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 Warnings, Precautions, Pregnancy, Nursing, Abuse - Norethindrone acetate and ethinyl estradiol
Femhrt Warnings, