Public Disclosure Synopsis
Protocol A0561023 – 21 January 2015 –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: Diflucan®/Fluconazole
PROTOCOL NO.: A0561023
PROTOCOL TITLE: A multicenter open-label non-comparative study of fluconazole forthe treatment of vulvovaginal candidiasis
Study Center(s): 10 centers in Japan
Study Initiation Date and Primary Completion or Final Completion Dates: 05 March2013 and 22 November 2013
Phase of Development: Phase 3
Study Objective(s): Primary objective: To confirm the efficacy and safety of single oral
administration of fluconazole 150 mg for the treatment of vulvovaginal candidiasis inJapanese patients.
Secondary objective: To measure the concentration of fluconazole in plasma and vaginal
discharge in Japanese patients following single oral administration of fluconazole 150 mg
and evaluate the drug disposition in Japanese patients.
METHODS
Study Design: This study was conducted as a multicenter, open-label, non-comparative
study (Phase 3 study) in Japan. Three fluconazole 50 mg capsules were orally administeredonly once on the first day of the treatment of vulvovaginal candidiasis. Evaluation time
points were as follows: Day 1 (the start of the treatment), Day 2, Day 3, Day 7, Day 14,
Day 28.
Number of Subjects (Planned and Analyzed): Planned number of subjects and analyzed
number of subjects were both 99 in modified-Intent to Treat (m-ITT) whose therapeutic
responses were evaluated at Day 28 as effective or ineffective.
Diagnosis and Main Criteria for Inclusion: Female Japanese patients aged 18 years orolder (<80 years as a general), who had clinical symptoms and signs of vulvovaginal
candidiasis, who were positive for Candida by fungal culture.
Study Treatment: Fluconazole was supplied as 50 mg capsules. All subjects received asingle oral dose of 150 mg of fluconazole (three 50 mg capsules) on Day 1.
Efficacy and Pharmacokinetic Endpoints:

Template version 1.1

Page 1

Public Disclosure Synopsis
Protocol A0561023 – 21 January 2015 –Final

Efficacy endpoints
Primary endpoint: Therapeutic outcome [7th day of treatment (Day 7), Day 14, Day 28].
Primary evaluation was the therapeutic outcome on Day 28. Secondary endpoints: Clinicalefficacy (Day 7, Day 14, Day 28), mycological efficacy (Day 7, Day 14, Day 28), andclinical symptoms (Day 3, Day 7, Day 14, Day 28).
Pharmacokinetic endpoints
Pharmacokinetic parameters of fluconazole concentrations in plasma, potassium-correctedfluconazole concentrations in vaginal discharge, and weight-corrected fluconazole
concentrations in vaginal discharge. Samples of plasma and vaginal discharge werecollected before dosing and 2 hours (1.8-2.2 hours), 24 hours (20.4-27.6 hours), 48 hours(Day 3-Day 4), and 168 hours (Day 6-Day 8) after the dosing in order to analyze theconcentration of fluconazole in plasma and vaginal discharge. A validated highly sensitiveand specific high-performance liquid chromatography/tandem mass spectrometry method
was used for analysis.
Safety Evaluations: Adverse events were recorded on the case report form from the time of
the first treatment (Day 1) through the last subject visit, or including the 28 calendar days
after the last administration of the investigational product, whichever is later. Serious
adverse events were reported from the time that the signed informed consent was obtained
through and including the 28 calendar days after the last administration of the investigational
product. Clinical laboratory tests were performed and blood pressure (sitting
systolic/diastolic) and heart rate were both measured prior to the first dose (Day 1), and on
Day 7, Day 14, and Day 28.
Statistical Methods: The primary analysis population was m-ITT, which included subjects
with vulvovaginal candidiasis who received the investigational products, who tested positive
for Candida in the vulva and/or vagina at Day 1 (before dosing), and whose clinical efficacy
was evaluated. The Per Protocol Set (PPS) included subjects in the above m-ITT who had
incurred no major violation from the protocol, such as a violation of the inclusion criteria,
and who underwent the evaluation specified for the observation time points defined in the
protocol.
The plasma concentration analysis set was defined as those subjects who received theinvestigational products and whose plasma concentrations were measured at least once. The
plasma parameter analysis set was defined as those subjects who were included in the plasma
concentration analysis set and for whom at least one plasma concentration parameter was
calculated. The vaginal discharge concentration analysis set and the vaginal dischargeparameter analysis set were defined likewise.
For plasma concentration, weight-corrected vaginal discharge concentration, and potassiumcorrected vaginal discharge concentration of fluconazole, and the pharmacokinetic
parameters for fluconazole were estimated by using non-compartmental methods.
The safety analysis set was defined as all subjects who received the investigational products.

