Effect of butoconazole nitrate 2% vaginal cream and miconazole nitrate 2% vaginal cream treatments in patients with vulvovaginal candidiasis


Lappin, M.A.; Brooker, D.C.; Francisco, C.A.; Dorfman, J.

Infectious Diseases in Obstetrics and Gynecology 4(6): 323-328

1996


In a multicentre, randomized, investigator-blind, parallel study, 398 women from California, USA, were dispensed topical butoconazole nitrate 2% cream for 3 days (n=199) or miconazole nitrate 2% cream for 7 days (n=199) for the treatment of vulvovaginal candidosis. Efficacy analyses included 254 patients with culture-confirmed Candida (119 butoconazole and 135 miconazole users). Of the 398 patients issued study medication, 9 were lost to follow-up. Therefore, safety analyses included 389 patients (197 butoconazole and 192 miconazole users). Evaluations upon admission and approx. 8 and 30 days post-treatment included Candida cultures, KOH wet mounts and vulvovaginal examinations, with rating of vulvovaginal signs and symptoms using a 4-point scale. Rates of clinical cure (based on sign/symptom scores), microbiological cure (based on cultures and wet mounts) and therapeutic cure (both clinical and microbiological cures) were assessed and were similar between the regimens. C. albicans was the causative organism in the majority of cases; 18 patients had non-albicans isolates, including Torulopsis glabrata, C. tropicalis, C. parapsilosis and C. stellatoidea. Therapeutic cure rates were 57.8% and 61.4% for butoconazole and miconazole, respectively. It is concluded that 3-day butoconazole treatment is as safe and effective as 7-day miconazole therapy in treating vulvovaginal candidosis.

Infectious
Diseases
in
Obstetrics
and
Gynecology
4:323-328
(1996)
©
1997
Wiley-Liss,
Inc.
Effect
of
Butoconazole
Nitrate
2%
Vaginal
Cream
and
Miconazole
Nitrate
2%
Vaginal
Cream
Treatments
in
Patients
with
Vulvovaginal
Candidiasis
Myra
A.
Lappin,
1
*
Doris
C.
Brooker,
2
Carol
A.
Francisco,
3
and
Joan
Dorfman
4
1
Student
Health
Service,
San
Francisco
State
University,
San
Francisco,
CA
2
Department
of
Obstetrics
and
Gynecology,
University
of
Minnesota,
Minneapolis,
MN
3
Department
of
Biostatistics,
Syntex
Laboratories,
Inc.,
Palo
Alto,
CA
4
Department
of
Clinical
Investigations,
Syntex
Laboratories,
Inc.,
Palo
Alto,
CA
ABSTRACT
In
a
multicenter,
randomized,
investigator-blind,
parallel
study,
398
patients
were
dispensed
topical
butoconazole
nitrate
2%
cream
for
3
days
(n
=
199)
or
miconazole
nitrate
2%
cream
for
7
days
(n
=
199)
for
vaginal
use.
Efficacy
analyses
included
254
patients
with
culture-confirmed
Candida
(119
butoconazole
and
135
miconazole
users).
Of
the
398
patients
issued
study
medication,
9
were
lost
to
follow-up.
Therefore,
safety
analyses
included
389
patients
(197
butoconazole
and
192
micona-
zole
users).
Evaluations
upon
admission
and
approximately
8
and
30
days
post-treatment
included
Candida
cultures,
potassium
hydroxide
(KOH)
wet
mounts,
and
vulvovaginal
examinations,
with
rating
of
vulvovaginal
signs
and
symptoms
using
a
4-point
scale.
Rates
of
clinical
cure
(based
on
sign/symptom
scores),
microbiologic
cure
(based
on
cultures
and
wet
mounts),
and
therapeutic
cure
(both
clinical
and
microbiologic
cures)
were
assessed
and
were
to
be
similar
between
the
regimens.
Therapeutic
cure
rates
were
57.8%
and
61.4%
for
butoconazole
and
miconazole,
respectively.
Three-day
butoconazole
treatment
was
as
safe
and
effective
as
7-day
miconazole
therapy
in
treat-
ing
vulvovaginal
candidiasis.
