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
CombiPatch Warnings, Precautions, Pregnancy, Nursing, Abuse - Estradiol/norethindrone Acetate
CombiPatch Warnings, Precautions, Pregnancy, Nursing, Abuse - Estradiol/norethindrone Acetate
WARNINGS
See BOXED WARNINGS.
1. Cardiovascular disorders
Estrogen/progestin therapy has been associated with an increased
risk of cardiovascular events such as myocardial infarction and stroke, as well
as venous thrombosis and pulmonary embolism (venous thromboembolism or VTE).
Should any of these occur or be suspected, estrogens/progestins should be discontinued
immediately.
Risk factors for cardiovascular disease (e.g. hypertension,
diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) should be
managed appropriately.
a. Coronary heart disease and stroke
In the CE/MPA substudy of the Women’s Health Initiative study
(WHI), an increased risk of coronary heart disease (CHD) events (defined as
non-fatal myocardial infarction and CHD death) was observed in women receiving
CE/MPA compared to women receiving placebo (37 vs 30 per 10,000 person years).
The increase in risk was observed in year one and persisted (See CLINICAL
PHARMACOLOGY, Clinical Studies).
In the same substudy of WHI, an increased risk of stroke was
observed in women receiving CE/MPA compared to women receiving placebo (29 vs
21 per 10,000 person-years). The increase in risk was observed after the first
year and persisted.
In postmenopausal women with documented heart disease (n =
2,763, average age 66.7 years) a controlled clinical trial of secondary prevention
of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study; HERS)
treatment with CE/MPA-0.625 mg/ 2.5 mg per day demonstrated no cardiovascular
benefit. During an average follow-up of 4.1 years, treatment with CE/MPA did
not reduce the overall rate of CHD events in postmenopausal women with established
coronary heart disease. There were more CHD events in the CE/MPA-treated group
than in the placebo group in year 1, but not during the subsequent years. Two
thousand three hundred and twenty one women from the original HERS trial agreed
to participate in an open label extension of HERS, HERS II. Average follow-up
in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates
of CHD events were comparable among women in the CE/MPA group and in the placebo
group in HERS, HERS II, and overall.
Large doses of estrogen (5 mg conjugated estrogens 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 risks 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 associated with high estrogen
doses, the dose for estrogen replacement therapy should not exceed the lowest
effective dose.
b. Venous thromboembolism (VTE)
In the CE/MPA substudy of WHI, a 2-fold greater rate of VTE,
including deep venous thrombosis and pulmonary embolism, was observed in women
receiving CE/MPA compared to women receiving placebo. The rate of VTE was 34
per 10,000 woman-years in the CE/MPA group compared to 16 per 10,000 woman-years
in the placebo group. The increase in VTE risk was observed during the first
year and persisted. (See CLINICAL PHARMACOLOGY,
Clinical Studies.)
If feasible, estrogens should be discontinued at least 4 to
6 weeks before surgery of the type associated with an increased risk of thromboembolism,
or during periods of prolonged immobilization.
2. Malignant Neoplasms
a. Breast cancer
Estrogen/progestin therapy in postmenopausal women has been
associated with an increased risk of breast cancer. In the CE/MPA substudy of
the Women’s Health Initiative study (WHI), a 26% increase of invasive breast
cancer (38 vs 30 per 10,000 woman-years) after an average of 5.2 years of treatment
was observed in women receiving CE/MPA compared to women receiving placebo.
The increased risk of breast cancer became apparent after 4 years on CE/MPA.
The women reporting prior postmenopausal use of estrogen and/or estrogen with
progestin had a higher relative risk for breast cancer associated with CE/MPA
than those who had never used these hormones. (See CLINICAL
PHARMACOLOGY, Clinical Studies.)
Epidemiologic studies have reported an increased risk of breast
cancer in association with increasing duration of postmenopausal treatment with
estrogens with or without a progestin. This association was reanalyzed in original
data from 51 studies that involved various doses and types of estrogens, with
and without progestins. In the reanalysis, an increased risk of having breast
cancer diagnosed became apparent after about 5 years of continued treatment,
and subsided after treatment had been discontinued for 5 years or longer. Some
later studies have suggested that postmenopausal treatment with estrogens and
progestin increase the risk of breast cancer more than treatment with estrogen
alone. A postmenopausal woman without a uterus who requires estrogen should
receive estrogen-alone therapy, and should not be exposed unnecessarily to progestins.
All postmenopausal women should receive yearly breast exams by a health care
provider and perform monthly breast self-examinations. In addition, mammography
examinations should be scheduled as suggested by providers based on patient
age and risk factors.
b. Endometrial Cancer
The reported endometrial cancer risk among users of unopposed
estrogen is about 2- to 12-fold or greater than in nonusers, and appears dependent
on duration of treatment and on estrogen dose. Most studies show 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 for five to ten years or more and this risk has been
shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.
