Tmax (hr)Genotypeof
CYP2C19
EM
HEM
PM
EM
HEM
PM
EM
HEM
PM
EM
HEM
PM
EM
HEM
PM
EM
HEM
PM

N
8
10
2
8
10
2
8
10
2
6
10
2
6
10
2
6
10
2

Geometric Mean
(Coefficient of
Variation%)
35.96 (61)56.44 (50)
127.5 (49)5.321 (42)8.116 (37)15.71 (32)NANANA
31.19 (102)49.34 (79)99.14 (24)5.489 (70)7.657 (49)12.28 (8)NA
NA
NAMedian(Range)37.60 (14.2-70.0)
66.55 (23.0-103)
134.4 (91.8-177)
5.965 (2.32-8.31)
8.745 (4.62-12.5)
16.10 (12.6-19.6)
3.49 (1.00-4.20)
2.88 (0.950-4.00)
2.95 (2.92-2.97)
39.60 (10.0-80.8)
45.60 (14.5-156)
100.5 (84.0-117)
5.925 (2.03-11.0)
6.475 (4.45-18.3)
12.30 (11.6-13.0)
1.50 (0.950-3.78)
1.05 (0.917-2.17)
1.02 (0.950-1.08)

N = number of subjects contributing to the summary statistics. Only median (range) is presented for Tmax.
CYP = cytochrome P450; NA = not applicable; IV = intravenous administration; PO = oral administration; AUC12,ss = area
under the curve over dosing interval at steady state; Cmax,ss = peak plasma concentration at steady state; Tmax = time to reach
Cmax; EM = extensive metabolizer; HEM = heterozygous extensive metabolizer; PM = poor metabolizer

Inter-individual variability in voriconazole exposure was high, based on a more than 10-foldrange in individual AUC12,ss values following either IV administration (14.2 to177 µg•hr/mL) or oral administration (10.0 to 156 µg•hr/mL).
The average ratios of oral to IV AUC12,ss were about 1.0 for the 14 younger subjects (2 to<12 years), about 0.6 for 3 subjects aged 12 to <15 years and <50 kg, and about 0.5 for 1
subject aged 12 to <15 years and ≥50 kg. Based on the CYP2C19 genotype, the average
ratio of oral/IV AUC12,ss was about 1.0 for 6 EM subjects and 10 HEM subjects, and about
0.8 for 2 PM subjects. Individual values for the ratio of AUC12,ss ranged from 0.21 to 2.15
(Table 6).

Template version 1.1

Page 8

Public Disclosure Synopsis
Protocol A1501096-2014 December 17-Final

Table 6.

Ratio of oral to IV AUC12,ss for Plasma Voriconazole Concentration
N

All
Age-Weight

Genotype of
CYP2C192≤ age (years) <1212≤ age (years) <15 and weight (kg) <50
12≤ age (years) <15 and weight (kg) ≥50
EM
HEM
PM

18
14
3
1
6
10
2

Ratio of oral to IV AUC12,ss
Arithmetical MeanMediana±Standard Deviation(Range)0.972 ± 0.521
0.814 (0.21～2.15)
1.077 ± 0.547
1.037 (0.21～2.15)
0.648 ± 0.015
0.652 (0.63～0.66)
NA
0.476a0.929 ± 0.536
0.819 (0.45～1.86)
1.035 ± 0.579
0.900 (0.21～2.15)
0.788 ± 0.180
0.788 (0.66～0.92)

N = number of subjects contributing to the summary statistics.
IV = intravenous administration; PO = oral administration; AUC12,ss = area under the curve over dosing interval at steadystate; NA = not applicable (summary statistics were not calculated if N=1); CYP = cytochrome P450; EM = extensive
metabolizer; HEM = heterozygous extensive metabolizer; PM = poor metabolizer
a. Individual value if N=1

The median Tmax of UK-121,265 (N-oxide-voriconazole) concentration was longer after IVadministration (4 to 5 hours) than after oral administration (2 hours), while the time course of
the plasma concentration of UK-121,265 was relatively flat throughout the dosing interval of
12 hours, with individual Tmax values ranging from 0 to 11.8 hours. The exposure to UK121,265 (AUC12,ss and Cmax,ss) was generally similar to the results of exposure tovoriconazole described earlier (Table 7).
Table 7.