Infect.
Dis.
Obstet.
Gynecol.
4:323-328,
1996.
©
1997
Wiley-Liss,
Inc.
KEY
WORDS
antifungal;
Candida;
yeast;
cure;
clinical;
butoconazole;
miconazole
B
utoconazole
nitrate
2%
cream
and
miconazole
nitrate
2%
cream
have
both
been
used
as
ef-
fective
intravaginal
antifungal
agents
to
treat
vul-
vovaginal
candidiasis,
one
of
the
most
common
gy-
necological
problems.
1
'
2
It
is
important
for
women
who
are
first-time
suf-
ferers
to
consult
their
physicians
before
using
any
over-the-counter
products
to
treat
vulvovaginal
candidiasis,
thus
ensuring
an
accurate
diagnosis.
With
the
diagnosis
of
vulvovaginal
candidiasis
comes
the
challenge
to
health
care
professionals
of
patient
compliance.
Several
factors
may
influence
compliance,
including
length
of
antifungal
therapy.
To
that
end,
physician
recommendations
which
The
following
practitioners
also
participated
in
this
study:
Dale
Brown,
Jr.,
Houston,
TX;
Fred
W.
Schnepper,
Chula
Vista,
CA;
Kathleen
O'Hare,
Champaign,
IL;
Stephen
F.
Gordon,
Atlanta,
GA;
and
the
Butoconazole
OTC
Study
Group,
including
Robert
I.
Fulmer,
Austin,
TX;
Russel
Graham,
Altamonte
Springs,
FL;
Judson
E.
Jones,
Aurora,
IL;
Joseph
Liotti,
West
Orange,
NJ;
Elizabeth
Nye,
Chicago,
IL;
Anthony
Puopolo,
Milford,
MA;
Terry
O'Reilly,
Olympia,
WA;
Meenakshi
Patel,
Dayton,
OH;
William
Schultz,
Springfield,
IL;
John
M.
Stafford,
St.
Joseph,
MN;
Kumjad
Unnoppet,
Birmingham,
AL;
Arthur
Waldbaum,
Denver,
CO;
Paul
F.
Whitsitt,
Oshawa,
Ontario,
Canada,
Marian
Diermayer,
Co-
investigator,
SHS,
SFSh,
San
Francisco,
CA.
*Correspondence
to:
Myra
A.
Lappin,
MD,
Student
Health
Service,
San
Francisco
State
University,
MS
4200,
1600
Holloway
Avenue,
San
Francisco,
CA
94132-4200.
Received
18
July
1996
Clinical
Study
Accepted
14
January
1997
VAGINAL
CREAMS
FOR
VULVOVAGINAL
CANDIDIASIS
LAPPIN
ET
AL.
encourage
compliance
may
include
short-term
an-
tifungal
therapy.
3
'
4
The
primary
objective
of
this
study
was
to
com-
pare
the
effectiveness
and
safety
of
3-day
buto-
conazole
with
7-day
miconazole
treatments
in
women
with
vulvovaginal
candidiasis.
Therapeutic,
microbiologic,
and
clinical
cure
rates
were
deter-
mined
after
consecutive
daily
intravaginal
treat-
ment
with
either
butoconazole
nitrate
2%
cream
(3
days)
or
miconazole
nitrate
2%
cream
(7
days).
SUBJECTS
AND
METHODS
The
study
had
a
multicenter,
randomized,
investi-
gator-blind,
parallel
design.
Eligible
patients
were
randomly
assigned
to
treatment
once
daily
at
bed-
time
with
either
butoconazole
nitrate
cream
for
3
consecutive
days
or
miconazole
nitrate
cream
for
7
consecutive
days.
Butoconazole
nitrate
was
pre-
sented
to
patients
in
one
box
containing
3
applica-
tors
prefilled
with
butoconazole
nitrate
cream.
Mi-
conazole
nitrate
was
presented
to
patients
in
one
box
containing
7
applicators
and
a
tube
of
'micona-
zole
cream.
Boxes
were
identically
packaged.