Template version 1.1

Page 2

Public Disclosure Synopsis
Protocol A0561023 – 21 January 2015 –Final

The point estimate of efficacy rate (rate of effectiveness) of the therapeutic outcome and thecorresponding 95% confidence interval (CI) were calculated. The primary analysis of the
primary endpoint was the efficacy rate of the therapeutic outcome in the m-ITT on Day 28,
and efficacy in this study would be confirmed if the lower bound of the 95% CI of thetherapeutic outcome on Day 28 was greater than 38% (threshold value). For the clinicalefficacy, the point estimate of cure rate and cure or improvement rate and the corresponding
95% CIs were calculated, respectively. For the mycological efficacy, the point estimate oferadication rate and the corresponding 95% CI were calculated. For the clinical symptoms,
the frequency and proportion for each category were summarized.
Major safety analyses were summarized according to algorithms and forms specified in the
Pfizer Data Standards (PDS). Adverse events were coded by system organ class andpreferred term from the Medical Dictionary for Regulatory Activities (MedDRA) version
16.1.
RESULTS
Subject Disposition and Demography: Table 1 summarizes the subject disposition andanalysis set. In this study, 157 subjects were assigned and all of them received fluconazole
150 mg. A total of 99 subjects completed the study, and 58 subjects discontinued the study.
The reasons for discontinuation of the study were “does not meet the inclusion criteria” (56subjects), “no longer willing to participate in the study” (1 subject), and “adverse events not
related to the study drug” (1 subject). Of the 56 subjects who did not meet the inclusion
criteria, 55 subjects were negative for Candida by fungal culture, and the remaining 1 subject
had abnormal liver function test, which met the exclusion criteria. For efficacy, among all
157 subjects who received the investigational products, 102 subjects were included in the mITT, and 100 subjects were included in the PPS. A total of 55 subjects were excluded fromthe m-ITT for efficacy because they were negative for Candida by fungal test. A total of 57
subjects including the above 55 and 2 subjects (1 subject who discontinued the study becauseof abnormal liver function test values before the administration of the investigational productand did not undergo evaluation on Day 28 and the other subject who was no longer willing toparticipate in the study) were excluded from the PPS. For the pharmacokinetics population,
all 157 subjects were included in the plasma pharmacokinetics concentration, the plasma
pharmacokinetics parameters, the vaginal discharge pharmacokinetics concentration, and thevaginal discharge pharmacokinetics parameters analysis sets. For the safety analysis set, all
157 subjects who took the investigational products were included.

Template version 1.1

Page 3

Public Disclosure Synopsis
Protocol A0561023 – 21 January 2015 –Final

Table 1.

Subject Disposition and Analysis Set

Assigned to study treatment
TreatedCompleted
Discontinued
Does not meet the inclusion criteria
No longer willing to participate in the study
Adverse events not related to the study drug
Analyzed for efficacy:
m-ITT
PPS
Analyzed for pharmacokinetics:
Plasma concentration analysis set
Plasma parameter analysis set
Vaginal discharge concentration analysis
Vaginal discharge parameter analysis set
Analyzed for safety:
Adverse events
Laboratory data
m-ITT = modified-Intent to Treat, PPS = Per Protocol Set

Number (%) of Subjects
157
157
99 (63.1)
58 (36.9)
56 (35.7)
1 (0.6)
1 (0.6)102 (65.0)
100 (63.7)
157 (100.0)
157 (100.0)
157 (100.0)
157 (100.0)
157 (100.0)
157 (100.0)

For all of the 157 subjects who received the investigational products, the mean age was
31.8 years (range: 18 to 57 years), the mean weight was 54.0 kg (range: 39.8 to 136.8 kg),and the mean body mass index was 21.3 kg/m2 (range: 15.9 to 47.4 kg/m2). There were noapparent differences in demographic characteristics among the analysis populations (Table 2).

Template version 1.1

Page 4

Public Disclosure Synopsis
Protocol A0561023 – 21 January 2015 –Final

Table 2.

Demographic Characteristics

Number (%) of Subjects
GenderFemaleRace
AsianAge (years)<18
18 - 4445 - 64≥65
Mean ± Standard Deviation
Range
Weight (kg)<40
40 - <50
50- <60≥60
Mean ± Standard Deviation
Range
BMI (kg/m2)
Mean ± Standard Deviation
Range
Height (cm)Mean ± Standard Deviation
Range

ALL Treated
N=157

m-ITT
N=102

PPS
N=100

157 (100.0)

102 (100.0)

100 (100.0)

157 (100.0)

102 (100.0)

100 (100.0)0
141 (89.8)
16 (10.2)031.8±8.5
18～57

0
91 (89.2)
11 (10.8)031.9±8.2
18～55

0
89 (89.0)
11 (11.0)032.1±8.1
18～55

1 (0.6)55 (35.0)
74 (47.1)
27 (17.2)
54.0±10.9
39.8～136.8

037 (36.3)
48 (47.1)
17 (16.7)
53.9±11.5
40.0～136.8

036 (36.0)
47 (47.0)
17 (17.0)
53.9±11.6
40.0～136.8

21.3±3.7
15.9～47.4

21.2±3.9
15.9～47.4

21.2±3.9
15.9～47.4

159.2±5.5145.0～173.0

159.2±5.3145.0～172.0

159.2±5.3145.0～172.0

m-ITT = modified-Intent to Treat，PPS = Per Protocol Set，BMI = body mass index
BMI = Weight / (Height × 0.01)2

Among all of the 157 subjects who received the investigational products, 102 subjects tested
positive for Candida by fungal culture at baseline: Candida detected included Candida
albicans (100 strains), C.parapsilosis (2 strains), C.glabrata (1 strain), and Candida species(1 strain). The remaining 55 subjects were negative for Candida.
Efficacy, Pharmacokinetic Research Results:
Efficacy results
Table 3 summarizes the therapeutic outcomes in the m-ITT. The therapeutic outcome wasconsidered as effective when the clinical efficacy was cure and the mycological efficacy waseradication. The efficacy rate for the therapeutic outcome on Day 28 in the m-ITT (primary
analysis population) was 74.7% [95% CI: 65.0% to 82.9%]. Efficacy was confirmed since
the lower bound of the 95% CI of the efficacy rate of the therapeutic outcome on Day 28 was
greater than 38% (pre-specified threshold value). The same result was also obtained in the
PPS.

Template version 1.1

Page 5

Public Disclosure Synopsis
Protocol A0561023 – 21 January 2015 –Final

Table 3.

Therapeutic Outcome (m-ITT, Day 28: Primary Analysis of Primary
endpoint)
Number of
Evaluated
Subjects

Day 7
Day 14
Day 2895
100
102

Therapeutic Outcome
Effective
Number (%)
of Subjects
31 (32.6)
52 (52.0)
74 (72.5)

Ineffective
Number (%)
of Subjects
61 (64.2)
44 (44.0)
25 (24.5)

Indeterminate
Number (%) of
Subjects
3 (3.2)4 (4.0)3 (2.9)Efficacy
Ratea
%
33.7
54.2
74.7