Clinical surveillance of all women taking estrogen/progestin
combinations is important. Adequate diagnostic measures, including endometrial
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 the use of natural estrogens results in a different endometrial
risk profile than synthetic estrogens of equivalent estrogen dose.
3. Gallbladder Disease
A 2- to 4-fold increase in the risk of gallbladder disease
requiring surgery in postmenopausal women receiving estrogens has been reported.
4. Hypercalcemia
Administration of estrogen may lead to severe hypercalcemia
in patients with breast cancer and bone metastases. If this occurs, use of the
drug should be stopped and appropriate measures taken to reduce the serum calcium
level.
4. Visual abnormalities
Retinal vascular thrombosis has been reported in patients receiving
estrogens. Discontinue medication pending examination if there is sudden partial
or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine.
If examination reveals papilledema or retinal vascular lesions, estrogens should
be discontinued.
PRECAUTIONS
A. General
1. Addition of a progestin when a woman has not
had a hysterectomy. Studies of the addition of a progestin for 10 or
more days of a cycle of estrogen administration, or daily with estrogen in a
continuous regimen, have reported a lowered incidence of endometrial hyperplasia
than would be induced by estrogen treatment alone. Endometrial hyperplasia may
be a precursor to endometrial cancer. There are, however, possible risks that
may be associated with the use of progestins with estrogens compared to estrogen-alone
regimens. These include a possible increased risk of breast cancer.
2. Elevated blood pressure. In a small
number of case reports, substantial increases in blood pressure have been attributed
to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled
clinical trial, a generalized effect of estrogen therapy on blood pressure was
not seen. Blood pressure should be monitored at regular intervals with estrogen
use.
3. Familial hyperlipoproteinemia. In patients
with familial defects of lipoprotein metabolism, estrogen therapy may be associated
with elevations of plasma triglycerides leading to pancreatitis and other complications.
4. Impaired liver function. Although transdermally
administered estrogen therapy avoids first-pass hepatic metabolism, estrogens
may be poorly metabolized in patients with impaired liver function. For patients
with a history of cholestatic jaundice associated with past estrogen use or
with pregnancy, caution should be exercised and in the case of recurrence, medication
should be discontinued.
5. Hypothyroidism. Estrogen administration
leads to increased thyroid-binding globulin (TBG) levels. Patients with normal
thyroid function can compensate for the increased TBG by making more thyroid
hormone, thus maintaining free T4 and T3 serum concentrations
in the normal range. Patients dependent on thyroid hormone replacement therapy
who are also receiving estrogens may require increased doses of their thyroid
replacement therapy. These patients should have their thyroid function monitored
in order to maintain their free thyroid hormone levels in an acceptable range.
6. Fluid retention. Because estrogens
and progestins may cause some degree of fluid retention, conditions which might
be influenced by this factor, such as asthma, epilepsy, migraine, and cardiac
or renal dysfunction, warrant careful observation when estrogens are prescribed.
7. Hypocalcemia. Estrogens should be used
with caution in individuals with severe hypocalcemia.
8. Ovarian cancer. Use of estrogen-only
products, in particular for ten or more years, has been associated with an increased
risk of ovarian cancer in some epidemiological studies. Other studies did not
show a significant association. Data are insufficient to determine whether there
is an increased risk with estrogen/progestin combination therapy in postmenopausal
women.
9. Exacerbation of endometriosis. Endometriosis
may be exacerbated with administration of estrogen therapy.
10. Exacerbation of other conditions. Estrogens
may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine or
porphyria and should be used with caution in women with these conditions.
B. Patient Information.
Physicians are advised to discuss the Patient
Information leaflet with patients for whom they prescribe CombiPatch.
C. Laboratory Tests.
Estrogen administration should be initiated at the lowest dose
for the approved indication and then guided by clinical response, rather than
by serum hormone levels (e.g., estradiol, FSH).
E. Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term continuous administration of natural and synthetic
estrogens in certain animal species increases the frequency of carcinomas of
the breast, uterus, cervix, vagina, testis, and liver. (See BOXED
WARNING, CONTRAINDICATIONS and WARNINGS.)
Norethindrone acetate was not mutagenic in a battery of in
vitro or in vivo genetic toxicity assays.
F. Pregnancy
Estrogens and progestins should not be used during pregnancy.
(See CONTRAINDICATIONS.)
G. Nursing Mothers
Estrogen administration to nursing mothers has been shown to
decrease the quantity and quality of the milk. Detectable amounts of estrogens
and progestins have been identified in the milk of mothers receiving this drug.
Caution should be exercised when CombiPatch is administered to a nursing mother.
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