Admission
Criteria
Patients
admitted
to
the
trial
were
generally
healthy
women
with
pseudohyphae
on
potassium
hydroxide
(KOH)
wet
mount,
which
was
con-
firmed
by
a
positive
Candida
culture.
Enrolled
pa-
tients
signed
an
informed
consent
and
agreed
to
abstain
from
sexual
intercourse
during
the
treat-
ment
period
and
to
use
condoms
for
the
remainder
of
the
study
period.
During
the
study
they
also
agreed
to
abstain
from
using
any
vaginal
product
containing
nonoxynol-9,
vaginal
douches,
other
vaginal
or
vulvar
topical
therapeutics,
vaginal
con-
traceptives,
or
feminine
sprays.
Excluded
from
the
study
were
patients
with
evidence
of
trichomonads
or
clue
cells
(indicative
of
bacterial
vaginosis);
vul-
var,
cervical,
or
vaginal
lesions
other
than
candidi-
asis
(e.g.,
herpes);
diabetes
mellitus,
acquired
im-
munodeficiency
syndrome
(AIDS),
or
any
uncon-
trolled
systemic
disease;
and
urinary
tract
infection
or
any
genitourinary
condition
including
sexually
transmitted
disease.
Candidates
were
also
ex-
cluded
if
they
were
pregnant
or
breast-feeding;
had
been
treated
for
vulvovaginal
candidiasis
within
the
week
preceding
study
entry;
had
used
any
vagi-
nal
preparations
within
24
h
before
study
entry;
were
receiving
anti-inflammatory,
antihistamine,
or
analgesic
drugs
on
an
ongoing
basis;
or
would
re-
quire
oral
antibiotics
during
the
study
treatment.
Assessments
Patients
had
an
admission
visit
and
two
follow-up
visits
scheduled
as
close
as
possible
to
8
and
30
days
after
the
end
of
treatment.
At
the
admission
visit,
a
medical
history
was
obtained
and
a
physical
including
vulvovaginal
examination
was
per-
formed.
Vulvovaginal
signs
(erythema,
swelling,
excoriation,
ulceration)
and
symptoms
(burning,
itching)
were
recorded
and
rated
on
a
4-point
scale
(0
=
none;
1
=
mild;
2
=
moderate;
3
=
severe).
Each
patient
had
a
sodium
chloride
and
KOH
wet
mount,
Candida
yeast
culture
(including
species
identification)
to
confirm
the
presence
of
Candida,
Pap
smear
(if
not
done
within
the
previous
6
months),
urine
pregnancy
test
(if
the
patient
was
of
child-bearing
potential),
and
urinalysis.
At
the
two
follow-up
visits
(visits
2
and
3),
KOH
wet
mount
and
vaginal
Candida
culture
were
obtained.
In
ad-
dition,
vulvovaginal
signs
and
symptoms,
concomi-
tant
medication
use,
and
adverse
events
were
monitored.
Cure
Definitions
Clinical
response
was
assessed
at
both
follow-up
visits
on
the
basis
of
presence
or
absence
of
vulvo-
vaginal
signs/symptoms
(e.g.,
burning,
itching,
er-
ythema,
swelling,
excoriation,
and
ulceration)
rated
on
a
4-point
categorical
scale
(i.e.,
0
=
none;
1
=
mild;
2
=
moderate;
3
=
severe).
Clinical
cure
was
achieved
when
all
of
the
following
conditions
were
met
at
a
follow-up
visit:
all
vulvovaginal
sign
and
symptom
severity
scores
were
0
or
1;
each
of
the
patient's
sign
and
symptom
scores
was
not
greater
(getting
worse)
than
the
score
for
the
previous
visit
(baseline
or
the
first
follow-up
visit);
and
at
least
half
of
the
sign
and
symptom
scores
that
were
..--1
in
the
preceding
visit
(including
baseline)
im-
proved
to
scores
of
0
or
1.
There
was
one
exception
to
these
guidelines:
a
patient
was
considered
clini-
cally
cured
at
the
second
follow-up
visit
if
all
as-
sessments
at
the
first
follow-up
visit
were
0
except
for
one
score
of
1,
and
the
assessments
remained
the
same
at
the
second
follow-up
visit
(with
no
missing
assessments
at
either
visit).
