J Infect Chemother xxx (2015) 1e7

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Journal of Infection and Chemotherapy

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Original article

Efcacy and safety of a single oral 150 mg dose of uconazole for the
treatment of vulvovaginal candidiasis in Japan
Hiroshige Mikamo a, Miyako Matsumizu b, *, Yoshiomi Nakazuru c, Akifumi Okayama c,
Masahito Nagashima a, b
a
Department of Clinical Infectious Diseases, Aichi Medical University Graduate School of Medicine, Aichi, Japan
b
Clinical Research, Development Japan, Pzer Japan Inc., Tokyo, Japan
c
Clinical Statistics, Development Japan, Pzer Japan Inc., Tokyo, Japan

a r t i c l e i n f o a b s t r a c t

Article history: Vulvovaginal candidiasis is the second most common cause of vaginal infections following bacterial
Received 15 December 2014 vaginosis. For the treatment of vulvovaginal candidiasis, antifungal agents are used either as topical
Received in revised form (vaginal tablets and cream) or oral formulations. A single oral 150 mg dose of uconazole has been
19 March 2015
recommended as the standard therapy for uncomplicated, acute vulvovaginal candidiasis in global
Accepted 22 March 2015
Available online xxx
guidelines; however, in Japan oral uconazole therapy has not been approved. We conducted a phase 3
study to evaluate the efcacy and safety of a single oral 150 mg dose of uconazole in Japanese subjects
with vulvovaginal candidiasis for regulatory submission. A total of 157 subjects received a single oral
Keywords:
Fluconazole
150 mg dose of uconazole. Candida species (104 strains) were identied by fungal culture from 102
Single oral dose subjects at baseline, including Candida albicans (100 strains). The efcacy rate for the therapeutic
Vulvovaginal candidiasis outcome (assessed based on a comprehensive evaluation of the clinical and mycological efcacy in each
Candidal vulvovaginitis subject) was 74.7% (74/99) on Day 28 in the modied Intent-To-Treat (m-ITT) population. Concerning the
clinical and mycological efcacy on Day 28 in the m-ITT population, the cure, cure or improvement, and
eradication rates were 81.6%, 95.9%, and 85.9%, respectively. The most common treatment-related
adverse events were diarrhea and nausea (1.9% for each). No clinically signicant safety issues were
reported. A single oral 150 mg dose of uconazole demonstrated excellent therapeutic efcacy and was
well tolerated in Japanese subjects with vulvovaginal candidiasis.
Clinical registration number: NCT01806623.
2015, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases.
Published by Elsevier Ltd. All rights reserved.

1. Introduction [1e3]. A positive vaginal culture for Candida species is found in

Vulvovaginal candidiasis is an infection of the vulva and/or va-
gina caused by Candida species. Vulvovaginal candidiasis is the
second most common cause of vaginal infections after bacterial
vaginosis, and is often diagnosed at primary care clinics for ob-
stetrics and gynecology [1e3].
The most common causative pathogen of vulvovaginal candi-
diasis is Candida albicans, followed by Candida glabrata, which are
part of the indigenous ora of the gastrointestinal tract and skin
* Corresponding author. Clinical Research, Development Japan, Pzer Japan Inc.,
3-22-7 Yoyogi, Shibuya-ku, Tokyo 151-8589, Japan. Tel.: 81 3 5309 7010; fax: 81
3 5309 9060. .
E-mail address: miyako.matsumizu@pzer.com (M. Matsumizu).
approximately 15% of non-pregnant adolescent women, and 30% of
pregnant women in Japan, but most women only have Candida
species in the vagina and are asymptomatic, but are not diagnosed
as having candidiasis, and do not require treatment. Treatment is
required by approximately 35% of non-pregnant women with
vaginal Candida species, and 15e30% of pregnant women with
vaginal Candida species [1]. The infection caused by Candida affects
70e75% of women at least once during their lives, and is most
common in young women of childbearing age [1e3].
For the treatment of vulvovaginal candidiasis, antifungal agents,
either as topical (vaginal tablets and cream) or oral formulations,
are used. In European countries and the United States (US), for the
treatment of uncomplicated vaginal candidiasis, a single oral
150 mg dose of uconazole is recommended by the 2010 Sexually

