CLINICAL PHARMACOLOGY
Estraderm
The Estraderm system releases estradiol, the major estrogenic
hormone secreted by the human ovary. Estradiol transdermal
system provides systemic estrogen replacement therapy.
Among numerous effects, estradiol is largely responsible
for the development and maintenance of the female reproductive
system and of secondary sexual characteristics. It promotes
growth and development of the vagina, uterus, fallopian
tubes, and breasts. Indirectly, estradiol contributes
to the shaping of the skeleton, to the maintenance of
tone and elasticity of urogenital structures, to changes
in the epiphyses of the long bones that allow for the
pubertal growth spurt and its termination, to the growth
of axillary and pubic hair, and to the pigmentation of
the nipples and genitals.
In the anovulatory cycle estrogen is the primary determinant
in the onset of menstruation. Estradiol also affects the
release of pituitary gonadotropins.
Loss of ovarian estradiol secretion after menopause can
result in instability of thermoregulation, causing hot
flushes associated with sleep disturbance and excessive
sweating, and urogenital atrophy, causing dyspareunia
and urinary incontinence. Estradiol replacement therapy
alleviates many of these symptoms of estradiol deficiency
in the menopausal woman.
Orally administered estradiol is rapidly metabolized
by the liver to estrone and its conjugates, giving rise
to higher circulating levels of estrone than estradiol.
In contrast, the skin metabolized estradiol only to a
small extent. Therefore, transdermal administration produces
therapeutic serum levels of estradiol with lower circulating
levels of estrone and estrone conjugates, and requires
smaller total doses than does oral therapy. Because estradiol
has a short half-life (approximately 1 hour), transdermal
administration of estradiol allows a in blood levels after
an Estraderm is removed, (e.g., in a cycling regimen).
In a study transdermally using estradiol, 0.1 mg daily,
plasma levels increased by 66 pg/ml resulting in an average
plasma level of 73 pg/ml. There were no significant increases
in the concentration of renin substrate or other hepatic
proteins (sex-hormone-binding globulin, thyroxine-binding
globulin and corticosteroid-binding globulin).
Pharmacokinetics
Administration of Estraderm produces mean serum concentrations
of estradiol comparable to those produced by daily oral
administration estradiol at about 20 times the daily transdermal
dose. In single-application studies in 14 postmenopausal
women using Estraderms that provided 0.05 and 0.1 mg of
exogenous estradiol per day, these systems produced increased
blood levels within 4 hours and maintained respective
mean serum estradiol concentrations of 32 and 67 pg/ml
above baseline over the application period. At the same
time, increases in estrone serum concentration averaged
only 9 and 27 pg/ml above baseline, respectively. Serum
concentrations of estradiol and estrone returned to preapplication
levels within 24 hours after removal of the system. The
estimated daily urinary output of estradiol conjugates
increased 5 to 10 times the baseline values and returned
to near baseline within 2 day after removal of the system.
By comparison, estradiol (2 mg per day) administered
orally to postmenopausal women resulted in increases in
mean serum concentration 59 pg/ml of estradiol and 302
pg/ml of estrone above baseline on the third consecutive
day dosing. Urinary output of estradiol conjugates after
oral administration increased to about 100 times the baseline
values and did not approach baseline until 7-8 days after
the last dose.
In a 3 week multiple-application study of 14 postmenopausal
women in which Estraderms 0.05 was applied twice weekly,
the mean increments in steady-state serum concentration
were 30 pg/ml for estradiol and 12 pg/ml for estrone.
Urinary output of estradiol conjugates returned to baseline
within 3 days after removal of the last (6th) indicating
little or no estrogen accumulation in the body.
Climara
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 in the development
and maintenance of the female reproductive system and
secondary sex 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 it metabolites,
estrone and estriol, at the receptor.
The primary source of estrogen in normally cycling adult
women is the ovarian follicle, which secretes 70 to 500
mcg 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.
Circulating estrogens modulate the pituitary secretion
of the gonadotropins. Luteinizing hormone (LH) and follicle
stimulating hormone (FSH) through 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 6 studies. In 5
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 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 transdermal route.
The bioavailability of Climara was determined in two
single dose studies after 1 week application of the Climara
system versus two consecutive 3 day and 4 day applications
of the Estraderm system. Both sizes of Climara maintained
significantly lower peak and mean steady state estradiol
levels than did the Estraderm system; however, towards
the end of each treatment period, the Climara system maintained
similar (day 6) or higher (day 7) serum estradiol levels
than did the Estraderm system. The fluctuation index with
the Climara system was 1/4 to 1/3 the fluctuation index
observed with Estraderm. However, this has not been shown
to be clinically significant.
In a third bioavailability study, the Climara 6.5 cm2
was studied with Climara 12.5 cm2 as reference. Dose proportionality
was demonstrated for the Climara 6.5 cm2 patch as compared
to the Climara 12.52 patch in a 2 week crossover study
with a one week washout period between the two patches
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
Race: There is no information to establish the relevance
of race for the absorption and pharmacokinetics of estradiol
following transdermal application.
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.
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