Patients
not
clinically
cured
were
considered
clinical
treatment
failures.
Any
patient
who
was
not
clinically
cured
at
the
first
follow-up
visit
was
excluded
from
the
clinical
cure
rate
analysis
at
the
second
follow-up
visit.
324
INFECTIOUS
DISEASES
IN
OBSTETRICS
AND
GYNECOLOGY
VAGINAL
CREAMS
FOR
VULVOVAGINAL
CANDIDIASIS
LAPPIN
ET
AL.
Assessment
of
microbiologic
response
was
based
on
results
of
fungal
culture
and
KOH
wet
mount.
A
patient
was
considered
microbiologically
cured
if
her
fungal
culture
was
negative
and
her
KOH
wet
mount
result
was
either
negative
or
missing.
Any
patient
who
was
not
microbiologically
cured
at
the
first
follow-up
visit
was
excluded
from
the
micro-
biological
cure
rate
analysis
at
the
second
follow-up
visit.
Therapeutic
cure
was
defined
as
clinical
and
mi-
crobiologic
cures
at
both
follow-up
visits,
and
therapeutic
failure
as
either
a
clinical
or
a
micro-
biologic
failure
at
either
follow-up
visit.
Patients
who
were
never
clinical
or
microbiologic
failures,
but
who
did
not
have
all
four
cure
rate
results
were
considered
to
have
insufficient
data
for
determina-
tion
of
their
results.
Therefore,
their
results
were
considered
missing,
and
they
were
excluded
from
the
therapeutic
cure
analysis,
as
well
as
from
the
clinical
or
microbiologic
cure
analysis
for
that
visit.
Statistical
Analysis
Baseline
comparability
of
the
treatment
groups
was
assessed
using
a
two-way
analysis
of
variance
(ANOVA)
with
factors
of
treatment,
investigator,
and
treatment-by-investigator
interaction
for
con-
tinuous
variables
and
a
Cochran-Mantel-Haenszel
test
(controlling
for
investigator)
for
discrete
vari-
ables.
A
significance
level
of
0.10
was
used
for
baseline
treatment
comparisons
and
for
testing
treatment-by-investigator
interaction.
The
primary
efficacy
variables
were
the
clinical
and
microbiologic
cure
rates
at
each
follow-up
visit
and
overall
therapeutic
cure
rate.
Valid
follow-up
visits
had
to
be
within
a
7
day
to
15
post-treatment
day
window
for
visit
2
and
within
a
27
day
to
45
post-treatment
day
window
for
visit
3.
Clinical
and
microbiologic
cure
rates
for
each
treatment
group
were
calculated
at
each
follow-up
visit
by
dividing
the
number
of
cured
patients
by
the
total
number
of
patients
analyzed.
As
an
alternative,
a
more
con-
servative
procedure
for
the
second
follow-up
visit
was
also
applied.
This
entailed
counting
patients
as
failures
if
they
were
cured
at
the
first
follow-up
visit
(visit
2)
but
had
no
results
available
from
the
last
visit
(visit
3).
Therapeutic
cure
rate
was
calcu-
lated
by
dividing
the
number
of
therapeutic
cures
by
the
total
number
of
patients
analyzed,
excluding
those
who
had
insufficient
data
for
this
analysis.
Cure
rates
were
analyzed
as
two
independent
binomial
proportions.
Both
a
95%
two-tailed
confi-
dence
interval
and
a
lower
limits
of
95%
one-tailed
confidence
interval
for
the
difference
in
cure
rates
(butoconazole
minus
miconazole)
were
calculated
using
a
normal
approximation
to
the
binomial
dis-
tribution.
Yate's
continuity
correction
was
incorpo-
rated.
5
Cure
rates
for
the
two
treatment
groups
were
also
compared
using
the
Cochran-Mantel-
Haenszel
test
for
general
association,
controlling
for
investigator,
6
and
a
z-test
that
used
the
mini-
mum-variance
estimator
of
the
overall
cure
rate
dif-
ferences
across
sites
(butoconazole
minus
micona-
zole)
in
order
to
test
the
hypothesis
that
the
treat-
ment
difference
was
zero.?