Pharmacokinetic Parameters for Plasma UK-121265 Concentration

Route

Parameter (Units)

N

IV

AUC12,ss (µg•hr/mL)
Cmax,ss (µg/mL)
Tmax (hr)
AUC12,ss (µg•hr/mL)
Cmax,ss (µg/mL)
Tmax (hr)

20
20
20
18
18
18

PO

Geometric Mean
(Coefficient of
Variation%)
65.74 (35)6.356 (34)NA
77.86 (39)7.784 (34)NAMediana(Range)68.25 (32.1～135)
6.650 (3.12～12.9)
5.05 (1.00～11.8)
77.00 (34.4～158)
7.490 (3.72～14.1)
2.07 (0.00～7.78)

N = number of subjects contributing to the summary statistics. Only median (range) is presented for Tmax. Summary
statistics were not calculated if N=1.
NA = not applicable; IV = intravenous administration; PO = oral administration; AUC12,ss = area under the curve overdosing interval at steady state; Cmax,ss = peak plasma concentration at steady state; Tmax = time to reach Cmax
a. Individual value if N=1

Safety Results: Overview of adverse events is provided in Table 8 (by age- weight) andTable 9 (by genotype of CYP2C19).

Template version 1.1

Page 9Public Disclosure Synopsis
Protocol A1501096-2014 December 17-Final

Table 8.

Overview of Adverse Events by Age-Weight

Number (%) of Subjects

Number of adverse events
Subjects with adverse events
Subjects with serious adverse
eventsSubjects with severe adverse
eventsSubjects discontinued due toadverse events
Subjects with dose reduced or
temporary discontinuation due
to adverse events

Table 9.

All

2≤ Age (years) <1212≤ Age (years) <15 12≤ Age (years) <15
and Weight (kg) <50 and Weight (kg) ≥50
N=21
N=15
N=4
N=2
All
Treatment
All
Treatment
All
Treatment
All
Treatment
Causalities Related Causalities Related Causalities Related Causalities Related
80
19
50
11
26
6
4
2
18 (85.7) 12 (57.1) 13 (86.7) 8 (53.3) 4 (100.0) 3 (75.0) 1 (50.0) 1 (50.0)
0
0
0
0
0
0
0
0
4 (19.0)

1 (4.8)2 (13.3)02 (50.0)

1 (25.0)00

2 (9.5)2 (9.5)1 (6.7)1 (6.7)

1 (25.0)

1 (25.0)

0

0

0

0

0

0

0

0

0

0

Overview of Adverse Events by Genotype of CYP2C19

Number (%) of Subjects

EM
N=9
All
Treatment
Causalities
Related42
13
7 (77.8)
6 (66.7)
00
3 (33.3)
1 (11.1)
2 (22.2)
2 (22.2)

HEM
N=10
All
Treatment
Causalities
Related29
6
9 (90.0)
6 (60.0)00
1 (10.0)000Number of adverse events
Subjects with adverse events
Subjects with serious adverse events
Subjects with severe adverse events
Subjects discontinued due to adverse
eventsSubjects with dose reduced or0000
temporary discontinuation due toadverse events
EM = extensive metabolizer; HEM = heterozygous extensive metabolizer; PM = poor metabolizer

PM
N=2
All
Treatment
Causalities
Related90
2 (100.0)
0
0
0
0
0
0
0
0

0

In total, all-causality adverse events were reported 80 cases in 18 subjects (85.7%) andtreatment-related adverse events were reported 19 cases in 12 subjects (57.1%). No apparent
trend was observed in the incidences of adverse events by age-weight, by genotype of
CYP2C19. The incidence of adverse events related to liver disorder was lower following IV
administration compared to the overall period.
No deaths or serious adverse events were reported in this study. Discontinuations due toadverse events were reported in 2 subjects (hepatic function abnormal and liver function test
abnormal in 1 subject each). Both events were considered as treatment-related. Both events
required treatment but were confirmed to have resolved after the discontinuation of study
treatment (Table 10).