95%CI
24.2 - 44.3
43.7 - 64.4
65.0 - 82.9

m-ITT = modified-Intent to Treat, CI = confidence interval
a. Efficacy Rate (%) = Number of Subjects with Effective result/ Number of Evaluated Subjects excluding Number of
Subjects with Indeterminate result × 100

Table 4 summarizes the clinical efficacy in the m-ITT. Subjects with complete
disappearance of clinical symptoms were considered as cure, and those with improved
clinical symptoms were considered as improvement. The cure rate was 34.8% on Day 7,
57.3% on Day 14, and 81.6% on Day 28. The cure and improvement rate was 100.0% on
Day 7, 99.0% on Day 14, and 95.9% on Day 28. The results were also the same in the PPS.
Table 4.

Clinical Efficacy (m-ITT)

Clinical Efficacy
NumberCure Improvement Failure Indeterminate
Cure Ratea
of
NumberNumberNumber Number (%)
Evaluated(%) of(%) of(%) ofof Subjects
Subjects
Subjects
Subjects
Subjects
%
95%CI
Day 7
Day 14
Day 2899
101102

32 (32.3)
55 (54.5)
80 (78.4)

60 (60.6)
40 (39.6)
14 (13.7)

0
1 (1.0)4 (3.9)7 (7.1)5 (5.0)4 (3.9)

34.8
57.3
81.6

Cure and
Improvement
Rateb
%
95%CI
25.1 - 45.4 100.0 96.1 - 100.0
46.8 - 67.3 99.0 94.3 - 100.0
72.5 - 88.7 95.9 89.9 - 98.9

m-ITT = modified-Intent to Treat, CI = confidence intervala. Cure Rate (%) = Number of Subjects with Cure/ Number of Evaluated Subjects excluding Number of Subjects with
Indeterminate result × 100
b. Cure and Improvement Rate (%) = Number of Subjects with Cure and Improvement/ Number of Evaluated Subjects
excluding Number of Subjects with Indeterminate result × 100

Table 5 summarizes the mycological efficacy in the m-ITT. The eradication rate was 95.7%
on Day 7, 89.8% on Day 14, and 85.9% on Day 28. The results were also the same in the
PPS.

Template version 1.1

Page 6

Public Disclosure Synopsis
Protocol A0561023 – 21 January 2015 –Final

Table 5.

Mycological Efficacy (m-ITT)
Number of
Evaluated
Subjects

Day 7
Day 14
Day 2895100102

Mycological Efficacy
Eradication
Number (%) of
Subjects
90 (94.7)
88 (88.0)
85 (83.3)

Persistence
Number (%)
of Subjects
4 (4.2)10 (10.0)
14 (13.7)

Indeterminate
Number (%)
of Subjects
1 (1.1)2 (2.0)3 (2.9)Eradication
Ratea
%
95.7
89.8
85.9

95%CI
89.5 - 98.8
82.0 - 95.0
77.4 - 92.0

m-ITT = modified-Intent to Treat, CI = confidence intervala Eradication Rate (%) = Number of Subjects with Eradication/ Number of Evaluated Subjects excluding Number of
Subjects with Indeterminate result ×100

For clinical symptoms, the total scores for clinical symptoms for each subject in the m-ITT
improved from Day 3. The mean total scores were 4.5 at Day 3, 0.8 at Day 14, and 0.4 at
Day 28 (Table 6).
Table 6.

Summary of Total Score for Clinical Symptoms (m-ITT)

Day 1
Day 3
Day 7
Day 14
Day 28

Number of
Evaluated
Subjects
102
98
93
98
99

m-ITT = modified-Intent to Treat

Mean

Min

Max

Median

11.0
4.5
1.8
0.8
0.4

4
0
0
0
0

19
12
10
7
9

11.0
4.0
1.0
0.0
0.0

Individual clinical symptoms also improved from Day 3 (Table 7). The results were also thesame in the PPS.

Template version 1.1

Page 7

Public Disclosure Synopsis
Protocol A0561023 – 21 January 2015 –Final

Table 7.