The
use
of
these
statistical
analyses
was
justi-
fied
by
the
assumption
that
there
was
no
treat-
ment-by-investigator
interaction
(i.e.,
that
data
from
all
sites
could
be
pooled).
This
assumption
was
tested
by
establishing
the
homogeneity
of
the
treatment
odds
ratios
(butoconazole
odds
divided
by
miconazole
odds)
across
investigator
sites
us-
ing
Zelen's
8
test
and
then
testing
that
the
common
odds
ratio
was
equal
to
one,
9
and
by
a
chi-
square
statistic
that
examined
the
homogeneity
of
cure
rate
differences
across
the
sites.
7
"
Adverse
events
were
recorded
and
summarized
using
the
COSTART
mapping
system."
RESULTS
Nineteen
investigators
enrolled
403
patients,
5
of
whom
did
not
receive
the
study
medication
after
enrollment,
were
not
randomized,
and
were
there-
fore
excluded
from
all
analyses.
Thus,
398
patients
(199
in
each
treatment
group)
were
randomly
as-
signed
to
treatment
with
butoconazole
nitrate
cream
or
miconazole
nitrate
cream.
Nine
patients
(2
butoconazole
and
7
miconazole
users)
were
lost
to
follow-up
and
were
excluded
from
the
safety
analyses,
which
included
389
patients
(197
buto-
conazole
and
192
miconazole
users).
Included
in
the
efficacy
analyses
were
254
participants,
com-
prising
119
butoconazole
recipients
and
135
mi-
conazole
users.
Exclusions
from
the
efficacy
analy-
ses
are
detailed
in
Table
1.
The
treatment
groups
in
the
efficacy
analyses
were
comparable
with
respect
to
demographic
characteristics
of
age
(mean
32
years,
SD
10
years;
range
17-67
years),
ethnicity
(73%
European,
15%
African
American,
8%
Latina,
3%
Asian-American,
1%
other),
and
height
(mean
64.5
in.,
SD
2.8
in.;
INFECTIOUS
DISEASES
IN
OBSTETRICS
AND
GYNECOLOGY
325
VAGINAL
CREAMS
FOR
VULVOVAGINAL
CANDIDIASIS
LAPPIN
ET
AL.
TABLE
I
.
Patients
excluded
from
efficacy
analyses
Reason
for
exclusion
Total
(%)
Butoconazole
(%)
Miconazole
(%)
No
confirmation
that
study
drug
was
used
9(2)
2(1)
7(4)
Negative
or
missing
fungal
culture/KOH*
92(23)
53(27)
39(20)
Positive
urine
glucose
or
dysplasia
on
Pap
smear
4(1) 4(2)
0
Non-compliance
with
study
medication
14(3)
7(4)
7(4)
Medication
applied
but
no
follow-up
visits
2(<1)
2(1)
0
First
follow-up
visit
outside
7-15
day
window
13(3)
7(4)
6(3)
Used
prohibited
concomitant
medication
2(<1)
1(1)
1(1)
Evidence
of
trichomonads,
Gardnerella,
bacterial
vaginitis,
or
cervicitis
8(2)
4(2)
4(2)
Total
excluded**
144(36)
80(40)
64(32)
Total
included
254(64)
119(60) 135(68)
Total
enrolled,
received
study
drug
398
199
199
*P
=
0.071
(Cochran-Mantel-Haenszel
test).
**P
=
0.079
(Cochran-Mantel-Haenszel
test).
range
51-72
in.).
There
were
significant
differ-
ences
between
the
treatment
groups
in
systolic
blood
pressure
(P
=
0.06),
and
there
were
signifi-
cant
treatment-by-investigator
interactions
for
weight
(P
=
0.003),
systolic
blood
pressure
(P
=
0.098),
and
diastolic
blood
pressure
(P
=
0.053).
These
variables
were
not
considered
to
have
an
impact
on
the
cure
rate
outcomes.
The
groups
were
comparable
in
baseline
(pretreatment)
signs
of
er-
ythema,
ulceration,
and
presence
and
quantity
of
discharge.