http://dx.doi.org/10.1016/j.jiac.2015.03.011
1341-321X/ 2015, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: Mikamo H, et al., Efcacy and safety of a single oral 150 mg dose of uconazole for the treatment of
vulvovaginal candidiasis in Japan, J Infect Chemother (2015), http://dx.doi.org/10.1016/j.jiac.2015.03.011
2 H. Mikamo et al. / J Infect Chemother xxx (2015) 1e7
transmitted disease treatment guidelines of the CDC [3] and the
Sanford Guide to Antimicrobial Therapy 2014 [4].
In Japan, oral therapy with antifungal triazoles such as ucon-
azole has not been approved for vulvovaginal candidiasis, and
topical therapies such as vaginal tablets and cream has been clin-
ically used. In accordance with the Diagnosis and Treatment
Guidelines for Sexually Transmitted Diseases 2011 in Japan, 100 mg
of either clotrimazole, miconazole, isoconazole or oxiconazole is
recommended as a daily treatment with vaginal tablets or pessary
for uncomplicated acute vulvovaginal candidiasis, which in prin-
ciple requires daily hospital visits and a vaginal douche prior to
administration. For patients who cannot visit the hospital daily,
vaginal administration of a weekly dose of 600 mg isoconazole or
oxiconazole is recommended after vaginal douche [1]. However, it
is difcult for patients to administer vaginal tablets or a pessary,
which is painful, by themselves, and therefore it often results in
incompliance due to the burden of treatment [5e7].
Fluconazole, a triazole antifungal agent, has clinically been
widely used with the indication for deep mycosis as an oral drug
(capsules) and injection in Japan since it was launched in 1989. As
for the treatment of vulvovaginal candidiasis, a single oral 150 mg
dose of uconazole, if implemented in Japan, would be of clinical
signicance as a new and satisfactory treatment option providing
better dose compliance than topical therapies.
The aim of this study was to investigate the efcacy and safety
prole of a single oral 150 mg dose of uconazole for the treatment
of Japanese subjects with vulvovaginal candidiasis for regulatory
submission.
2. Subjects and methods
This study was conducted in accordance with the International
Conference on Harmonisation of Good Clinical Practice Guidelines,
the principle of the Declaration of Helsinki, and all applicable laws
and regulations at 10 medical centers nationwide in Japan between
March 2013 and November 2013. The protocol was approved by the
Institutional Review Boards of all participating study sites. All
subjects provided written informed consent before enrollment. The
study was conducted in accordance with advice from the Phar-
maceuticals and Medical Devices Agency (PMDA) after the appro-
priateness of the study design, endpoints, analysis set, inclusion
criteria, and so on were discussed with the PMDA.
2.1. Study design
This multicenter, open-label, non-comparative phase 3 study
was designed to evaluate the efcacy and safety of a single oral
150 mg dose of uconazole in Japanese subjects with vulvovaginal
candidiasis. The target number of subjects was 99 who were in the
modied Intent-To-Treat (m-ITT) population and whose thera-
peutic outcomes on Day 28 would be evaluated as effective or
ineffective. All the subjects took 3 uconazole 50 mg capsules orally
only once on the rst day of the treatment. The efcacy and safety
were evaluated up to Day 28.
2.2. Eligibility criteria
Female Japanese subjects aged 18 years or older (<80 years in
principle), who had clinical signs and symptoms of vulvovaginal
candidiasis with a total symptom severity scores of 4 or higher, and
were positive for Candida by fungal culture were eligible. Clinical
signs and symptoms were evaluated as follows: (A) symptom
severity scores: 0 no symptoms, 1 mild, 2 moderate, and