Clinical Symptoms (m-ITT)N

None(Score 0)

Clinical Symptoms
Mild
Moderate(Score 1)(Score 2)

Vulvovaginal Itching
Day 1
102
4 (3.9)33 (32.4)
44 (43.1)
Day 3
99
27 (27.3)
62 (62.6)
9 (9.1)Day 7
98
70 (71.4)
27 (27.6)
1 (1.0)Day 1499
83 (83.8)
16 (16.2)
0
Day 2899
92 (92.9)
6 (6.1)1 (1.0)Vulvovaginal Burning Sensation
Day 1
102
31 (30.4)
44 (43.1)
21 (20.6)
Day 3
99
77 (77.8)
16 (16.2)
6 (6.1)Day 7
98
90 (91.8)
6 (6.1)2 (2.0)Day 1499
95 (96.0)
4 (4.0)0
Day 2899
98 (99.0)
1 (1.0)0
Vaginal Discharge
Day 1
102
9 (8.8)39 (38.2)
41 (40.2)
Day 3
99
51 (51.5)
38 (38.4)
10 (10.1)
Day 7
98
74 (75.5)
22 (22.4)
2 (2.0)Day 1499
91 (91.9)
7 (7.1)1 (1.0)Day 2899
91 (91.9)
7 (7.1)1 (1.0)Excoriation
Day 1
102
50 (49.0)
26 (25.5)
22 (21.6)
Day 3
99
70 (70.7)
26 (26.3)
2 (2.0)Day 7
98
82 (83.7)
10 (10.2)
1 (1.0)Day 1499
97 (98.0)
1 (1.0)0
Day 2899
98 (99.0)
1 (1.0)0
Vulval Oedema
Day 1
102
58 (56.9)
27 (26.5)
17 (16.7)
Day 3
99
81 (81.8)
17 (17.2)
0
Day 7
98
92 (93.9)
1 (1.0)0
Day 1499
98 (99.0)00
Day 2899
99 (100.0)
00Redness of Vulva
Day 1
102
12 (11.8)
42 (41.2)
39 (38.2)
Day 3
99
40 (40.4)
53 (53.5)5 (5.1)Day 7
98
71 (72.4)
19 (19.4)
3 (3.1)
Day 1499
91 (91.9)
7 (7.1)0
Day 2899
93 (93.9)
6 (6.1)0
Vaginal Redness
Day 1
102
23 (22.5)
39 (38.2)
32 (31.4)
Day 3
99
54 (54.5)
36 (36.4)
8 (8.1)Day 7
98
74 (75.5)
18 (18.4)
1 (1.0)Day 1499
88 (88.9)
10 (10.1)
0Day 2899
98 (99.0)0
1 (1.0)Vaginal content character
N
NormalMucoidPaste-Like(Score 0)(Score 1)(Score 2)
Day 1
102
1 (1.0)3 (2.9)41 (40.2)
Day 3
99
19 (19.2)
50 (50.5)
29 (29.3)
Day 7
98
55 (56.1)
26 (26.5)
12 (12.2)
Day 1499
74 (74.7)
21 (21.2)
3 (3.0)Day 2899
91 (91.9)
5 (5.1)2 (2.0)m-ITT = modified-Intent to Treat , NA = not applicable

Template version 1.1

Page 8

Number (%) of subjects
Severe(Score 3)NA

21 (20.6)
1 (1.0)
0
0
0

0
0
0
0
0

6 (5.9)
0
0
0
0

0
0
0
0
0

13 (12.7)
0
0
0
0

0
0
0
0
0

4 (3.9)00
0
00
1 (1.0)5 (5.1)1 (1.0)
0

0
0
0
0
0

0
1 (1.0)5 (5.1)1 (1.0)09 (8.8)00
000
1 (1.0)5 (5.1)1 (1.0)08 (7.8)00
000
1 (1.0)5 (5.1)1 (1.0)0

