Single-dose miconazole-nitrate vaginal ovule in the treatment of vulvovaginal candidiasis: two single-blind, controlled studies versus miconazole-nitrate 100 mg cream for 7 days


Upmalis, D.H.; Cone, F.L.; Lamia, C.A.; Reisman, H.; Rodriguez-Gomez, G.; Gilderman, L.; Bradley, L.

Journal of Women's Health & Gender-Based Medicine 9(4): 421-429

2000


To determine the efficacy and safety of a single-dose (1200 mg) soft gel insert (vaginal ovule) with miconazole nitrate (2%) topical cream compared with Monistat 7 (miconazole nitrate 2%) Vaginal Cream (Advanced Care Products, North Brunswick NJ) in treating vulvovaginal candidiasis (VVC), two randomized, single-blind, multicenter, controlled, comparative phase III studies were performed. Five hundred fifty-eight patients received either a single-dose miconazole nitrate (1200 mg) ovule or seven consecutive doses of Monistat 7. Ovule arm patients also received miconazole nitrate 2% cream for symptom relief, as needed, up to twice daily. The primary end point was a therapeutic cure. Also evaluated were time to complete symptom relief, safety, and patient preference. The ovule had overall cure rates of 71.7% (71 of 99 patients) and 61.5% (64 of 104 patients). Monistat 7 had overall cure rates of 70.1% (68 of 97 patients) and 61.1% (55 of 90 patients). A significantly greater proportion of patients experienced complete symptom relief by day 3 with the ovule (p = 0.008 and p = 0.025), and time to complete relief was significantly faster (median 4 versus 5 days and 3 versus 4 days). Overall safety results were consistent between groups in both studies. Miconazole nitrate vaginal ovule is as safe and efficacious in curing VVC as Monistat 7 while providing complete symptom relief significantly faster. Patients preferred the ovule to prior therapy.

JOURNAL
OF
WOMEN'S
HEALTH
&
GENDER-BASED
MEDICINE
Volume
9,
Number
4,
2000
Mary
Ann
Liebert,
Inc.
Single-Dose
Miconazole
Nitrate
Vaginal
Ovule
in
the
Treatment
of
Vulvovaginal
Candidiasis:
Two
Single-Blind,
Controlled
Studies
Versus
Miconazole
Nitrate
100
mg
Cream
for
7
Days
DAVID
H.
UPMALIS,
M.D.,
1
FREDERICK
L.
CONE,
B.A.,
1
CATHLEEN
A.
LAMIA,
M.S.,
1
HOWARD
REISMAN,
M.D.,
2
GUILLERMO
RODRIGUEZ-GOMEZ,
M.D.,
3
LARRY
GILDERMAN,
D.O.,
4
and
LYNN
BRADLEY,
M.S.,
C.R.N.M.
5
ABSTRACT
To
determine
the
efficacy
and
safety
of
a
single-dose
(1200
mg)
soft
gel
insert
(vaginal
ovule)
with
miconazole
nitrate
(2%)
topical
cream
compared
with
Monistat
®
7
(miconazole
nitrate
2%)
Vaginal
Cream
(Advanced
Care
Products,
North
Brunswick
NJ)
in
treating
vulvovaginal
candidiasis
(VVC),
two
randomized,
single-blind,
multicenter,
controlled,
comparative
phase
III
studies
were
performed.
Five
hundred
fifty-eight
patients
received
either
a
single-dose
mi-
conazole
nitrate
(1200
mg)
ovule
or
seven
consecutive
doses
of
Monistat
7.
Ovule
arm
patients
also
received
miconazole
nitrate
2%
cream
for
symptom
relief,
as
needed,
up
to
twice
daily.
The
primary
end
point
was
a
therapeutic
cure.
Also
evaluated
were
time
to
complete
symp-
tom
relief,
safety,
and
patient
preference.
The
ovule
had
overall
cure
rates
of
71.7%
(71
of
99
patients)
and
61.5%
(64
of
104
patients).
Monistat
7
had
overall
cure
rates
of
70.1%
(68
of
97
patients)
and
61.1%
(55
of
90
patients).
A
significantly
greater
proportion
of
patients
experi-
enced
complete
symptom
relief
by
day
3
with
the
ovule
(p
=
0.008
and
p
=
0.025),
and
time
to
complete
relief
was
significantly
faster
(median
4
versus
5
days
and
3
versus
4
days).
Over-
all
safety
results
were
consistent
between
groups
in
both
studies.
Miconazole
nitrate
vaginal
ovule
is
as
safe
and
efficacious
in
curing
VVC
as
Monistat
7
while
providing
complete
symp-
tom
relief
significantly
faster.