3 severe, for vulvovaginal itching, vulvovaginal burning sensa-
tion, excoriation of the vulva, vaginal discharge, vulva edema,
Please cite this article in press as: Mikamo H, et al., Efcacy and safety of a single oral 150 mg dose of uconazole for the treatment of
vulvovaginal candidiasis in Japan, J Infect Chemother (2015), http://dx.doi.org/10.1016/j.jiac.2015.03.011
redness of the vulva, and vaginal redness; and (B) property of
vaginal content scores: 0 normal, 1 mucoid, 2 paste-like, and
3 cottage cheese-like, cheese-like or granular.
Exclusion criteria included the following: a history of hyper-
sensitivity to uconazole; diabetes; severe renal dysfunction; liver
disorder; heart disease or electrolyte abnormality; pregnancy or
lactation; serious underlying diseases or complications; possible
accompanying trichomonas vaginitis or bacterial vaginosis, vagi-
nitis caused by Chlamydia or Gonococcus, or herpes simplex;
chronic vulvovaginal candidiasis; vaginal pH  5.0; the previous
use of systemic antifungals within 4 weeks before starting the
study medication, or the previous use of local (vulval or intra-
vaginal) antifungals within 2 weeks before starting the study
medication; not willing to avoid sexual relations up to 28 days after
the dosing; menstruation at enrollment, or next menstruation ex-
pected to start within 1 week after the study medication; diagnosis
of being immunocompromised.
The following concomitant medications and therapy were pro-
hibited up to Day 28: antifungals, antimicrobials, and antiallergic
drugs (oral, injection, topical [vulval or intravaginal] drugs); human
immunoglobulin; colony stimulating factor; corticosteroids;
vaginal douching after the study medication; and other investiga-
tional drugs or medical devices. The use of antimicrobials was
allowed for subjects who turned out to have accompanying tri-
chomonas vaginitis, bacterial vaginosis, vaginitis caused by Chla-
mydia or Gonococcus or herpes simplex after enrollment.
2.3. Assessments
The primary endpoints included therapeutic outcomes deter-
mined by investigators on Days 7, 14, 28, and at discontinuation.
Primary evaluation was therapeutic outcome on Day 28.
Therapeutic outcome was assessed based on the comprehensive
evaluation of clinical and mycological efcacy of each subject ac-
cording to the criteria shown in Table 1.
2.3.1. Clinical efcacy
Clinical efcacy was assessed based on the evaluation of clinical
signs and symptoms (vulvovaginal itching, vulvovaginal burning
sensation, excoriation of the vulva, vaginal discharge, vulval edema,
redness of the vulva, vaginal redness, property of vaginal content).
Clinical efcacy was judged as cured or improved if the clinical
symptoms at the start of treatment had resolved or improved at the
assessment time point; ineffective if neither the criteria for
cured nor improved were met, or the treatment failed and other
antifungals were administered for the treatment of vulvovaginal
candidiasis; indeterminate if efcacy assessment was difcult or
not determined because of missing data or failure to conduct the
test, or other antifungals were administered for the treatment of
other infections than vulvovaginal candidiasis.
2.3.2. Mycological efcacy
The causative pathogen was identied by vaginal discharge
culture before the study medication on Day 1 and on Days 7, 14 and
Table 1
Criteria for determining the therapeutic outcomes.
Clinical efcacy Mycological efcacy
Eradication Persistent Indeterminate
Cure Effective Ineffective Indeterminate
Improvement Ineffective Ineffective Indeterminate
Ineffective Ineffective Ineffective Ineffective
Indeterminate Indeterminate Ineffective Indeterminate
 H. Mikamo et al. / J Infect Chemother xxx (2015) 1e7 3

