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
Femhrt Pharmacology, Pharmacokinetics, Studies, Metabolism - Norethindrone acetate and ethinyl estradiol
Femhrt Pharmacology, Pharmacokinetics, Studies, Metabolism - Norethindrone acetate and ethinyl estradiol
CLINICAL PHARMACOLOGY
Estrogens are largely responsible for 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 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 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 sulphate conjugated form, estrone sulphate, are the most abundant circulating
estrogens in postmenopausal women. The pharmacologic effects of ethinyl estradiol
are similar to those of endogenous estrogens.
Circulating estrogens modulate the pituitary secretion of the
gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH)
through a negative feedback mechanism. Estrogens act to reduce the elevated
levels of these hormones seen in postmenopausal women.
Progestin compounds enhance cellular differentiation and generally
oppose the actions of estrogens by decreasing estrogen receptor levels, increasing
local metabolism of estrogens to less active metabolites, or inducing gene products
that blunt cellular responses to estrogen. Progestins exert their effects in
target cells by binding to specific progesterone receptors that interact with
progesterone response elements in target genes. Progesterone receptors have
been identified in the female reproductive tract, breast, pituitary, hypothalamus,
bone, skeletal tissue and central nervous system. Progestins produce similar
endometrial changes to those of the naturally occurring hormone progesterone.
The use of unopposed estrogen therapy has been associated with
an increased risk of endometrial hyperplasia, a possible precursor of endometrial
adenocarcinoma. The addition of continuous administration of progestin to an
estrogen regimen reduced the incidence of endometrial hyperplasia, and the attendant
risk of carcinoma in women with intact uteri.
Pharmacokinetics
Absorption and Bioavailability
Norethindrone acetate (NA) is completely and rapidly deacetylated
to norethindrone after oral administration, and the disposition of norethindrone
acetate is indistinguishable from that of orally administered norethindrone.
Norethindrone acetate and ethinyl estradiol (EE) are rapidly absorbed from femhrt
1/5 tablets, with maximum plasma concentrations of norethindrone and ethinyl
estradiol generally occurring 1 to 2 hours postdose. Both are subject to first-pass
metabolism after oral dosing, resulting in an absolute bioavailability of approximately
64% for norethindrone and 55% for ethinyl estradiol. Bioavailability of femhrt
1/5 tablets is similar to that from solution for norethindrone and slightly
less for ethinyl estradiol. Administration of norethindrone acetate/ethinyl
estradiol (NA/EE) tablets with a high fat meal decreases rate but not extent
of ethinyl estradiol absorption. The extent of norethindrone absorption is increased
by 27% following administration of NA/EE tablets with food.
The full pharmacokinetic profile of femhrt 1/5 (1 mg
norethindrone acetate/5 mcg ethinyl estradiol) was not characterized
due to assay sensitivity limitations. However, the multiple-dose pharmacokinetics
were studied at a dose of 1 mg NA/10 mcg EE in 18 post-menopausal
women. Mean plasma concentrations are shown below and pharmacokinetic parameters
are found in Table 1. Based on a population pharmacokinetic analysis, mean steady-state
concentrations of norethindrone for 1 mg NA/5 mcg EE and 1/10
are slightly more than proportional to dose when compared to 0.5 mg NA/2.5
mcg EE tablets. It can be explained by higher sex hormone binding globulin
(SHBG) concentrations. Mean steady-state plasma concentrations of ethinyl estradiol
for the 0.5 mg NA/2.5 mcg EE tablets and femhrt 1/5 tablets
are proportional to dose, but there is a less than proportional increase in
steady-state concentrations for the NA/EE 1/10 tablet.