Patients
preferred
the
ovule
to
prior
therapy.
INTRODUCTION
been
reported
that
three
of
four
women
experi-
ence
at
least
one
episode
of
VVC
in
their
fife-
NT
ULVOVAGINAL
CAN
DIDIASIS
(VVC)
is
a
com-
time.
4
'
5
Although
VVC
is
seldom
a
serious
infec-
mon
cause
of
vaginitis,
1,2
accounting
for
tion,
it
presents
distressing
symptoms
and
has
a
20%-33%
of
all
symptomatic
vaginitis.
2
'
3
It
has
significant
impact
on
a
patient's
quality
of
life.
Ef-
1
Department
of
Clinical
Affairs,
Advanced
Care
Products,
North
Brunswick,
New
Jersey.
2
Atlanta
North
Gynecology,
P.C.,
Roswell,
Georgia.
3
Instituto
Costarricense
de
Investigaciones
Clinicas,
San
Jose,
Costa
Rica.
4
University
of
Clinical
Research
Association,
Inc.,
Pembroke
Pines,
Florida.
5
Johns
Hopkins
Medical
Services
Corporation,
Wyman
Park
Medical
Center,
Baltimore,
Maryland.
These
studies
were
supported
by
Advanced
Care
Products,
North
Brunswick,
New
Jersey.
421
422
UPMALIS
ET
AL.
ficacious
and
safe
medication
is
available
to
re-
lieve
the
itching
and
burning
associated
with
VVC.
Miconazole
nitrate
has
proven
broad-spectrum
fungistatic
activity
in
vitro
against
a
variety
of
pathogenic
fungi,
including
the
Candida
species,
C.
albicans,
C.
glabrata,
C.
tropicalis,
C.
parapsilosis,
and
C.
krusei.
It
has
been
proven
effective
in
vivo
against
VVC,
and
its
efficacy
has
been
established
with
many
different
formulations.
One
of
the
early
formulations,
marketed
worldwide
as
Monistat®
Vaginal
Cream
(100
mg)
(Advanced
Care
Products,
North
Brunswick,
NJ)
was
ap-
proved
in
1974
as
a
14-day
therapy.
Since
then,
many
different
Monistat
vaginal
products
have
been
approved
and
are
available
for
either
pre-
scription
or
over-the-counter
(OTC)
use
in
the
treatment
of
VVC.
An
estimated
10
million
courses
of
treatment
with
Monistat
are
dispensed
annually.
Despite
this
widespread
use,
there
have
been
relatively
few
reports
of
resistance
by
Can-
dida
species
6
and
no
evidence
of
diminishing
cure
rates.
Over
the
years,
the
duration
of
treatment
has
grown
progressively
shorter,
from
14
days
to
7
days
to
3
days
to
a
single
dose
with
either
a
vagi-
nal
or
oral
product.
Miconazole
nitrate
(1200
mg)
soft
gel
insert
(vaginal
ovule)
is
administered
as
a
single
dose
that
contains
70%
more
miconazole
ni-
trate
than
Monistat
7,
but
a
similar
amount
to
the
originally
marketed
100
mg
x
14-day
product.
The
drug
is
suspended
in
an
ointment
base
and
en-
closed
in
a
gelatin
capsule.
The
1200-mg
ovule
has
been
marketed
in
19
countries
outside
the
United
States,
including
the
United
Kingdom.
A
total
dose
of
1200
mg
has
been
approved
in
Canada
and
else-
where
as
OTC
products,
both
in
the
1200-mg
ovule
and
as
a
3-day,
400-mg
ovule
regimen.
This
study
was
designed
to
determine
the
effi-
cacy
and
safety
of
a
new
regimen
of
miconazole
nitrate
(1200
mg)
vaginal
ovule
administered
in
one
evening
dose
(to
be
used
in
combination
with
Monistat
External
Vulvar
Cream
[miconazole
ni-
trate
2%]
applied
on
an
as
needed
basis
to
relieve
itching
and
burning)
compared
with
the
efficacy
and
safety
of
Monistat
7
Vaginal
Cream
admin-
istered
for
7
consecutive
nights
in
the
treatment
of
patients
with
VVC.
MATERIALS
AND
METHODS
The
investigational
product
is
a
single
vagi-
nal
ovule
consisting
of
a
gelatin
shell
contain-
ing
1200
mg
miconazole
nitrate
formulated
in
liquid
paraffin,
white
petroleum,
and
lecithin.
The
ovule
was
dispensed
with
Monistat
Exter-
nal
Vulvar
Cream.