28. Mycological response was assessed based on the results of Table 2

culture. Mycological efcacy was judged as eradication if the Baseline demographic and other characteristics of subjects with vulvova-
ginal candidiasis in the m-ITT population.
original pathogen was not identied in the vaginal discharge;
persistence if the original pathogen remained in the specimens or Variable m-ITT population (N 102)
other antifungals were administered for the treatment of vulvo- Age (years)
vaginal candidiasis; indeterminate if efcacy assessment could Mean (SD) 31.9 (8.2)
not be determined because of a failure to conduct the vaginal Range 18e55

discharge culture etc., or other antifungals were administered for

the treatment of other infections than vulvovaginal candidiasis.
2.4. Safety assessment
Safety data were obtained from the ndings of clinical signs/
symptoms, physical examinations, vital signs, and laboratory data
up to Day 28. The causality and severity of the adverse events were
evaluated by the investigators (or sub-investigators), based on the
Medical Dictionary for Regulatory Activities terminology.
2.5. Statistical analysis
Efcacy analyses were mainly conducted of m-ITT subjects with
vulvovaginal candidiasis who received the study drug, were posi-
tive for Candida by culture on Day 1 (before dosing), and whose
therapeutic outcome on Day 28 was evaluated as effective or
ineffective.
The primary endpoint was the efcacy rate of the therapeutic
outcome in the m-ITT population on Day 28, and the efcacy would
be conrmed if the lower bound of the 95% condence interval (CI)
of the therapeutic success rate was greater than 38% (pre-specied
threshold value).
The safety analysis set was dened as all subjects who received
the study drug.
Assuming that the therapeutic success rate in this study would
be 54% based on the efcacy results of 2 previous US phase 3
studies, and the lower bound of the 95% CI (threshold value) for the
success rate was set to be 38%, which was derived from the
mycological eradication rate in meta-analysis literature [8], 99
subjects were needed in the m-ITT population to ensure a statistical
power of 90% at a one-sided signicance level of 0.025. Assuming
that Candida was detected in the vulva and/or vagina in 80% of the
subjects presenting with such symptoms as vulvovaginal itching
and increase in vaginal discharge, 130 subjects were needed to be
enrolled.
3. Results
3.1. Subject disposition and demography
In this study, a total of 157 subjects were assigned and all of
them received the study drug. Of these, 99 subjects completed the
study, and 58 discontinued the study due to the following: (A) not
meeting the inclusion criteria in 56 subjects (55 were negative for
Candida by fungal culture, and 1 had abnormal values for liver
function tests, which met the exclusion criteria); (B) voluntary
withdrawal from the study in 1 subject; and (C) adverse events not
related to the study drug (vulvovaginitis trichomonal) in 1 subject.
Of the 157 subjects who received the study medication, 55 were not
included in the m-ITT population because they were negative for
Candida by fungal culture, and the remaining 102 subjects formed
the m-ITT population. The safety analysis set included all 157
subjects.
Table 2 summarizes the baseline demographic and other char-
acteristics of the subjects.
At baseline, 104 strains of Candida were identied by fungal
culture in 102 of 157 subjects: C. albicans (100 strains), Candida
Body weight (kg)
Mean (SD) 53.9 (11.5)
Range 40.0e136.8
Severity of vulvovaginal candidiasis (n (%))
Mild 11 (10.8)
Moderate 73 (71.6)
Severe 18 (17.6)
Number of occurrence of vulvovaginal candidiasis for the last 1 year (n (%))
0 80 (78.4)
1 or more 22 (21.6)
1e3 22
1 16
2 4
3 2
4 or more 0
m-ITT, modied intent-to-treat.
parapsilosis (2 strains), C. glabrata, and Candida sp. (1 strain each)
(multiple strains were identied in 2 subjects). The MICs50 and
MICs90 of uconazole, oxiconazole, isoconazole, clotrimazole, and
miconazole for C. albicans, C. parapsilosis, and C. glabrata isolates are
shown in Table 3. Severity scores assigned to each clinical symptom
at baseline are summarized in Fig. 1. More than half of the subjects
had moderate to severe vulvovaginal itching and vaginal discharge.
The property of vaginal content was paste-like, cottage cheese-like,
or granular in most subjects.
3.2. Efcacy results
The rate of effective for the therapeutic outcome in the m-ITT
population was 33.7% (95% CI: 24.2e44.3%) on Day 7, 54.2%
(43.7e64.4%) on Day 14, and 74.7% (65.0e82.9%) on Day 28
(Table 4). Efcacy was conrmed since the lower bound of the 95%
CI of the therapeutic success rate on Day 28 (65.0%) was greater
than 38% (pre-specied threshold value).
For clinical efcacy in the m-ITT population, the cure rate was
34.8% on Day 7, 57.3% on Day 14, and 81.6% on Day 28. The cure or
improvement rate was 100.0% on Day 7, 99.0% on Day 14, and 95.9%
on Day 28 (Table 5).
For the mycological efcacy in the m-ITT population, the
mycological eradication rate was 95.7% on Day 7, 89.8% on Day 14,
and 85.9% on Day 28 (Table 6).
Most subjects whose therapeutic outcomes were assessed as
ineffective showed improvement and eradication for clinical
and mycological efcacy, respectively (57/61 on Day 7, 33/44 on
Day 14, and 10/25 on Day 28). Three subjects had ineffective for
clinical efcacy and persistence for mycological efcacy on Day
28.
Changes in the percentages of subjects with some clinical signs
and symptoms are shown in Fig. 2. All the clinical signs and
symptoms improved from Day 3.
3.3. Safety results
Among the 157 subjects in the safety analysis set, 12 subjects
(7.6%) experienced treatment-related adverse events (Table 7).

Please cite this article in press as: Mikamo H, et al., Efcacy and safety of a single oral 150 mg dose of uconazole for the treatment of
vulvovaginal candidiasis in Japan, J Infect Chemother (2015), http://dx.doi.org/10.1016/j.jiac.2015.03.011
4 H. Mikamo et al. / J Infect Chemother xxx (2015) 1e7

Table 3
MICs of uconazole, oxiconazole, isoconazole, clotrimazole, and miconazole for C. albicans, C. parapsilosis and C. glabrata isolates.

C. albicans (N 100) C. parapsilosis (N 2) C. glabrata (N 1)

Range MIC50 MIC90 Range MIC50 MIC90 Range MIC50 MIC90

Fluconazole 0.12e4 0.25 0.25 1e1 e e 8e8 e e

Oxiconazole 0.06e0.25 0.06 0.06 0.25e0.5 e e 0.06e0.06 e e
Isoconazole 0.06e0.25 0.06 0.06 0.5e0.5 e e 0.5e0.5 e e
Clotrimazole 0.06e0.06 0.06 0.06 0.06e0.06 e e 0.5e0.5 e e
Miconazole 0.06e1 0.06 0.06 0.5e0.5 e e 0.5e0.5 e e

Fig. 1. Percentage graphs of severity scores of clinical signs and symptoms at baseline in the m-ITT population. Clinical signs and symptoms: A vulvovaginal itching,
B vulvovaginal burning sensation, C vaginal discharge, D excoriation, E vulval edema, F redness of vulva, G vaginal redness, and H Property of vaginal content. Scores:
0 normal, 1 mild, 2 moderate, and 3 severe in A to G; and 0 normal, 1 mucoid, 2 paste-like, and 3 cottage cheese-like, cheese-like or granular in H.

The most common treatment-related adverse events were
diarrhea and nausea (1.9% each). All adverse events were mild or
moderate in severity, and no deaths, serious adverse events, or
discontinuations due to treatment-related adverse event were
reported.
4. Discussion
Overall, in this non-comparative phase 3 study, a single oral
150 mg dose of uconazole was effective for the treatment of Jap-
anese subjects with vulvovaginal candidiasis.
The efcacy rate for the therapeutic outcome on Day 28 in the
m-ITT population in this study was comparable to the clinical ef-
cacy rates of a single oral 150 mg dose of uconazole (80% at
short-term assessment [Days 5e15] and 76% at long-term assess-
ment [Days 30e60]) reported in previous clinical trials in Japanese
subjects with vulvovaginal candidiasis [9,10]. The mycological ef-
cacy on Day 28 in the present study was higher than 76% (short-
term assessment) and 70% (long-term assessment) in previous
Japanese studies. The difference in mycological efcacy between
the current and previous studies may partly be due to the differ-
ence in the assessment time (Day 28 versus Days 5e15 or 30e60).

Table 4
Therapeutic outcome in the m-ITT population.