Cottage Cheese-Like,CheeseLike Or Granular (Score 3)
57 (55.9)
000
1 (1.0)NA01 (1.0)5 (5.1)1 (1.0)0Public Disclosure Synopsis
Protocol A0561023 – 21 January 2015 –Final

Pharmacokinetic results
Table 8 shows plasma concentration, weight-corrected vaginal discharge concentration, andpotassium-corrected vaginal discharge concentration of fluconazole in 157 Japanese subjects
with vulvovaginal candidiasis following a single oral administration of fluconazole 150 mg.
Following the single oral administration of fluconazole 150 mg, fluconazole was rapidly
absorbed and the mean plasma fluconazole concentration reached the maximum at 2 hours
after dose administration. Thereafter, it was moderately eliminated, and plasma fluconazole
concentration was detected over 168 hours after dose administration in all subjects for whomsamples were collected, except for 1 subject.
Fluconazole was relatively moderately transferred from the systemic circulation to thevaginal discharge, and both the mean weight-corrected and mean potassium-correctedfluconazole concentration in vaginal discharge showed maximum values at 24 hours after
dose administration. Thereafter, both concentrations moderately decreased similarly as theplasma concentration. The weight-corrected and potassium-corrected fluconazole
concentration in vaginal discharge was detected at 168 hours after dose administration in all
subjects for whom samples were collected, but the potassium-corrected concentration invaginal discharge could not be calculated in 2 subjects as potassium concentration in vaginal
discharge was below the quantifiable limit.
Table 8.

Plasma and Vaginal Discharge Fluconazole Concentration (µg/mL) in
Japanese Subjects with Vulvovaginal Candidiasis Following a Single Oral
Administration of Fluconazole 150 mg

SamplePlasmaVaginal Discharge(weight-corrected)
Vaginal Discharge(potassium-corrected)

Nominal Time
Post Dose (h)Number of subjects
Mean±SD
Number of subjects
Mean±SD
Number of subjects
Mean±SD

2

24

48

168

157
3.76±1.13
157
1.06±0.763154
1.32±1.0666
2.44±0.41465
1.65±0.685652.10±1.03154
1.06±0.431
153
0.793±0.493
153
0.839±0.553

146
0.138±0.115
140
0.118±0.180
138
0.107±0.105

Table 9 summarizes the ratio of vaginal discharge fluconazole concentration (weightcorrected and potassium-corrected) to plasma fluconazole concentration in each subject. The
mean ratios of vaginal discharge concentration (weight-corrected and potassium-corrected) toplasma concentration of fluconazole were 0.28 and 0.35, respectively, at 2 hours after dose
administration. After 24 hours post dose, the ratios of both weight-corrected and potassiumcorrected concentration to plasma concentration were 0.67 or more through 168 hours after
dose administration when the last samples for pharmacokinetics analysis were collected.

Template version 1.1

Page 9Public Disclosure Synopsis
Protocol A0561023 – 21 January 2015 –Final

Table 9.

Descriptive Summary of the Ratio of Vaginal Discharge Fluconazole
Concentration to Plasma Fluconazole Concentration in Japanese Subjects
with Vulvovaginal Candidiasis Following a Single Oral Administration of
Fluconazole 150 mg

Adjustment
concentration
Weight-correctedPotassium-corrected

Nominal Time
Post Dose (h)Number of subjects
Mean±SD
Number of subjects
Mean±SD

2

24

48

168

157
0.28±0.19154
0.35±0.2765
0.67±0.2265
0.84±0.37152
0.74±0.32
152
0.81±0.45140
0.92±1.2138
0.81±0.49