The
vulvar
cream
was
pack-
aged
in
9-g
tubes
and
was
to
be
applied
up
to
two
times
daily
for
up
to
7
days
to
relieve
external
itching
and
burning,
on
an
as
needed
basis.
The
product
is
referred
to
as
the
"ovule
regimen."
The
active
control
was
Monistat
7
(miconazole
nitrate
2%)
Vaginal
Cream,
containing
100
mg
mi-
conazole
nitrate
per
5-g
dose
in
a
water-miscible
cream.
This
product
was
packaged
in
seven
pre-
filled
5-g
(100
mg)
applicators,
or
a
total
700
mg
of
therapy.
The
control
formulation
is
identical
to
the
OTC
formulation
currently
available.
Study
design
Two
individual
studies
(96-002
and
97-006)
were
conducted
for
registration
of
the
product
in
the
United
States.
Both
were
single-blind,
ran-
domized,
multicenter,
phase
III,
outpatient,
com-
parative
studies
of
patients
with
documented
VVC.
Patients
were
equally
randomized
to
either
a
single
nighttime
dose
of
miconazole
nitrate
(1200
mg)
or
Monistat
7
Vaginal
Cream
formula-
tion
for
7
nights.
Patients
in
the
ovule
regimen
group
were
also
given
Monistat
External
Vulvar
Cream
packaged
in
9-g
tubes
to
be
applied
up
to
two
times
daily
to
relieve
external
itching
and
burning,
on
an
as
needed
basis.
Each
study
was
blinded
only
to
the
point
of
dispensing
of
treatment
in
standard
white
cartons
and
was
open
thereafter.
Double-blinding
the
study
would
have
required
double-dummying,
that
is,
the
concurrent
administration
of
drug
and
placebo.
In
the
case
of
the
1-day
product
con-
taining
active
ingredient,
this
would
have
neces-
sitated
the
administration
of
placebo
cream
for
7
days.
The
effects
of
administration
of
extra
cream
or
ointment
could
have
confounded
results,
be-
cause
of
either
a
drug
dilution
effect
or
potential
symptom
relief
effects
of
a
placebo
cream.
For
these
reasons,
a
double-blind
design
was
rejected.
The
study
protocol
and
informed
consent
were
approved
by
local
ethical
committees
and
by
a
central
ethical
review
committee.
Patients
Study
96-002
enrolled
between
5
and
30
pa-
tients
in
12
U.S.
centers
and
1
Latin
American
cen-
ter,
for
a
total
enrollment
of
278
patients.
One
ad-
ditional
center
enrolled
no
patients.
Study
97-006
enrolled
between
1
and
30
patients
in
each
of
16
SINGLE-DOSE
VAGINAL
OVULE
FOR
TREATMENT
OF
VVC
423
centers
in the
United
States
for
a
total
of
280
pa-
tients.
One
additional
center
enrolled
no
patients.
Demographics
Patients
in
study
96-002
had
an
age
range
of
18-79
years,
with
a
mean
age
of
33-34
years.
They
were
60%
white
and
40%
black
or
Hispanic.
There
were
no
positive
pregnancies
or
cases
of
gonor-
rhea.
Ninety
percent
of
all
patients
reported
mild
or
moderate
disease
severity,
with
only
4%-7%
reporting
severe
disease.
Nearly
90%
reported
vulvovaginal
itching,
and
>80%
noted
vulvo-
vaginal
burning.
The
demographic
parameters
were
similar
in
the
two
treatment
groups.
Patients
in
study
97-006
had
an
age
range
of
17-76
years,
with
a
mean
age
of
36-37
years.
Sev-
enty
percent
were
white,
with
most
of
the
rest
being
black
or
Hispanic.
There
were
no
positive
pregnancies,
but
there
was
one
positive
test
for
gonorrhea.
In
this
study,
95%
of
all
patients
re-
ported
mild
or
moderate
disease
severity,
with
only
2%
reporting
severe
disease.
Approximately
90%
reported
vulvovaginal
itching,
and
>75%
reported
vulvovaginal
burning
or
irritation.
The
demographic
parameters
were
similar
in
the
two
treatment
groups.
Methods
Each
patient
was
seen
by
examiners
a
total
of
three
times:
on
admission
(day
1),
at
return
visit
1
(between
day
15
and
day
19),
and
at
return
visit
2
(between
day
35
and
day
43).
At
admission,
a
medical
history
was
taken,
a
symptom
evaluation
was
performed,
and
a
diagnosis
was
ascertained.
Inclusion
and
exclusion
criteria
Only
patients
with
vulvovaginal
candidiasis
who
satisfied
all
of
the
inclusion
criteria
and
had
none
of
the
exclusion
criteria
were
entered
into
the
study.
All
patients
included
in
the
study
were
to
be
at
least
18
years
of
age
(although
one
17-
year-old
patient
who
satisfied
all
other
criteria
was
admitted
in
study
97-006),
nonpregnant
and
nonnursing
women
who
used
effective,
nonbar-
rier
methods
of
contraception,
and
who
agreed
to
avoid
tampon
use
for
the
duration
of
the
study.
Women
must
have
reported
at
least
one
sign
(identified
by
the
physician)
or
symptom
of
VVC,
including
vulvovaginal
itching,
burning,
or
irri-
tation,
vulvar
erythema,
edema,
or
excoriation,
or
vaginal
erythema
or
edema.
If
all
seven
clinical
signs
and
symptoms
were
classified
as
normal
or
absent
at
baseline,
the
patient
was
considered
in-
valid
for
all
efficacy
analyses
and
was
classified
as
being
indeterminate
for
a
clinical
cure
at
both
return
visits.
All
patients
had
a
Pap
smear
eval-
uation
on
admission
to
rule
out
carcinoma
in
situ
or
more
serious
lesions.
To
document
the
presence
of
VVC
and
elimi-
nate
the
possibility
of
infection
associated
with
pathogens
other
than
Candida,
patients
were
ex-
amined
and
had
to
meet
the
following
criteria:
(1)
a
positive
10%
KOH
preparation
for
yeast,
(2)
a
negative
wet
mount
for
Trichomonas
vaginalis
and
clue
cells,
(3)
a
positive
BiGGY
culture
for
Can-
dida
species,
and
(4)
a
negative
test
for
Neisseria
gonorrhoeae.
All
tests
were
performed
as
part
of
the
admitting
process
and
were
necessary
for
evaluability.
Patients
were
asked
to
sign
a
consent
form,
agree
to
attend
follow-up
appointments,
and
com-
plete
a
patient
preference
survey
at
the
conclu-
sion
of
the
test
period.
Any
patient
with
an
affirmative
response
to
one
or
more
of
the
following
criteria
was
ex-
cluded
from
the
study:
1.
Use
of
systemic
antiinfective
or
vulvovaginal
or
cervical
contraceptive
devices,
vaginal
lu-
bricants,
foams,
jellies,
ointments,
medicated
douches,
or
feminine
sprays
within
the
study
period
2.
Use
of
water
douches
within
3
days
of
admis-
sion
(this
criterion
avoids
false
negative
KOH
preparations
and
cultures)
3.
Current
history
of
drug
or
alcohol
abuse
4.
History
of
sensitivity
to
the
imidazole
class
of
drugs
or
any
component
of
the
ovule
or
cream
formulations
5.
Vulvovaginal
infections
associated
with
patho-
gens
other
than
Candida
species
6.
Active
genital
herpetic
lesions
at
the
time
of
admission
7.
Presence
of
or
treatment
of
genital
condylo-
mata
within
30
days
of
admission
8.
Use
of
another
experimental
drug
or
device
within
30
days
prior
to
the
study
9.
More
than
one
documented
yeast
infection
within
a
2-month
period
or
yeast
infection
not
clearing
up
with
proper
treatment
Efficacy
assessment
An
overall
therapeutic
cure
was
the
primary
end
point
and
was
based
on
clinical
symptoms,
424
UPMALIS
ET
AL.
plus
physical
signs
and
microbiology
findings on
gynecological
examination.
Any
patient
who
would
otherwise
be
classified
as
a
microbiological
cure
but
was
missing
either
the
10%
KOH
preparation
or
culture
results
at
ei-
ther
return
visit
was
classified
as
"indeterminate"
rather
than
"cure"
for
that
visit.
Likewise,
if
a
pa-
tient
had
missing
information
for
any
of
the
clin-
ical
signs
or
symptoms
at
either
return
visit
but
would
otherwise
be
classified
as
"cure,"
she
would
be
considered
"indeterminate."
Any
pa-
tient
missing
microbiological
or
clinical
informa-
tion
who
would
otherwise
be
classified
as
"fail-
ure"
would
still
be
considered
"failure."
A
patient
was
considered
an
overall
microbio-
logical
cure
if
both
10%
KOH
preparation
and
culture
were
negative
at
both
return
visits
and
an
overall
clinical
cure
if
the
clinical
signs
and
symp-
toms
were
improved
at
the
first
return
visit
and
normal
or
absent
at
the
second
return
visit.
A
pa-
tient
was
classified
as
an
overall
therapeutic
cure
if
she
(1)
was
classified
as
an
overall
clinical
cure,
(2)
was
classified
as
an
overall
microbiological
cure,
and
(3)
had
completed
all
information
as
re-
quired
by
the
protocol.
Time
to
complete
relief
of
symptoms
was
de-
termined
through
daily
patient
recordings
in
a
treatment
diary
covering
the
first
7
days
of
treat-
ment.
Safety
was
assessed
by
review
and
analysis
of
adverse
experiences
as
reported
by
patients,
by
a
review
of
study
discontinuations,
and
by
the
find-
ings
on
gynecological
examinations
at
return
visit
1
and
return
visit
2.
Patient
preference
was
determined
by
a
ques-
tionnaire
completed
by
each
study
subject.
Com-
pliance
was
assured
via
patient
diary
cards
and
exclusion
from
the
study
if
more
than
1
day
of
treatment
was
missed.
RESULTS
Return
visit
1
cure
rates
As
investigators
expected,
the
cure
rates
for
both
groups
were
higher
at
return
visit
1
than
the
overall
cure
rates.
The
return
visit
1
clinical
cure
rates
(Table
1)
were
higher
for
the
Monistat
7
group
in
study
96-002
(97%
versus
93%)
and
higher
for
the
ovule
regimen
group
in
study
97-
006
(88%
versus
84%).
The microbiological
cure
rates
were
for
both
groups
slightly
higher
for
Monistat
7
at
return
visit
1
(study
96-002:
Moni-
stat
7,
92%;
ovule
regimen,
88%;
study
97-006:
Monistat
7,
81%;
ovule
regimen
79%).
The
thera-
peutic
cure
rates
followed
a
pattern
similar
to
the
clinical
cure
rates.
In
study
96-002,
the
Monistat
7
group
had
a
therapeutic
cure
rate
of
90%
ver-
sus
84%
for
the
ovule
regimen
group.
The
95%
confidence
interval
(CI)
for
the
difference
in
ther-
apeutic
cure
rates
(ovule
regimen
minus
Moni-
stat
7)
at
return
visit
1
in
study
96-002
is
(—
15.0%,
3.2%).
Study
97-006
showed
a
74%
cure
rate
for
the
ovule
regimen
versus
a
72%
cure
rate
in
the
Monistat
7
group.
The
95%
CI
for
the
difference
in
therapeutic
cure
rates
(ovule
regimen
minus
Monistat
7)
at
return
visit
1
in
study
97-006
is
(-10.7%,
13.7%).
There
was
no
statistical
differ-
ence
in
the
overall
therapeutic
cure
rate
of
either
study
at
return
visit
1.
Overall
cure
rates
Overall
clinical,
microbiological,
and
thera-
peutic
cure
rates
were
nearly
identical
for
the
two
treatment
groups
in
both
studies
(Table
2).
In
study
96-002,
the
therapeutic
cure
rate
in
the
ovule
regimen
group
was
72%,
compared
with
70%
in
the
Monistat
7
group.
The
95%
CI
for
the
difference
in
overall
therapeutic
cure
rates
(ovule
TABLE
1.
CURE
RATES
AT
RETURN
VISIT
1
BY
STUDY
NUMBER
Study
96-002
Study
97-006
Miconazole
Miconazole
nitrate
Monistat®
7
nitrate
MonistatT®
7
vaginal
ovule
Vaginal
Cream
vaginal
ovule
Vaginal
Cream
Type
of
cure
n
=
107
n
=
100
n
=
111
n
=
94
Clinical
cure
99
(93%)
97
(97%)
98
(88%)
79
(84%)
Microbiological
cure
94
(88%)
92
(92%)
88
(79%)
76
(81%)
Therapeutic
cure*
90
(84%)
90
(90%)
82
(74%)
68
(72%)
*p
>
0.05,
not
statistically
significantly
different
using
the
Cochran-Mantel-Haenszel
Test.
SINGLE-DOSE
VAGINAL
OVULE
FOR
TREATMENT
OF
VVC
425
TABLE
2.
OVERALL
CLINICAL,
MICROBIOLOGICAL,
AND
THERAPEUTIC
CURE
RATES
BY
STUDY
NUMBER
Miconazole
nitrate
vaginal
ovule
Monistat®
7
Vaginal
Cream
Clinical
cure
rates
Study
96-002
81/99
(82%)
79/97
(81%)
Study
97-006
72/104
(69%)
63/90
(70%)
Microbiological
cure
rates
Study
96-002
75/99
(76%)
71/97
(73%)
Study
97-006
72/104
(69%)
62/90
(69%)
Therapeutic
cure
rates*
Study
96-002
71
/
99
(72%)
68/97
(70%)
Study
97-006
64/104
(62%)
55/90
(61%)
*p
>
0.05,
not
statistically
significantly
different
using
the
Cochran-Mantel-
Haenszel
Test.
regimen
minus
Monistat
7)
in
study
96-002
is
(-11.1%,
14.3%).
In
study
97-006,
the
therapeutic
cure
rate
in
the
ovule
regimen
group
was
62%,
compared
with
61%
in
the
Monistat
7
group.
The
95%
CI
for
the
difference
in
overall
difference
in
overall
therapeutic
cure
rates
(ovule
regimen
mi-
nus
Monistat
7)
in
study
97-006
is
(-13.3%,
14.2%).
Data
from
both
studies
showed
that
ther-
apeutic
equivalence
was
achieved.
Time
to
symptom
relief
Time
to
complete
relief
of
symptoms
was
sig-
nificantly
faster
with
the
ovule
regimen
than
with
Monistat
7,
being
about
a
day
shorter
in
both
studies.
In
study
96-002,
median
time
to
complete
relief
of
symptoms
was
4
days
in
the
ovule
group
and
5
days
in
the
vaginal
cream
group.
In
study
97-006,
median
time
to
relief
was
3
days
in
the
ovule
group
and
4
days
in
the
vaginal
cream
group.
Relief
from
the
itching
and
burning/irri-
tation
by
day
3
occurred
in
significantly
more
pa-
tients
in
the
miconazole
nitrate
vaginal
ovule
reg-
imen
of
both
studies
(study
96-002:
p
=
0.025;
study
97-006:
p
=
0.008)
(Fig.
1).
As
would
be
ex-
pected
in
treatments
that
are
therapeutically
equivalent,
relief
was
comparable
in
both
groups
by
day
7.
The
symptom
relief
data
from
the
two
studies
were
combined
because
the
studies
were
similar
in
design.
The
combined
data
were used
to
ex-
plore
the
rate
at
which
symptom
relief
was
achieved,
using
time
to
success
(defined
as
the
time
to
first
symptom-free
day
during
treatment)
as
the
end
point.
An
analysis
of
time
to
success
indicated
that
the
symptoms
disappeared
more
rapidly
in the
ovule
regimen
group and
that
the
difference
from
the
Monistat
7
group
was
statis-
tically
significant
(p
=
0.003).
Safety
The
most
frequently
reported
adverse
events
in
all
treatment
groups
involved
the
genital-re-
productive
system
and
the
nervous
system.
Burn-
ing
or
irritation
of
the
genitalia,
pruritus
of
the
external
genitalia,
and
headache
were
the
most
frequently
reported
individual
events
(Table
3).
Adverse
events
occurred
less
frequently
in
the
respiratory
system
and
gastrointestinal
system.
Three
patients
in the
ovule
regimen
group
and
four
patients
in
the
Monistat
7
group
discontin-
ued
the
study
because
of
adverse
experiences.
Six
of
these
patients
experienced
vulvovaginal
itch-
ing,
burning,
or
irritation
or
a
combination
of
the
symptoms,
and
two
involved
a
more
generalized
reaction.
Approximately
20%
of
all
adverse
ex-
periences
reported
were
classified
as
severe,
but
<10%
were
considered
probably
or
highly
prob-
ably
related
to
the
study
medication.
There
were
no
clinically
significant
differences
between
the
treatment
groups
in
either
study
when
adverse
experiences
were
classified
by
either
severity
or
relationship
to
study
medication.
Patient
preference
The
miconazole
nitrate
vaginal
ovule
scored
higher
than
Monistat
7
Vaginal
Cream
on
ques-
tions
regarding
"overall
opinion
of
the
product,"
"overall
product
preference,"
and
"preference
over
last
product
used."
"Overall
product
pref-
erence"
was
significant
at
a
99%
CI
in
both
stud-
ies,
and
"preference
over
last
product
used"
was
80
70
60
5
0
40
3
0
2
0
1
0
0
P
=
0.025
29/94
pts*
15/92
pts*
Study
96-002
Study
97-006
Miconazole
Miconazole
nitrate
Monistat
®
7
nitrate
Monistat
®
7
vaginal
ovule
Vaginal
Cream
vaginal
ovule
Vaginal
Cream
n
=
134
n
=
132
n
=
138
n
=
133
426
UPMALIS
ET
AL.
P
=
0.008
Miconazole
Nitrate
Vaginal
Ovule
Monistat®7
Vaginal
Cream
19/85
pts*
31%
16%
96-002
41%
22%
97-006
41
/1
0
.