|
Table 1. Mean (SD) Single-Dose (Day 1) and Steady-State
(Day 87) Pharmacokinetic Parametersa Following Administration
of 1 mg NA/10 mcg EE Tablets
|
| |
Cmax
|
Tmax
|
AUC(0-24)
|
CL/F
|
t½
|
|
Norethindrone
|
ng/mL
|
hr
|
ng·hr/mL
|
mL/min
|
hr
|
|
Day 1
|
6.0 (3.3)
|
1.8 (0.8)
|
29.7 (16.5)
|
588 (416)
|
10.3 (3.7)
|
|
Day 87
|
10.7 (3.6)
|
1.8 (0.8)
|
81.8 (36.7)
|
226 (139)
|
13.3 (4.5)
|
|
Ethinyl Estradiol
|
pg/mL
|
hr
|
pg·hr/mL
|
mL/min
|
hr
|
|
Day 1
|
33.5
|
2.2 (1.0)
|
339 (113)
|
NDb
|
NDb
|
| |
(13.7)
|
|
|
|
|
|
Day 87
|
38.3
|
1.8 (0.7)
|
471 (132)
|
383 (119)
|
23.9 (7.1)
|
| |
(11.9)
|
|
|
|
|
|
a Cmax = Maximum plasma concentration; tmax
= time of Cmax; AUC(0-24) = Area under the plasma
concentration-time curve over the dosing interval; and CL/F = Apparent
oral clearance; t½ = Elimination half-life
|
|
bND=Not determined
|
Based on a population pharmacokinetic analysis, average steady-state
concentrations (Css) of norethindrone and ethinyl estradiol for femhrt
1/5 (1 mg NA/5 mcg EE) tablets are estimated to be 2.6 ng/mL and
11.4 pg/mL, respectively.
The pharmacokinetics of ethinyl estradiol and norethindrone
acetate were not affected by age, (age range 40-62 years), in the postmenopausal
population studied.
Distribution
Volume of distribution of norethindrone and ethinyl estradiol
ranges from 2 to 4 L/kg. Plasma protein binding of both steroids is extensive
(>95%); norethindrone binds to both albumin and sex hormone binding globulin
(SHBG), whereas ethinyl estradiol binds only to albumin. Although ethinyl estradiol
does not bind to SHBG, it induces SHBG synthesis.
Metabolism
Norethindrone undergoes extensive biotransformation, primarily
via reduction, followed by sulfate and glucuronide conjugation. The majority
of metabolites in the circulation are sulfates, with glucuronides accounting
for most of the urinary metabolites. A small amount of norethindrone acetate
is metabolically converted to ethinyl estradiol, such that exposure to ethinyl
estradiol following administration of 1 mg of norethindrone acetate is
equivalent to oral administration of 2.8 mcg ethinyl estradiol. Ethinyl
estradiol is also extensively metabolized, both by oxidation and by conjugation
with sulfate and glucuronide. Sulfates are the major circulating conjugates
of ethinyl estradiol and glucuronides predominate in urine. The primary oxidative
metabolite is 2-hydroxy ethinyl estradiol, formed by the CYP3A4 isoform of cytochrome
P450. Part of the first-pass metabolism of ethinyl estradiol is believed to
occur in gastrointestinal mucosa. Ethinyl estradiol may undergo enterohepatic
circulation.
Excretion
Norethindrone and ethinyl estradiol are excreted in both urine
and feces, primarily as metabolites. Plasma clearance values for norethindrone
and ethinyl estradiol are similar (approximately 0.4 L/hr/kg). Steady-state
elimination half-lives of norethindrone and ethinyl estradiol following administration
of 1 mg NA/10 mcg EE tablets are approximately 13 hours and 24
hours, respectively.
Special Populations
Pediatric
femhrt 1/5 is not indicated in children.
Geriatrics
The pharmacokinetics of femhrt 1/5 have not been studied
in a geriatric population.
Race
The effect of race on the pharmacokinetics of femhrt
1/5 has not been studied.
Patients with Renal Insufficiency
The effect of renal disease on the disposition of femhrt
1/5 has not been evaluated. In premenopausal women with chronic renal failure
undergoing peritoneal dialysis who received multiple doses of an oral contraceptive
containing ethinyl estradiol and norethindrone, plasma ethinyl estradiol concentrations
were higher and norethindrone concentrations were unchanged compared to concentrations
in premenopausal women with normal renal function (see PRECAUTIONS,
Fluid Retention).