Table 10 summarizes the pharmacokinetics parameters estimated from the plasma
concentration, weight-corrected vaginal discharge concentration, and potassium-correctedvaginal discharge concentration of fluconazole in 157 Japanese subjects with vulvovaginal
candidiasis following a single oral administration of fluconazole 150 mg. Following thesingle oral administration of fluconazole 150 mg, the geometric means of maximum
observed concentration (Cmax) for plasma concentration, weight-corrected vaginal discharge
concentration, and potassium-corrected vaginal discharge concentration were 3.71, 1.33, and1.53 µg/mL, respectively; the median time to reach maximum observed concentration (Tmax)
were 1.9, 20.5, and 20.5 hours, respectively; and the geometric means of area under theconcentration-time curve from zero to time of last measurable concentration (AUClast) were156.1, 79.5, and 85.3 µg•h/mL, respectively. Because of the limited numbers of sample
collection points, half-life (t½) and area under the concentration-time curve from time zero to
infinity (AUCinf) could not be estimated in half or more of the subjects, and the summary
statistics for these parameters were not calculated.
Table 10. Descriptive Summary of Pharmacokinetics Parameters for Plasma andVaginal Discharge Fluconazole Concentration in Japanese Subjects with
Vulvovaginal Candidiasis Following a Single Oral Administration of
Fluconazole 150 mg
SamplePlasmaCmax (µg/mL)
157
3.71 (24)Tmaxa (h)157
1.9 (1.8 - 70.3)

AUClast (µg•h/mL)
Number of subjects
149
Geometric Mean
156.1 (22)(%CV)
Vaginal Discharge
Number of subjects
157
157
144
(weight-corrected)
Geometric Mean
1.33 (49)79.5 (43)20.5 (1.8 - 116.6)(%CV)
Vaginal Discharge
Number of subjects
157
157
142
(potassium-corrected) Geometric Mean
1.53 (59)85.3 (48)20.5 (1.8 - 116.6)(%CV)
a. Median (range)
Cmax = maximum observed concentration, Tmax = time to reach maximum observed concentration, AUClast = area under theconcentration-time curve from zero to time of last measurable concentration, CV = coefficient of variation

Table 11 shows the ratio of pharmacokinetics parameters (Cmax and AUClast) for the vaginal
discharge fluconazole concentration to the corresponding parameters for the plasma

Template version 1.1

Page 10

Public Disclosure Synopsis
Protocol A0561023 – 21 January 2015 –Finalfluconazole concentration. The mean ratios of pharmacokinetics parameters for the vaginal
discharge fluconazole concentration (weight-corrected and potassium-corrected) to thecorresponding parameters for the plasma fluconazole concentration were 0.41 and 0.49 for
Cmax, and 0.55 and 0.60 for AUClast, respectively. As AUCinf could not be estimated in half
or more of the subjects, the summary statistics for the ratio of AUCinf were not calculated.
Table 11. Descriptive Summary of the Ratio of Pharmacokinetics Parameters for
Vaginal Discharge Fluconazole Concentration to the Corresponding
Pharmacokinetics Parameters for Plasma Fluconazole Concentration in
Japanese Subjects with Vulvovaginal Candidiasis Following a Single Oral
Administration of Fluconazole 150 mg
Adjustment concentration
Weight-corrected

Cmax
AUClastNumber of subjects
157
143
Mean±SD
0.41±0.22
0.55±0.19
Potassium-corrected
Number of subjects
157
141
Mean±SD
0.49±0.28
0.60±0.26
Cmax = maximum observed concentration, AUClast = area under the concentration-time curve from zero to time of lastmeasurable concentration

Safety Results: A summary of the adverse events is shown in Table 12. Among the
157 subjects who received the investigational product, 37 subjects (23.6%) reported allcausality adverse events (49 events) and 12 subjects (7.6%) reported treatment-related
adverse events (14 events)
Table 12. Summary of Adverse Events
Number (%) of subjects:

All-causalities49
37 (23.6)
00
1 (0.6)0

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

N=157

Treatment-related14
12 (7.6)0000Common adverse events are shown in Table 13. The most common (≥2 subjects) allcausality adverse events were nasopharyngitis (8 subjects, 5.1%); cystitis, genital herpes, andeczema (4 subjects, 2.5%, each); diarrhoea, nausea, and genital haemorrhage (3 subjects,
1.9%, each); and pyrexia and bronchitis (2 subjects, 1.3%, each). The most common (≥2subjects) treatment-related adverse events were diarrhoea and nausea (3 subjects, 1.9%, each).
All adverse events were mild or moderate in severity and no severe adverse events werereported.