Assessment time point N Therapeutic outcome

Effective Ineffective Indeterminate Efcacy ratea

n (%) n (%) n (%)
(%) 95% CI (%)

Day 7 95 31 (32.6) 61 (64.2) 3 (3.2) 33.7 24.2e44.3

Day 14 100 52 (52.0) 44 (44.0) 4 (4.0) 54.2 43.7e64.4
Day 28 102 74 (72.5) 25 (24.5) 3 (2.9) 74.7 65.0e82.9

m-ITT, modied intent-to-treat; CI, condence interval.

a
Efcacy rate (%) (number of subjects considered effective/[number of evaluated subjects  number of subjects considered indeterminate])  100.

Please cite this article in press as: Mikamo H, et al., Efcacy and safety of a single oral 150 mg dose of uconazole for the treatment of
vulvovaginal candidiasis in Japan, J Infect Chemother (2015), http://dx.doi.org/10.1016/j.jiac.2015.03.011
 H. Mikamo et al. / J Infect Chemother xxx (2015) 1e7 5

Table 5
Clinical efcacy in the m-ITT population.

Assessment time point N Clinical efcacy

Cure Improvement Ineffective Indeterminate Cure ratea Cure or improvement rateb

n (%) n (%) n (%) n (%)
% 95% CI (%) % 95% CI (%)

Day 7 99 32 (32.3) 60 (60.6) 0 7 (7.1) 34.8 25.1e45.4 100.0 96.1e100.0

Day 14 101 55 (54.5) 40 (39.6) 1 (1.0) 5 (5.0) 57.3 46.8e67.3 99.0 94.3e100.0
Day 28 102 80 (78.4) 14 (13.7) 4 (3.9) 4 (3.9) 81.6 72.5e88.7 95.9 89.9e98.9

m-ITT, modied intent-to-treat; CI condence interval.

a
Cure rate (%) (number of subjects considered cure/[number of evaluated subjects  number of subjects considered indeterminate])  100.
b
Cure or improvement rate (%) (number of subjects considered cure or improvement/[number of evaluated subjects  number of subjects considered
indeterminate])  100.

Table 6
Mycological efcacy in the m-ITT population.

Assessment time point N Mycological efcacy

Eradication Persistence Indeterminate Eradication ratea

n (%) n (%) n (%)
(%) 95% CI (%)

Day 7 95 90 (94.7) 4 (4.2) 1 (1.1) 95.7 89.5e98.8

Day 14 100 88 (88.0) 10 (10.0) 2 (2.0) 89.8 82.0e95.0
Day 28 102 85 (83.3) 14 (13.7) 3 (2.9) 85.9 77.4e92.0

m-ITT, modied intent-to-treat; CI condence interval.

a
Eradication rate (%) (number of subjects considered eradication/[number of evaluated subjects  number of subjects considered indeterminate])  100.

Fig. 2. Changes in the percentages of subjects with clinical signs and symptoms. Percentage (number of subjects with clinical signs and symptoms/[N  NA])  100. NA, number
of subjects whose data were not available due to menstruation.

Similarly, in 2 global clinical studies of a single oral 150 mg dose of
uconazole, the clinical efcacy rates (97 and 94%, respectively) at
the short-term follow-up visit (Day 7 and Days 5e16, respectively)
remained at a high level (87 and 84%, respectively) at the long-term
follow-up visit (Day 21 and Days 26e50, respectively), while the
mycological efcacy rates were lower at the long-term follow-up
visit (76 and 59%, respectively) than those at the short-term follow-
up visit (97 and 81%, respectively) [11,12]. This may reect that the
indigenous ora of the vagina that was affected once by a single oral
dose of uconazole returned to normal after administration [5]. In
other words, mycological assessment at the long-term follow-up
visit detected Candida as normal vaginal ora.
Mizuno et al. conducted 2 clinical studies of vaginal tablets
[13,14]. They reported the cure rates and improvement rates at 3
weeks after the treatment were respectively 61.5% and 92.3% for 1-
day treatment with oxiconazole, 72.8% and 95.7% for 6-day treat-
ment with oxiconazole, 63.3% and 90.8% for 1-day treatment with
isoconazole, and 73.9% and 95.7% for 6-day treatment with clotri-
mazole. Mikamo et al. also reported the clinical efcacy of clotri-
mazole was 58% on Days 30e60 [9,10]. Although the evaluation
methods and timing in these studies were different from those in
our study, the results of our study were generally consistent with
those of these studies.
A single oral 150 mg dose of uconazole is an easy-to-manage
dosing regimen and has many advantages. Research based on in-
terviews with prescription doctors in the UK revealed that 27% of
patients complaint of pain and difculties with insertion of vaginal
tablets and pessary, and 62% of prescription doctors also think there

