A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Climara Pharmacology, Pharmacokinetics, Studies, Metabolism - Estradiol transdermal
Climara Pharmacology, Pharmacokinetics, Studies, Metabolism - Estradiol transdermal
CLINICAL PHARMACOLOGY
The Climara® system provides systemic estrogen
replacement therapy by releasing 17b-estradiol, the
major estrogenic hormone secreted by the human ovary.
Estrogens are largely responsible for the development and maintenance
of the female reproductive system and secondary sexual characteristics. Although
circulating estrogens exist in a dynamic equilibrium of metabolic interconversions,
estradiol is the principal intracellular human estrogen and is substantially
more potent than its metabolites, estrone and estriol at the receptor level.
The primary source of estrogen in normally cycling adult women is the ovarian
follicle, which secretes 70 to 500 µg of estradiol daily, depending on the phase
of the menstrual cycle. After menopause, most endogenous estrogen is produced
by conversion of androstenedione, secreted by the adrenal cortex, to estrone
by peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone
sulfate, are the most abundant circulating estrogens in postmenopausal women.
Estrogens act through binding to nuclear receptors in estrogen-responsive tissues.
To date, two estrogen receptors have been identified. These vary in proportion
from tissue to tissue.
Circulating estrogens modulate the pituitary secretion of the
gonadotro-pins luteininizing hormone (LH) and follicle stimulating hormone (FSH)
through a negative feedback mechanism and estrogen replacement therapy acts
to reduce the elevated levels of these hormones seen in postmenopausal women.
A two-year clinical trial enrolled a total of 175 healthy, hysterectomized,
postmenopausal, non-osteoporotic (i.e., lumbar spine bone mineral density >
0.9 gm/cm2) women at 10 study centers in the United States. 129 subjects
were allocated to receive active treatment with 4 different doses of 17b-estradiol
patches (6.5, 12.5, 15, 25 cm2) and 46 subjects were allocated to
receive placebo patches. 77% of the randomized subjects (100 on active drug
and 34 on placebo) contributed data to the analysis of percent change of A-P
spine bone mineral density (BMD), the primary efficacy variable. A statistically
significant overall treatment effect at each timepoint was noted, implying bone
preservation for all active treatment groups at all timepoints, as opposed to
bone loss for placebo at all timepoints.
Percent change in BMD of the total hip was also statistically
significantly different from placebo for all active treatment groups. The results
of the measurements of biochemical markers supported the finding of efficacy
for all doses of transdermal estradiol. Serum osteocalcin levels decreased,
indicative of a decrease in bone formation, at all timepoints for all active
treatment doses, statistically significantly different from placebo (which generally
rose). Urinary deoxypyridinoline and pyridinoline changes also suggested a decrease
in bone turnover for all active treatment groups.
PHARMACOKINETICS
Transdermal administration of Climara® produces
mean serum concentrations of estradiol comparable to those produced by premenopausal
women in the early follicular phase of the ovulatory cycle. The pharmacokinetics
of estradiol following application of the Climara® system were
investigated in 197 healthy postmenopausal women in six studies. In five of
the studies Climara® system was applied to the abdomen and in
a sixth study application to the buttocks and abdomen were compared.
Absorption: The Climara® transdermal
delivery system continuously releases estradiol which is transported across
intact skin leading to sustained circulating levels of estradiol during a 7-day
treatment period. The systemic availability of estradiol after transdermal administration
is about 20 times higher than that after oral administration. This difference
is due to the absence of first pass metabolism when estradiol is given by the
transder-mal route.
In a bioavailability study, the Climara® 6.5
cm2 was studied with the Climara® 12.5 cm2 as
reference.
Dose proportionality was demonstrated for the Climara®
6.5 cm2 transder-mal system as compared to the Climara®
12.5 cm2 transdermal system in a 2-week crossover study with
a 1-week washout period between the two transdermal systems in 24 postmenopausal
women.
Dose proportionality was also demonstrated for the Climara®
system (12.5 cm2 and 25 cm2) in a 1-week study conducted
in 54 postmenopausal women. The mean steady state levels (Cavg) of the estradiol
during the application of Climara® 25 cm2 and 12.5
cm2 on the abdomen were about 80 and 40 pg/mL, respectively.