There
were
significant
differences
be-
tween
the
groups
in
baseline
vulvovaginal
burning
(P
=
0.004)
and
itching
(P
=
0.078),
with
a
greater
proportion
in
the
butoconazole
group
having
severe
symptoms
(burning:
19
patients
[16%]
for
buto-
conazole
and
8
patients
[6%]
for
miconazole;
itch-
ing:
34
patients
[29%]
for
butoconazole
and
26
pa-
tients
[19%]
for
miconazole).
Similarly,
statistically
significant
differences
were
also
found
for
swelling
and
excoriation
at
baseline
(P
=
0.04
and
0.077,
respectively),
and
these
significant
differences
in
baseline
characteristics
were
due
to
a
treatment-by-
investigator
interaction,
with
most
cases
of
swelling
or
excoriation
reported
by
only
a
few
investigators.
When
the
Cochran-Mantel-Haenszel
test
was
ap-
plied
to
the
data
collapsing
on
investigator,
there
were
no
statistically
significant
differences
(P
.--
0.197).
Efficacy
Cure
rate
data
were
pooled
across
all
investigators
because
the
results
of
tests
for
homogeneity
among
investigators
showed
no
statistically
significant
treatment-by-investigator
interactions
(Zelen's
test
P
values
=
0.152-0.916;
common
odds
ratios
not
significantly
different
from
1
and
all
95%
confi-
dence
intervals
for
these
ratios
contained
the
value
1;
and
chi-square
P
values
=
0.152-0.514).
Clinical,
microbiologic,
and
therapeutic
cure
rates
for
butoconazole
and
miconazole
were
similar
between
treatment
groups,
regardless
of
whether
patients
with
missing/insufficient
data
from
the
second
follow-up
examination
were
excluded
from
the
analysis
or
included
as
treatment
failures
(Table
2).
No
differences
between
butoconazole
nitrate
and
miconazole
nitrate
were
statistically
sig-
nificant.
Clinical
cure
rates
at
the
first
follow-up
examination
(approximately
8
days
post-treatment)
were
92.4%
for
butoconazole
and
94.8%
for
mi-
conazole;
at
the
second
follow-up
assessment
(ap-
proximately
30
days
post-treatment),
clinical
cure
rates
were
88.5%
for
butoconazole
and
85.7%
for
miconazole.
Microbiologic
cure
rates
at
the
first
fol-
low-up
visit
were
88.1%
for
butoconazole
and
89.6%
for
miconazole,
and
at
the
second
follow-up
examination
they
were
75.5%
and
78.4%,
respec-
tively.
An
alternate
procedure
counted
patients
as
failures
who
were
cured
at
the
first
follow-up
visit
but
missing
their
second
follow-up
data.
This
al-
ternate,
more
conservative
procedure
for
estimat-
ing
clinical
and
microbiologic
cure
rates
resulted
in
somewhat
lower
clinical
cure
rates
at
the
second
follow-up
visit
(butoconazole:
77.3%;
miconazole:
79.7%)
and
microbiologic
cure
rates
(butoconazole:
68.3%;
miconazole:
72.5%).
Therapeutic
cure
rates
were
57.8%
for
butoconazole
and
61.4%
for
mi-
conazole.
Eighteen
patients,
11
in
the
butoconazole
group
and
7
in
the
miconazole
group,
had
fungal
cultures
positive
for
organisms
other
than
C.
albicans.
In
the
326
INFECTIOUS
DISEASES
IN
OBSTETRICS
AND
GYNECOLOGY
Butoconazole
Cure
rate
Miconazole
Difference
b
(%)
Two-sided
95%
confidence
interval
(%)
Treatment
groups
VAGINAL
CREAMS
FOR
VULVOVAGINAL
CANDIDIASIS
LAPPIN
ET
AL.
TABLE
2.
