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
Activella Warnings, Precautions, Pregnancy, Nursing, Abuse - Estradiol/Norethindroneacetate
Activella Warnings, Precautions, Pregnancy, Nursing, Abuse - Estradiol/Norethindroneacetate
WARNINGS
ALL
WARNINGS
BELOW PERTAIN TO THE USE OF THIS COMBINATION PRODUCT.
Based on experience with estrogens and/or progestins:
1. Induction of malignant neoplasms
Endometrial cancer. The reported en-dometrial cancer risk among
unopposed estrogen users is about 2- to 12-fold greater than in non-users, and
appears dependent on duration of treatment and on estrogen dose. There is no
significant increased risk associated with the use of estrogens for less than
one year. The greatest risk appears to be associated with prolonged use with
increased risks of 15- to 24-fold with five or more years of use. In three studies,
persistence of risk was demonstrated for 8 to over 15 years after cessation
of estrogen treament. In one study, a significant decrease in the incidence
of endometrial cancer occurred six months after withdrawal. Progestins taken
with estrogens have been shown to significantly reduce, but not eliminate, the
risk of endometrial cancer associated with estrogen use. In a large clinical
trial, the incidence of endometrial hyperplasia with Activella™ was
0.4% (one simple hy-perplasia without atypia) compared to 14.6% with 1 mg estradiol
unopposed (see CLINICAL STUDIES). Clinical
surveillance of all women taking estrogen/progestin combinations is important.
Adequate diagnostic measures, including endome-trial sampling when indicated,
should be undertaken to rule out malignancy in all cases of undiagnosed persistent
or recurring abnormal vaginal bleeding. There is no evidence that "natural"
estrogens are more or less hazardous than "synthetic" estrogens at equivalent
estrogen doses. Breast cancer. While the majority of studies have not shown
an increased risk of breast cancer in women who have ever used estrogen replacement
therapy, some have reported a moderately increased risk (relative risks of 1.3-2.0)
in those taking higher doses, or in those taking lower doses for prolonged periods
of time, especially in excess of 10 years.
While the effects of added pro-gestins on the risk of breast
cancer are also unknown, available epidemi-ological evidence suggest that progestins
do not reduce, and may enhance, the moderately increased breast cancer risk
that has been reported with prolonged estrogen replacement therapy.
In a one-year trial among 1,176 women who received either unopposed
1 mg estradiol or a combination of 1 mg estradiol plus one of three different
doses of NETA (0.1, 0.25 and 0.5 mg), seven new cases of breast cancer were
diagnosed, two of which occurred among the group of 295 Activella™
(estradiol/norethindrone acetate tablets) treated women.
Women on hormone replacement therapy should have regular breast
examinations and should be instructed in breast self-examination, and women
over the age of 40 should have regular mammograms.
2. Congenital lesions with malignant potential. Estrogen
therapy during pregnancy is associated with an increased risk of fetal congenital
reproductive tract disorders, and possible other birth defects. Studies of women
who received di-ethylstilbestrol (DES) during pregnancy have shown that female
offspring have an increased risk of vaginal adenosis, squamous cell dysplasia
of the uterine cervix, and clear cell vaginal cancer later in life; male offspring
have an increased risk of urogenital abnormalities and possibly testicular cancer
later in life.
Although some of these changes are benign, others are precursors
of malignancy.
3. Cardiovascular disease. Large doses of estrogens
(5 mg conjugated estrogen per day), comparable to those used to treat cancer
of the prostate and breast, have been shown in a large prospective clinical
trial in men to increase the risk of nonfatal myocardial infarction, pulmonary
embolism, and thrombophlebitis.
These risks cannot necessarily be extrapolated from men to
women or from unopposed estrogen to combination estrogen/progestin therapy.
However, to avoid the theoretical cardiovascular risk to women caused by high
estrogen doses, the dose for estrogen replacement therapy should not exceed
the lowest effective dose.
4. Hypercalcemia. Administration of estrogens may lead
to severe hyper-calcemia in patients with breast cancer and bone metastases.
If this occurs, the drugs should be stopped and appropriate measures taken to
reduce the serum calcium level.
5. Effects during pregnancy. Use in pregnancy is not
recommended.
6. Gallbladder disease. Two studies have reported a
2- to 4-fold increase in the risk of surgically confirmed gallbladder disease
in women receiving postmenopausal estrogens. Among the 1,516 women treated in
clinical trials with 1 mg estradiol alone or in combination with several doses
of NETA, 3 women had surgically confirmed cholelithiasis, none of them on Activella™
(estradiol/norethindrone acetate tablets) treatment.
7. Elevated blood pressure.
Occasional blood pressure increases during estrogen replacement
therapy have been attributed to idiosyncratic reactions to estrogens. More often,
blood pressure has remained the same or has dropped. One study showed that postmenopausal
estrogen users have higher blood pressure than non-users. Two other studies
showed slightly lower blood pressure among estrogen users compared to non-users.
Postmenopausal estrogen use does not increase the risk of stroke. Nonetheless,
blood pressure should be monitored at regular intervals with estrogen use.
8. Thromboembolic disorders. The physician should be
alert to the earliest manifestations of thrombotic disorders (thrombophlebitis,
cerebrovas-cular disorders, pulmonary embolism, and retinal thrombosis). Should
any of these occur or be suspected, the drugs should be discontinued immediately.
In a one-year study where 295 women were exposed to Activella™,
there were two cases of deep vein thromboses reported.
9. Visual abnormalities. Discontinue medication pending
examination if there is a sudden partial or complete loss of vision, or a sudden
onset of proptosis, diplopia, or migraine. If examinations reveal papilledema
or retinal vascular lesions, medication should be withdrawn.