0
pts*
FIG.
1.
Proportion
of
subjects
with
complete
relief
of
symptoms
at
day
3:
miconazole
nitrate
(1200
mg)
vaginal
ovule
compared
with
Monistat
®
7
(2%)
Vaginal
Cream.
significant
at
95%
or
higher
CI
in
both
studies.
When
asked
their
overall
opinion
of
the
product
used,
35%
of
all
patients
in
the
ovule
regimen
group
in
study
96-002
rated
the
single-dose
prod-
uct
"excellent,"
and
34%
rated
it
"very
good"
(to-
tal
69%).
Twenty
percent
of
patients
in the
vagi-
nal
cream
group
rated
the
7-day
product
"excellent,"
and
51%
rated
it
"very
good"
(total
71%).
In
study
97-006,
27%
of
all
patients
in
the
ovule
regimen
group
rated
the
product
"excel-
lent,"
and
38%
rated
it
"very
good"
(total
65%).
Twenty-six
percent
of
all
patients
in
the
Monistat
7
group
rated
the
product
"excellent,"
and
35%
rated
it
"very
good"
(total
61%).
Although
the
ovule
regimen
had
a
slightly
greater
incidence
of
irritation,
patients
seemed
to
feel
that
the
positive
aspects
of
the
product
compensated
for
any
mi-
nor
discomfort.
Table
4
summarizes
patient
pref-
erence
for
the
ovule
regimen
and
Monistat
7
based
on
specific
product
attributes
(works
faster,
works
better,
less
leakage,
more
convenient,
more
immediate
relief)
compared
with
product
last
TABLE
3.
MOST
FREQUENTLY
REPORTED
ADVERSE
EXPERIENCES
IN
BOTH
STUDIES
Burning
32
(24%)
29
(22%)
39
(28%)
34
(26%)
Headache
31
(23%)
32
(24%)
17
(12%)
18
(14%)
Pruritus
30
(22%)
35
(27%)
22
(16%)
36
(27%)
Irritation
21*
(16%)
10*
(8%)
34
(25%)
31
(23%)
*Statistically
significant
difference
(p
>
0.04)
using
Fisher's
exact
test.
There
were
no
other
statistically
significant
differences.
SINGLE-DOSE
VAGINAL
OVULE
FOR
TREATMENT
OF
VVC
427
TABLE
4.
SUMMARY
OF
PATIENT
PREFERENCE:
MICONAZOLE
NITRATE
(1200
MG)
VAGINAL
OVULE
COMPARED
WITH
MONISTAT
®
7
(2%)
VAGINAL
CREAM
a
Preference
over
last
product
used
Miconazole
nitrate
vaginal
ovule
Monistat®
7
Vaginal
Cream
96-002
n
=
115
97-006
n
=
123
96-002
n
=
117
97-006
n
=
114
Works
faster
90
(78%)
89
(72%)
63
(54%)
62
(54%)
Works
better
76
(66%)
87
(71%)
59
(50%)
62
(54%)
Less
leakage
71
(62%)
84
(68%)
55
(47%)
56
(49%)
More
convenient
100
(87%)
N/Ab
66
(56%)
N/Ab
More
immediate
relief
N/A`
84
(68%)
N/A`
60
(53%)
allo
statistical
testing
was
performed.
b
Not
asked
of
participants
in
study
97-006.
`Not
asked
of
participants
in
study
96-002.
used.
Figure
2
shows
overall
product
preference
fering
from
VVC.
This
goal
was
achieved
at
both
compared
with
previous
therapy.
return
visit
1
and
in
overall
therapeutic
cure
rates.
The
time
to
complete
relief
of
symptoms
was
faster
in
both
studies
in
the
ovule
regimen
groups
DISCUSSION
(median
time
in
study
96-002,
4
days
versus
5
days;
median
time
in
study
97-006,
3
days
versus
The
goal
of
both
studies
was
to
demonstrate
4
days).
The
proportion
of
patients
symptom
free
therapeutic
equivalence
of
the
two
miconazole
ni-
on
day
3
in
the
ovule
regimen
groups
was
almost
trate
formulations
in
the
treatment
of
patients
suf-
double
that
of
the
7-day
cream,
statistically
sig-
56%
41%
80
70
60
50
40
30
20
10
75%
69%
96-002
97-006
96-002
97-006
Miconazole
Nitrate
Monistat®7
Vaginal
Ovule
Vaginal
Cream
FIG.
2.
Overall
product
preference.
Percent
of
subjects
preferring
use
of
miconazole
nitrate
(1200
mg)
vaginal
ovule
or
Monistat
®
7
(2%)
Vaginal
Cream
over
previous
therapy.