Summary
of
cure
rates'
First
follow-up
Clinical
110/119
128/135
(92.4%)
(94.8%)
—2.4
—9.2,
4.5
Microbiologic
104/118
120/134
(88.1%)
(89.6%)
I
.4
—10.0,
7.2
Second
follow-up
Clinical
85/96
102/119
(88.5%)
(85.7%)
2.8
—7.1,
12.7
Microbiologic
71/94
87/111
(75.5%) (78.4%)
—2.8
—15.4,
9.7
Therapeutic
cure
rate
63/109
78/127
(57.8%)
(61.4%)
—3.6
—17,
9.8
'Patients
with
missing/insufficient
data
from
the
second
follow-up
visit
were
excluded
from
the
analysis
for
that
visit.
b
Butoconazole
cure
rate
minus
miconazole
cure
rate.
butoconazole
group,
6
patients
had
Torulopsis
gla-
brata,
2
had
C.
tropicalis,
2
C.
parapsilosis,
and
1
other
non-albicans
Candida.
In
the
miconazole
group,
4
had
T.
glabrata,
1
C.
stellatoidea,
1
C.
parap-
silosis,
and
1
C.
tropicalis.
Therapeutic
cures
for
bu-
toconazole
recipients
were
achieved
in
4
of
the
9
patients
valid
for
efficacy
analysis,
2
with
C.
parap-
silosis,
1
with
C.
tropicalis,
and
1
with
T.
glabrata.
A
therapeutic
cure
was
achieved
in
1
of
the
5
micona-
zole
users
valid
for
efficacy
analysis.
This
subject
had
C.
tropicalis.
Four
patients
with
fungal
cultures
positive
for
non-albicans
organisms
were
not
ana-
lyzed
(i.e.,
2
treated
with
butoconazole
nitrate
and
2
with
miconazole
nitrate).
Safety
There
were
no
deaths
and
no
serious
adverse
events
reported.
Three
butoconazole-treated
pa-
tients
withdrew
prematurely
from
the
study
be-
cause
of
non-serious
adverse
events:
increased
burning
and
itching;
vaginal
burning;
and
itching
and
rash.
One
miconazole
user
withdrew
prema-
turely
because
of
moderate
lower
abdominal
cramping.
All
of
these
events
were
considered
probably
or
possibly
related
to
study
medication.
Two
patients
withdrew
prematurely
because
of
laboratory
abnormalities
(suspicious
Pap
smear
with
dysplasia)
and
5
because
of
intercurrent
ill-
nesses
(vaginal
trichomoniasis,
bladder
pressure,
cervicitis,
bacterial
vaginitis,
streptococcus
group
B
infection);
these
events
were
considered
by
the
in-
vestigators
to
be
probably
not
related
to
the
study
medications.
Of
all
389
patients
evaluated
in
the
safety
analy-
sis,
148
(38%)
reported
a
total
of
287
adverse
events:
70
of
197
butoconazole
recipients
(36%)
and
78
of
192
miconazole
users
(41%).
Overall
for
both
treatment
arms,
most
adverse
events
(88%)
were
rated
as
mild
or
moderate
in
severity
and
67%
of
all
events
were
considered
to
be
probably
not
related
to
butoconazole
nitrate
or
miconazole
ni-
trate
cream.
The
most
commonly
reported
adverse
event
was
"headache"
(butoconazole
nitrate
group:
9%;
miconazole
nitrate
group:
9%).
Events
related
to
the
urogenital
system
were
reported
by
60
patients
(15%):
29
(15%)
in
the
bu-
toconazole
group
and
31
(16%)
in
the
miconazole
group.
Urogenital
complaints
reported
by
more
than
3
patients
were
pain,
pruritus,
leukorrhea,
and
vaginitis,
as
detailed
in
Table
3.
Of
the
adverse
events
considered
by
the
investigators
to
be
possi-
bly
or
probably
related
to
study
medications,
among
the
most
frequently
reported
were
vaginal
pain
or
itching,
both
of
which
were
also
symptoms
of
the
underlying
disease.
DISCUSSION
The
lack
of
statistically
significant
differences
be-
tween
the
3-day
butoconazole
regimen
and
the
7-day
miconazole
regimen
with
respect
to
micro-
biologic,
clinical,
or
therapeutic
cure
rates
coupled
with
large
sample
sizes
indicate
that
the
two
study
medications
were
equally
effective
in
the
treat-
ment
of
vulvovaginal
candidiasis.