Template version 1.1

Page 11

Public Disclosure Synopsis
Protocol A0561023 – 21 January 2015 –Final

Table 13. Adverse Events (Reported for ≥2 Subjects)
System organ classpreferred term
MedDRA/ version 16.1
Gastrointestinal disorders

All-causalities

N=157

Treatment-related

diarrhoea
nausea3 (1.9)3 (1.9)3 (1.9)3 (1.9)pyrexia2 (1.3)1 (0.6)bronchitis
cystitisgenital herpes
nasopharyngitis

2 (1.3)4 (2.5)4 (2.5)8 (5.1)0
1 (0.6)
1 (0.6)0

genital haemorrhage

3 (1.9)1 (0.6)eczema4 (2.5)0General disorders and administration site conditions
Infections and infestations

Reproductive system and breast disorders
Skin and subcutaneous tissue disorders
MedDRA = Medical Dictionary for Regulatory Activities

No subject died or experienced serious adverse events. One subject discontinued the study
due to vulvovaginitis trichomonal, which was considered unrelated to the investigational
drug and was confirmed to have resolved.
Table 14. Discontinuations Due to Adverse Events
MedDRA version 16.1
Preferred term
Vulvovaginitis trichomonal

Severity

OutcomeCausality

Moderate

Resolved

Other-due totrichomonas infection

MedDRA = Medical Dictionary for Regulatory Activities

Throughout the study period, there were no apparent changes from baseline in laboratory
parameters. Abnormal laboratory values reported as adverse events were blood creatine
phosphokinase increased (1 subject, 0.6%) and hepatic enzyme increased (1 subject, 0.6%).
Both of them were mild in severity. There were no vital sign abnormalities reported asadverse events.

CONCLUSION(S): From this multicenter, open-label, non-comparative study conducted inJapanese patients with clinical symptoms and signs of vulvovaginal candidiasis, in which asingle oral dose of fluconazole 150 mg was administered, the following conclusions wereobtained:•

The efficacy rate for the therapeutic outcome (primary endpoint) (considered as
effective when the clinical efficacy was cure and the mycological efficacy waseradication) on Day 28 in the m-ITT population was 74.7% (95% CI: 65.0% to 82.9%),and efficacy was confirmed since the lower bound of the 95% CI was greater than 38%

Template version 1.1

Page 12

Public Disclosure Synopsis
Protocol A0561023 – 21 January 2015 –Finalof pre-specified threshold value. Regarding the secondary endpoint results on Day 28 in
the m-ITT: for the clinical efficacy, the cure rate was 81.6%, and the cure or
improvement rate was 95.9%. For the mycological efficacy, the eradication rate was
85.9%. For the clinical symptoms, the overall clinical symptoms improved from Day 3.
•

Through 2 to 168 hours post dose, fluconazole was detected in the plasma and vaginal
discharge in most of the subjects. Also, the mean ratios of vaginal discharge fluconazole
concentration versus plasma fluconazole concentration were 0.67 to 0.92 for 24 to
168 hours post dose.

•

The mean ratios of pharmacokinetics parameters for the vaginal discharge fluconazole
concentration (weight-corrected and potassium-corrected) versus the corresponding
pharmacokinetics parameters for plasma fluconazole concentration were 0.41 and 0.49
for Cmax, and 0.55 and 0.60 for AUClast, respectively.

•

All adverse events were mild or moderate in severity. No death or serious adverse event
was reported in the study. Adverse event resulting in study discontinuation was reported
in 1 subject, but it was considered as unrelated to the investigational drug and wasconfirmed to have resolved.

From these findings, a single oral administration of fluconazole 150 mg is confirmed to beeffective for the treatment of Japanese patients with vulvovaginal candidiasis, and no
significant safety issue was reported.

Template version 1.1

Page 13