Template version 1.1

Page 10

Public Disclosure Synopsis
Protocol A1501096-2014 December 17-Final

Table 10. Discontinuations Due to Adverse Events
MedDRA version 16.0
Preferred term
Hepatic function abnormal
Liver function test abnormal

MedDRA = Medical Dictionary for Regulatory Activities

Severity

OutcomeCausality

SevereModerate

Resolved
Resolved

Treatment-related
Treatment-related

Common adverse events were shown in Table 11. Frequently reported all-causality adverse
events (incidence ≥10% in total) were febrile neutropenia in 13 subjects (61.9%),
photophobia in 9 subjects (42.9%), rash in 4 subjects (19.0%), hepatic function abnormal in 3
subjects (14.3%), alanine aminotransferase increased in 3 subjects (14.3%), and aspartate
aminotransferase increased in 3 subjects (14.3%). Frequently reported treatment-related
adverse events (incidence ≥10% in total) were photophobia in 9 subjects (42.9%) and hepaticfunction abnormal in 3 subjects (14.3%).
The majority of adverse events were mild or moderate in severity. Severe all-causality
adverse events were reported in 4 subjects (abdominal pain, alanine aminotransferase
increased and oropharyngeal pain in 1 subject; febrile neutropenia and epistaxis in 1 subject;hepatic function abnormal in 1 subject; sepsis in 1 subject). Severe treatment-related adverse
events were reported in 1 subject (hepatic function abnormal). Except for alanine
aminotransferase increased in 1 subject, severe adverse events were confirmed to haveresolved.

Template version 1.1

Page 11

Public Disclosure Synopsis
Protocol A1501096-2014 December 17-Final

Table 11. Adverse Events (Reported for ≥2 Subjects)
System organ class
Preferred term
MedDRA/ version16.0
Blood and lymphatic system disorders
Febrile neutropenia
Eye disorders
Photophobia
Gastrointestinal disorders
Vomiting
General disorders and administration site
conditions
Pyrexia
Hepatobiliary disorders
Hepatic function abnormal
Infections and infestations
SepsisInvestigations
Alanine aminotransferase increased
Aspartate aminotransferase increased
Gamma-glutamyltransferase increased
Skin and subcutaneous tissue disorders
Dermatitis
Rash

MedDRA = Medical Dictionary for Regulatory Activities

N=21
All causalities

Treatment-related

13 (61.9)09 (42.9)9 (42.9)2 (9.5)02 (9.5)0

3 (14.3)

3 (14.3)

2 (9.5)0

3 (14.3)
3 (14.3)
2 (9.5)000

2 (9.5)4 (19.0)

2 (9.5)1 (4.8)As expected from the underlying disease and its treatment of subjects, the incidence ofhematology test abnormalities was high. Frequently observed non-hematology test
abnormalities (incidence ≥20%) were increases of C-reactive protein (76.2%), gammaglutamyltransferase increased (38.1%), aspartate aminotransferase increased (28.6%), andalanine aminotransferase increased (28.6%). Since most of the subjects of this study hadreceived prior chemotherapy for the treatment of the underlying disease, the abnormalities inliver function tests may have been a consequent of the chemotherapy. There were no vital
sign or electrocardiogram abnormalities reported as adverse events in this study.
CONCLUSION(S):•

Voriconazole at the dosing regimens in this study provided average steady-state exposure(AUC12,ss) of 51.13 µg•hr/mL for IV treatment and 45.76 µg•hr/mL for oral treatment in
immunocompromised children aged 2 to <15 years at high risk for systemic fungal
infection.

•

Systemic exposure in 2 subjects with CYP2C19 PM genotype in this study appeared to behigher than that in subjects categorized as EM or HEM. No apparent difference of
exposure was observed between the groups based on age and weight.

•

The IV and IV to oral switch regimen of voriconazole were safe and well tolerated,showing no obvious difference from the existing safety profile. The majority of adverse

Template version 1.1

Page 12

Public Disclosure Synopsis
Protocol A1501096-2014 December 17-Final

events were mild or moderate in severity. Frequently reported treatment-related adverse
events were photophobia and hepatic function abnormal. Discontinuations due to adverse
events were reported in 2 subjects and both events were confirmed to have resolved. No
subject experienced a serious adverse event.

Template version 1.1

Page 13