No
statistical
testing
was
performed.
428
UPMALIS
ET
AL.
nificant
in
both
studies.
By
day
7,
the
proportions
of
subjects
experiencing
symptomatic
relief
in
all
groups
were
similar,
ranging
between
66%
and
70%.
A
quicker
time
to
complete
relief
of
symp-
toms
is
important
in
patient
satisfaction
because
patients
judge
infection
onset
and
resolution
by
the
presence
or
absence
of
symptoms.
The
adverse
events
rate
was
consistent
with
other
studies.
There
were
no
statistical
differ-
ences
between
the
groups
in
either
study
in
the
severity
of
the
adverse
event
or
its
relationship
to
the
study
medication.
In
fact,
reporting
of
a
number
of
events
was
probably
partly
attribut-
able
to
the
use
of
a
diary
by
each
patient
to
record
all
events,
whether
or
not
they
were
attributable
to
the
study
medication.
Investigators
estimate
that
<10%
of
all
events
were
in
fact
attributable
to
the
medication.
These
events
were
self-limited
and
comparable
to
events
with
marketed
prod-
ucts.
Patients
prefer
a
one-dose
treatment.
Study
participants
believed
the
ovule
regimen
to
be
less
messy
and
more
convenient
than
the
vaginal
cream.
The
miconazole
nitrate
vaginal
ovule
reg-
imen
scored
higher
on
"overall
opinion
of
the
product,"
"overall
product
preference,"
and
"preference
over
last
product
used,"
all
strong
in-
dicators
of
patient
preference.
Research
on
pa-
tient
compliance
suggests
that
compliance
rates
increase
with
a
short-term,
convenient
dosage.?
A
previous
phase
I
pharmacokinetic
study
es-
tablished
that
the
total
systemic
drug
exposure
differs
little
between
the
single-dose
adminis-
tration
of
miconazole
nitrate
and
the
7-day
Moni-
stat
7
treatment.
8
The
use
of
pharmacokinetic
modeling
based
on
these
data
also
established
the
safety
of
the
ovule
regimen
even
in
the
presence
of
significant
misuse
(defined
as
daily
insertion
for
up
to
7
consecutive
days).
9
CONCLUSIONS
The
ideal
treatment
for
VVC
has
been
defined
as
easy
to
administer,
compliance
enhancing,
and
effective
in
a
short
course
of
therapy.lo
A
single-dose
vaginal
ovule
of
miconazole
ni-
trate
(1200
mg)
has
been
proven
effective
in
the
treatment
of
patients
with
documented
VVC
in
two
well-controlled,
multicenter
studies.
Clinical,
microbiological,
and
therapeutic
cure
rates
at
re-
turn
visit
1,
as
well
as
overall
cure
rates,
are
equivalent
to
those
obtained
with
Monistat
7
(mi-
conazole
nitrate
2%)
Vaginal
Cream.
As
a
result
of
the
extensive
experience
with
Monistat
7
Vagi-
nal
Cream,
both
as
a
prescription
product
and
in
the
OTC
market,
and
the
comparability
of
the
ovule
regimen
demonstrated
in
the
clinical
trials
reported
here,
one
can
conclude
that
the
ovule
regimen
is
entirely
appropriate
for
the
safe
and
effective
treatment
of
vulvovaginal
candidiasis.
The
miconazole
nitrate
vaginal
ovule
regimen
was
found
to
be
superior
to
Monistat
7
in
the
time
required
for
complete
relief
of
symptoms.
A
re-
view
of
the
literature
shows
that
no
other
com-
parative
study
has
shown
a
significant
difference
in the
time
to
cure.
The
ovule
appeals
to
patients
because
of
the
ease
of
treatment
and
offers
the
probability
of
100%
compliance
with
the
ovule
regimen.
The
new
one-dose
ovule
regimen
with
external
vulvar
cream
represents
a
valuable
new
therapy
for
the
treatment
of
VVC.
REFERENCES
1.
Paavonen
J,
Stamm
WE.
Lower
genital
tract
infections
in
women.
Infect
Dis
Clin
North
Am
1987;1:179.
2.
Sobel
JD.
Pathophysiology
of
vulvovaginal
candidia-
sis.
J
Reprod
Med
1989;34(Supp
1
8):572.
3.
Fleury
FJ.
Adult
vaginitis.
Clin
Obstet
Gynecol
1981;24:407.
4.
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Address
reprint
requests
to:
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H.
Llpmalis,
M.D.
Executive
Director
Clinical
Affairs
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Care
Products
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691
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South
North
Brunswick,
NJ
08902