PRECAUTIONS
GENERAL
Based on experience with estrogens and/or progestins:
1. Cardiovascular risk. A causal relationship between
estrogen replacement therapy and reduction of cardiovascular disease in postmenopausal
women has not been proven. Furthermore, the effect of added progestins on this
putative benefit is not yet known.
In recent years, many published studies have suggested that
there may be a cause-effect relationship between postmenopausal oral estrogen
replacement therapy without added progestins and a decrease in cardiovascular
disease in women. Although most of the observational studies that assessed this
statistical association have reported a 20% to 50% reduction in coronary heart
disease risk and associated mortality in estrogen takers, the following should
be considered when interpreting these reports. Because only one of these studies
was randomized and it was too small to yield statistically significant results,
all relevant studies were subject to selection bias. Thus, the apparently reduced
risk of coronary artery disease cannot be attributed with certainty to estrogen
replacement therapy. It may instead have been caused by life-style and medical
characteristics of the women studied with the result that healthier women were
selected for estrogen therapy. In general, treated women were of higher socioeconomic
and educational status, more slender, more physically active, more likely to
have undergone surgical menopause, and less likely to have diabetes than the
untreated women. Although some studies attempted to control for these selection
factors, it is common for properly designed randomized trials to fail to confirm
benefits suggested by less rigorous study designs. Thus, ongoing and future
large-scale randomized trials may fail to confirm this apparent benefit.
Current medical practice often includes the use of concomitant
pro-gestin therapy in women with intact uterus. While the effects of added progestins
on the risk of ischemic heart disease are not known, all available progestins
attenuate at least some of the favorable effects of estrogens on HDL levels,
although they maintain the favorable effect of estrogens on LDL levels.
The safety data regarding Activella™ (estradiol/norethindrone
acetate tablets) were obtained primarily from clinical trials and epidemiologic
studies of postmenopausal Caucasian women, who were at generally low risk of
cardiovascular disease and higher than average risk for osteoporosis. The safety
profile of Activella™ derived from these study populations
cannot necessarily be extrapolated to other populations of diverse racial and/or
demographic composition. When considering prescribing Activella™,
physicians are advised to weigh the potential benefits and risks of therapy
as applicable to each individual patient.
2. Use in hysterectomized women. Existing data do not
support the use of the combination of estrogen and progestin in postmenopausal
women without a uterus. Risks that may be associated with the inclusion of progestin
in estrogen replacement regimens include deterioration in glucose tolerance,
and less favorable effects on lipid metabolism compared to the effects of estrogen
alone.
The effects of Activella™ on glucose tolerance
and lipid metabolism have been studied (see CLINICAL
PHARMACOLOGY, Clinical Studies,
and PRECAUTIONS
,
Drug/Laboratory Test Interactions).
3. Physical examination. A complete medical and family
history should be taken prior to the initiation of any estrogen/progestin therapy.
The pretreatment and periodic physical examinations should include special reference
to blood pressure, breasts, abdomen, and pelvic organs, and should include a
Papanicolaou smear. As a general rule, estrogen should not be prescribed for
longer than one year without another physical examination being performed.
4. Fluid retention. Because estrogens/ progestins may
cause some degree of fluid retention, conditions that might be influenced by
this factor, such as asthma, epilepsy, migraine, and cardiac or renal dysfunction,
require careful observation.
5. Uterine bleeding. Certain patients may develop abnormal
uterine bleeding. In cases of undiagnosed abnormal uterine bleeding, adequate
diagnostic measures are indicated (see WARNINGS
).
6. The pathologist should be advised of estrogen/progestin
therapy when relevant specimens are submitted. Based on experience with estrogens:
1. Familial hyperlipoproteinemia.
Estrogen therapy may be associated with massive elevations
of plasma triglycerides leading to pancreatitis and other complications in patients
with familial defects in lipoprotein metabolism.
2. Hypercoagulability.
Some studies have shown that women taking estrogen replacement
therapy have hypercoagulability primarily related to decreased an-tithrombin
activity. This effect appears dose- and duration-dependent and is less pronounced
than that associated with oral contraceptive use. Also, postmenopausal women
tend to have changes in levels of coagulation parameters at baseline compared
to premenopausal women. Epidemiological studies have suggested that estrogen
use is associated with a higher relative risk of developing venous thromboembolism,
i.e., deep vein thrombosis or pulmonary embolism. The studies found a 2- 3-
fold higher risk for estrogen users compared to non-users. There is insufficient
information on hyper-coagulability in women who have had previous thromboembolic
disease. The effects of Activella™ (estradiol/norethindrone
acetate tablets) (n=40) compared to placebo (n=40) on selected clotting factors
were evaluated in a 12-month study with postmenopausal women. Activella™
decreased factor VII, plas-minogen activator inhibitor-1, and, to a lesser
extent, antithrombin III activity, compared to placebo. Fibrinogen remained
unchanged during Activella™ treatment in comparison with an
increase over time in the placebo group.
3. Mastodynia. Certain patients may develop undesirable
manifestations of estrogenic stimulation such as mastodynia. In clinical trials,
less than one-fifth of the women treated with Activella™ reported
breast tenderness or breast pain. The majority of the cases were reported as
breast tenderness, primarily during the initial months of the treatment. Based
on experience with progestins:
1. Lipoprotein metabolism.
(see CLINICAL STUDIES)
2. Impaired glucose tolerance.
Diabetic patients should be carefully observed while receiving
estrogen/progestin therapy.The effects of Activella™ on glucose
tolerance have been studied (see PRECAUTIONS
,
Drug/Laboratory Test Interactions).
3. Depression. Patients who have a history of depression
should be observed and the drugs discontinued if the depression recurs to a
serious degree.
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