In a 3 week multiple application study in 24 postmenopausal
women, the 25.0 cm2 Climara® system produced average
peak estradiol concentrations (Cmax) of approximately 100 pg/mL. Trough values
at the end of each wear interval (Cmin) were approximately 35 pg/mL. Nearly
identical serum curves were seen each week, indicating little or no accumulation
of estradiol in the body. Serum estrone peak and trough levels were 60 and 40
pg/mL, respectively.
In a single dose, randomized, crossover study conducted to
compare the effect of site of application, 38 postmenopausal women wore a single
Climara® 25 cm2 system for 1 week on the abdomen and
buttocks. Cmax and Cavg values were, respectively, 25% and 17% higher with the
buttock application than with the abdomen application.
Table 1 provides a summary of estradiol pharmacokinetic parameters
determined during evaluation of Climara®.
|
Table 1 Pharmacokinetic Summary (Mean Estradiol Values)
|
|
Climara® Delivery Rate
|
Surface Area(cm2)
|
Application Site
|
No. of Subjects
|
Dosing
|
Cmax(pg/mL)
|
Cmin(pg/mL)
|
Cavg(pg/mL)
|
|
0.025
|
6.5
|
Abdomen
|
24
|
Single
|
32
|
17
|
22
|
|
0.05
|
12.5
|
Abdomen
|
102
|
Single
|
71
|
29
|
41
|
|
0.1
|
25
|
Abdomen
|
139
|
Single
|
147
|
60
|
87
|
|
0.1
|
25
|
Buttock
|
38
|
Single
|
174
|
71
|
106
|
The relative standard deviation of each pharmacokinetic parameter
after application to the abdomen averaged 50%, which is indicative of the considerable
intersubject variability associated with transdermal drug delivery. The relative
standard deviation of each pharmacokinetic parameter after application to the
buttock was lower than that after application to the abdomen (e.g., for Cmax
39% vs 62%, and for Cavg 35% vs 48%).
Distribution: The distribution of exogenous
estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed
in the body and are generally found in higher concentrations in the sex hormone
target organs. Estradiol and other naturally occurring estrogens are bound mainly
to sex hormone binding globulin (SHBG), and to lesser degree to albumin.
Metabolism: Exogenous estrogens are metabolized
in the same manner as endogenous estrogens. Circulating estrogens exist in a
dynamic equilibrium of metabolic interconversions. These transformations take
place mainly in the liver. Estradiol is converted reversibly to estrone, and
both can be converted to estriol, which is the major urinary metabolite. Estrogens
also undergo enterohepatic recirculation via sulfate and glucuronide conjugation
in the liver, biliary secretion of conjugates into the intestine, and hydrolysis
in the gut followed by reabsorption. In postmenopausal women a significant portion
of the circulating estrogens exist as sulfate conjugates, especially estrone
sulfate, which serves as a circulating reservoir for the formation of more active
estrogens.
Excretion: Estradiol, estrone and estriol
are excreted in the urine along with glucuronide and sulfate conjugates. After
removal of the Climara® system, serum estradiol levels decline
in about 12 hours to preapplication levels with an apparent half-life of approximately
4 hours.
Special Populations:
Geriatric: There have not been sufficient
numbers of geriatric patients involved in clinical studies utilizing Climara®
to determine whether those over 65 years of age differ from younger subjects
in their response to Climara®. Pediatric: No pharmacokinetic
study for Climara® has been conducted in a pediatric population.
Gender: Climara® is indicated
for use in women only.
Race: No studies were done to determine
the effect of race on the pharma-cokinetics of Climara®.
Patients with Renal Impairment: Total
estradiol serum levels are higher in postmenopausal women with end stage renal
disease (ESRD) receiving maintenance hemodialysis than in normal subjects at
baseline and following oral doses of estradiol. Therefore, conventional transdermal
estradiol doses used in individuals with normal renal function may be excessive
for postmenopausal women with ESRD receiving maintenance hemodialysis.
Patients with Hepatic Impairment: Estrogens may
be poorly metabolized in patients with impaired liver function and should be
administered with caution.
DRUG INTERACTIONS
No drug interaction studies have been conducted.