Although
the
study
groups
were
demographically
well
matched,
clinical
and
therapeutic
cure
rate
differences
in
this
INFECTIOUS
DISEASES
IN
OBSTETRICS
AND
GYNECOLOGY
327
VAGINAL
CREAMS
FOR
VULVOVAGINAL
CANDIDIASIS
LAPPIN
ET
AL.
TABLE
3.
Urogenital
adverse
events
reported
by
>3
patients
No.
of
patients
reporting
Event
Butoconazole
Miconazole
Total
Pain
15
13
28
Pruritus
12
9
21
Leukorrhea
6
7
Vaginitis
3
2
5
study
may
have
been
affected
by
the
preponder-
ance
of
patients
with
severe
itching
or
burning
in
the
butoconazole
group
(16%
and
29%,
respec-
tively,
vs.
6%
and
19%,
respectively,
for
micona-
zole).
Nonetheless,
the
study
showed
that
both
drugs
were
equally
effective
in
alleviating
vaginitis
symptoms
at
visit
2,
with
continued
or
maintained
recovery
at
visit
3.
Both
study
drugs
were
well
tol-
erated,
and
no
serious
adverse
events
were
re-
ported.
The
findings
of
this
study
support
those
of
Kaufman
et
al.,
12
whose
large-scale
study
also
had
a
randomized,
investigator-blind
design,
and
dem-
onstrated
that
3-day butoconazole
treatment
was
equal
in
efficacy
to
7-day
miconazole
therapy.
These
authors
speculated
that
the
3-day
regimen
could
have
an
advantage
over
the
7-day
regimen
in
that
patients
might
be
more
likely
to
comply
with
the
full
therapeutic
regimen
if
given
a
shorter
treat-
ment
schedule.
Although
the
majority
of
patients
in
the
present
study
had
fungal
cultures
positive
for
C.
albicans,
18
patients
had
fungal
cultures
positive
for
organisms
other
than
C.
albicans.
Of
the
patients
with
non-
albicans
species,
therapeutic
cures
were
achieved
in
4
of
9
butoconazole
users
and
1
of
5
miconazole
users.
Two
butoconazole
patients
were
excluded
and
2
miconazole
patients
were
excluded
from
analysis.
The
sample
in
this
subgroup
was
too
small
to
draw
statistically
significant
or
clinically
relevant
conclusions.
In
a
separate
in
vitro
study,
however,
butoconazole
was
found
to
be
more
effective
at
lower
concentrations
than
miconazole
and
other
azoles
against
non-albicans
species.
2
In
tests
of
200
vaginal
yeast
isolates
of
9
species,
including
100
isolates
of
non-albicans
species,
Lynch
and
Sobel
2
found
only
2
isolates
of
C.
kansei
in
which
buto-
conazole
>0.001
pg/ml
was
required
to
reduce
mi-
croorganism
growth
by
80%.
The
minimal
inhibi-
tory
concentration
of
miconazole
was
10-fold
higher
than
the
butoconazole
concentration
in
173
isolates
of
C.
albicans,
C.
glabrata,
and
C.
parapsi/o-
sis.
Still
higher
concentrations
of
other
azoles
were
required
for
equivalent
inhibitory
effect.
CONCLUSIONS
Butoconazole
nitrate
2%
cream
applied
intravagi-
nally
for
3
days
and
miconazole
nitrate
2%
cream,
applied
for
7
days
demonstrated
comparable
effi-
cacy
in
the
treatment
of
vulvovaginal
candidiasis.
In
addition,
both
treatments
were
well
tolerated
and were
not
associated
with
any
serious
adverse
events.
These
results
indicate
that
butoconazole
nitrate
2%
cream,
applied
once
daily
for
3
days,
is
comparable
to
an
approved
over-the-counter
prod-
uct.
ACKNOWLEDGMENTS
This
study
was
funded
in
part
by
a
grant
from
Syntex
Laboratories,
Inc.
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Three-day
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IN
OBSTETRICS
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GYNECOLOGY