Please cite this article in press as: Mikamo H, et al., Efcacy and safety of a single oral 150 mg dose of uconazole for the treatment of
vulvovaginal candidiasis in Japan, J Infect Chemother (2015), http://dx.doi.org/10.1016/j.jiac.2015.03.011
6 H. Mikamo et al. / J Infect Chemother xxx (2015) 1e7
Table 7
Treatment-related adverse events in the safety analysis set.
Preferred terma Safety analysis set (N 157)
Treatment-related adverse event
n (%)
Palpitations 1 (0.6)
Abdominal distension 1 (0.6)
Diarrhea 3 (1.9)
Nausea 3 (1.9)
Pyrexia 1 (0.6)
Cystitis 1 (0.6)
Genital herpes 1 (0.6)
Hepatic enzyme increased 1 (0.6)
Genital hemorrhage 1 (0.6)
Urticaria 1 (0.6)
a
Medical Dictionary for Regulatory Activities Terminology version 16.1.
is a problem with leakage of vaginal cream [6]. There are also some
reports stating easy-to-administer oral therapies are preferred to
topical vaginal therapies among patients [5,7]. In this study, vul-
vovaginal redness, irritation, tingling, itching, and pain were not
reported as adverse events, suggesting that a single oral 150 mg
dose of uconazole had little adverse effect on the vulva and vagina
and the daily life of subjects compared with topical therapies, and
thus provides the improved quality of life and satisfaction of pa-
tients besides resolving the difculties with topical drug
administration.
Symptoms of vulvovaginal candidiasis often develop before
menstruation [15]. It is difcult to apply topical vaginal therapies
before and during menstruation, when a sufcient effect of treatment
cannot be expected because of leakage and reduction in drug contents
caused by menstrual bleeding. Single oral administration of ucona-
zole can be used regardless of the menstrual status of patients.
It is known that 6-day topical vaginal therapies show problems
of early discontinuation of treatment for the reason of disappear-
ance of symptoms and accidental dislodgement of inserted vaginal
tablets that are not in place, leading to reduce compliance. With a
single oral dose of uconazole, there is no concern about such
problems.
A single oral 150 mg dose of uconazole can be prescribed at
clinics of internal medicine as well as obstetrics and gynecology,
raising concern that some clinicians may make a diagnosis of vul-
vovaginal candidiasis based on the patient's complaints without
conrming the vulvovaginal ndings, and prescribe the drug,
resulting in delayed proper treatment of similar diseases such as
vaginal trichomoniasis and bacterial vaginosis. To prevent inap-
propriate use, clinicians should make a denite diagnosis of the
disease giving the utmost care before prescribing the drug.
In this study, 4 subjects had complications of genital infection
caused by other pathogens than Candida (1 with Trichomonas
vulvovaginitis, 3 with chlamydial cervicitis) at baseline. These
complications were found in the microbiological tests conducted at
baseline after a single oral 150 mg dose of uconazole on Day 1. A
subject with trichomonas vulvovaginitis received tinidazole and 3
subjects with chlamydial cervicitis received azithromycin. The
investigator considered that it was possible to assess the efcacy of
uconazole in these 4 subjects. For these 4 subjects, the clinical
efcacy was assessed as either cure or improvement, and the
mycological efcacy was assessed as either eradication or
persistence. For 3 of the 4 subjects, the therapeutic outcomes
were assessed as ineffective. These ndings suggest that a single
oral 150 mg dose of uconazole in combination with other anti-
microbial agents is effective for the treatment of vulvovaginal
candidiasis complicated with genital infection caused by other
pathogens than Candida.
Please cite this article in press as: Mikamo H, et al., Efcacy and safety of a single oral 150 mg dose of uconazole for the treatment of
vulvovaginal candidiasis in Japan, J Infect Chemother (2015), http://dx.doi.org/10.1016/j.jiac.2015.03.011
A subject had complications of diabetes mellitus in this study.