Adhesion
An open-label study of adhesion potentials of placebo transdermal
systems that correspond to the 6.5 cm2 and 12.5 cm2 sizes
of Climara® was conducted in 112 healthy women of 45-75 years
of age. Each woman applied both transdermal systems weekly, on the upper outer
abdomen, for 3 consecutive weeks. It should be noted that lower abdomen and
upper quadrant of the buttock are the approved sites of application for Climara®.
The adhesion assessment was done visually on Days 2, 4, 5,
6, 7 of each week of transdermal system wear. A total of 1654 adhesion observations
were conducted for 333 transdermal systems of each size.
Of these observations, approximately 90% showed essentially
no lift for both the 6.5 cm2 and 12.5 cm2 transdermal
systems. Of the total number of trans-dermal systems applied, approximately
5% showed complete detachment for each size.
Adhesion potentials of the 18.75 cm2 and 25.0 cm2
sizes of transdermal systems (0.075 mg/day and 0.1 mg/day) have not been
studied.
Clinical Studies
Climara® is effective in reducing moderate to
severe vasomotor symptoms in postmenopausal women.
A total of 214 patients were enrolled in a study, to determine
the efficacy of Climara® 0.05 mg/day and 0.1 mg/day compared
to placebo and an active comparator. Women took drug in a cyclical fashion (three
weeks on and one week off).
A study of 214 women 25 to 74 years old met the qualification
criteria and were randomly assigned to one of the three treatment groups: 72
to the 0.05 mg estradiol patch, 70 to the 0.1 mg estradiol patch, and 72 to
placebo. Potential subjects were postmenopausal women in good general health
who experienced vasomotor symptoms. Natural menopause patients had not menstruated
for at least 12 months and surgical menopause patients had undergone bilateral
oophorectomy at least 4 weeks before evaluation for study entry. In order to
enter the 11-week treatment phase of the study, potential subjects must have
experienced a minimum of five moderate to severe hot flushes per week, or a
minimum of 15 hot flushes of any severity per week, for 2 consecutive weeks.
Women wore the patches in a cyclical fashion (three weeks on and one week off).
During treatment, all subjects used diaries to record the number
and severity of hot flushes. Subjects were monitored by clinic visits at the
end of weeks 1, 3, 7, and 11 and by telephone at the end of weeks 4, 5, 8, and
9. Adequate data for the analysis of efficacy was available from 191 subjects.
The results are presented as the mean ± SD number of flushes in each of the
3 treatment weeks of each 4-week cycle. In the 0.05 mg estradiol group, the
mean weekly hot flush rate across all treatment cycles decreased from 46 ± 6.5
at baseline to 20 ± 3.0 (-67.0%). The 0.1 mg estradiol group had a decline in
the mean weekly hot flush rate from 52 ± 4.4 at baseline to 16 ± 2.4 (-72.0%).
In the placebo group, the mean weekly hot flush rate declined from 53 ± 4.5
at baseline to 46 ± 6.5 (-18.1%). Compared with placebo, the 0.05 mg and 0.1
mg estradiol groups showed a statistically significantly larger mean decrease
in hot flushes across all treatment cycles (P<0.05). When the response to
treatment was analyzed for each of the three cycles of therapy, similar statistically
significant differences were observed between both estradiol treatment groups
and the placebo group during all treatment cycles.
In a double-blind, placebo-controlled, randomized study of
187 women receiving Climara® 0.025 mg/day or placebo continuously
for up to three 28-day cycles, the Climara®‚ 0.025 mg/day dosage
was shown to be statistically better than placebo at weeks 4 and 12 for relief
of both the frequency and severity of moderate-to-severe vasomotor symptoms.
|
Table 2 Mean Change from Baseline in the Number of Moderate-to-Severe
Vasomotor Symptoms (ITT)
|
|
Treatment Group
|
Statistics
|
Week 4
|
Week 8
|
Week 12
|
|
E2 TDS
|
N
|
82
|
84
|
68
|
| |
Mean
|
-6.45
|
-7.69
|
-7.56
|
| |
SD
|
4.65
|
4.76
|
4.64
|
|
Placebo
|
N
|
83
|
71
|
65
|
| |
Mean
|
-5.11
|
-5.98
|
-5.98
|
| |
SD
|
7.43
|
8.63
|
9.69
|
| |
p-Value
|
<0.002
|
|
<0.003
|
A second active-control trial of 193 randomized subjects was
supportive of the placebo-controlled trial.
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