Patients with Hepatic Impairment
The effect of hepatic disease on the disposition of femhrt
1/5 has not been evaluated. However, ethinyl estradiol and norethindrone may
be poorly metabolized in patients with impaired liver function (see PRECAUTIONS).
DRUG INTERACTIONS
See PRECAUTIONS, Drug
Interactions.
Clinical Studies
Effects on Vasomotor Symptoms
A 12-week placebo-controlled, multicenter, randomized clinical
trial was conducted in 266 symptomatic women who had at least 56 moderate to
severe hot flashes during the week prior to randomization. On average, patients
had 12 hot flashes per day upon study entry.
A total of 65 women were randomized to receive femhrt
1/5 and 66 women were randomized to the placebo group.
Endometrial Hyperplasia
A 2-year, placebo-controlled, multicenter, randomized clinical
trial was conducted to determine the safety and efficacy of femhrt 1/5
on maintaining bone mineral density, protecting the endometrium, and to determine
effects on lipids. A total of 1265 women were enrolled and randomized to either
placebo, 0.2 mg NA/1 mcg EE, 0.5 mg NA/2.5 mcg EE,
femhrt 1/5 and 1 mg NA/10 mcg EE or matching unopposed
EE doses (1, 2.5, 5, or 10 mcg) for a total of 9 treatment groups. All
participants received 1000 mg of calcium supplementation daily. Of the 1265
women randomized to the various treatment arms of this study, 137 were randomized
to placebo, 146 to femhrt 1/5, and 141 to EE 5 mcg. Of these,
134 placebo, 143 femhrt 1/5, and 139 EE 5 mcg had a baseline endometrial
result. Baseline biopsies were classified as normal (in approximately 95% of
subjects), or insufficient tissue (in approximately 5% of subjects). Follow-up
biopsies were obtained in approximately 70-80% of patients in each arm after
12 and 24 months of therapy. Results are shown in Table 2.
|
Table 2. Endometrial Biopsy Results After 12 and 24 Months
of Treatment
|
| |
Placebo
|
femhrt 1/5
|
5 mcg
|
|
Number of Patients
|
|
|
ethinyl
|
|
Biopsied at Baseline
|
N= 134
|
N= 143
|
estradiol
|
| |
|
|
N=139
|
|
MONTH 12
|
|
|
|
|
Patients Biopsied (%)
|
113 (84)
|
110 (77)
|
114 (82)
|
|
Insufficient Tissue
|
30
|
45
|
20
|
|
Atrophic Tissue
|
60
|
41
|
2
|
|
Proliferative Tissue
|
23
|
24
|
91
|
|
Endometrial
|
0
|
0
|
1
|
|
Hyperplasiaa
|
|
|
|
|
MONTH 24
|
|
|
|
|
Patients Biopsied (%)
|
94 (70)
|
102 (71)
|
107 (77)
|
|
Insufficient Tissue
|
35
|
37
|
17
|
|
Atrophic Tissue
|
38
|
33
|
2
|
|
Proliferative Tissue
|
20
|
32
|
86
|
|
Endometrial
|
1
|
0
|
2
|
|
Hyperplasiaa
|
|
aAll patients with endometrial hyperplasia were carried forward
for all time points
|
Irregular Bleeding/Spotting
The cumulative incidence of amenorrhea, defined as no bleeding
or spotting, was evaluated over 12 months for femhrt 1/5 and placebo
arms.
Effect on Bone Mineral Density
In the 2 year study, trabecular bone mineral density (BMD)
was assessed at lumbar spine using quantitative computed tomography. A total
of 283 postmenopausal women with intact uteri and normal baseline bone mineral
density (124.14 mg/cc ± 9.60 mg/cc) were randomized to femhrt
1/5 (1 mg norethindrone acetate/5 mcg ethinyl estradiol) or placebo,
and 87% contributed data to the Intent-To-Treat analysis. All patients received
1000 mg calcium in divided doses. Vitamin D was not supplemented. femhrt
1/5 resulted in significant increases in BMD at each assessment. There was a
significant decrease in BMD in the placebo group.
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