Although the subject was considered to have had them before
enrollment, the investigator considered that it was possible to
assess the efcacy of uconazole in the subject because the dura-
tion of diabetes mellitus was short, and the subject was considered
not to be immunocompromised. The therapeutic outcome of the
subject was assessed as effective. There were few studies
reporting the efcacy of a single oral dose of uconazole in subjects
complicated with diabetes mellitus [16,17]. As diabetes mellitus is a
risk factor for vulvovaginal candidiasis, the efcacy in these sub-
jects has to be studied further.
In this study, the most commonly identied pathogen was
C. albicans (100/104 strains), and all isolates were highly susceptible
to uconazole judging from the uconazole breakpoints for
C. albicans in the criteria of Clinical and Laboratory Standards
Institute (CLSI) (susceptible  2 mg/ml, susceptible-dose
dependent 4 mg/ml, resistant  8 mg/ml) [18], and the criteria
of the European Committee on Antimicrobial Susceptibility Testing
(EUCAST) (susceptible  2 mg/ml, resistant  4 mg/ml) [19]. In this
study, C. glabrata was identied in a subject whose therapeutic
outcome was assessed as effective at all assessment time points.
This C. glabrata isolate (MIC of uconazole was 8 mg/ml) was not
classied into the category of resistant based on the uconazole
breakpoints for C. glabrata (susceptible-dose dependent 32 mg/ml,
resistant  64 mg/ml [CLSI criteria]; susceptible  0.002 mg/ml,
resistant > 32 mg/ml [EUCAST criteria]). C. glabrata, the second most
common pathogen of vulvovaginal candidiasis following C. albicans,
is however reported to be resistant to uconazole [20,21]. If u-
conazole is not effective, other topical drugs should be used instead.
The most common treatment-related adverse events occurring
in 1% or more of the subjects were only gastrointestinal-related
events (diarrhea and nausea), and there were no signicant
safety issues in this study. However, uconazole, even given as a
single oral dose, has more potential to produce side effects such as
gastrointestinal disorders and other systemic events compared
with topical vaginal therapies, and subjects treated with ucona-
zole should be monitored carefully. Since uconazole inhibits CYP
2C9 and 3A4, caution should be exercised when a single oral dose of
uconazole is applied in combination with other drugs to prevent
potential drug interactions.
There are 3 limitations to this study that should be considered
when these ndings are interpreted. First, this was not a controlled
study. Second, there were not sufcient other pathogens than
C. albicans to assess their efcacy. Although further investigation,
such as a large comparative study, accordingly needs to be per-
formed to conrm our study results, the methods of this study with
sufcient clinical efcacy will be useful for the treatment of pa-
tients with vulvovaginal candidiasis in Japan. Third, this was a
clinical study led by the sponsor and the possibility of conicts of
interest between the authors and the sponsor could not be ruled
out.
In conclusion, the results of this study demonstrated that a
single oral 150 mg dose of uconazole was effective for the treat-
ment of vulvovaginal candidiasis in Japanese subjects, and no sig-
nicant safety issues were reported. A single oral 150 mg dose of
uconazole is recommended for the treatment of vulvovaginal
candidiasis in global guidelines. Therefore, a single oral 150 mg
dose of uconazole will be positioned as one of the rst-line
treatment options for vulvovaginal candidiasis in Japan.
Conict of interest
H. Mikamo has received a consultant fee and a fee for partici-
pation in the Committee from Pzer Japan Inc. M. Matsumizu, Y.
 H. Mikamo et al. / J Infect Chemother xxx (2015) 1e7
Nakazuru, A. Okayama, and M. Nagashima are employees of Pzer
Japan Inc.
Acknowledgments
We wish to thank the investigators who have contributed to this
clinical study. This study was sponsored by Pzer Japan Inc.
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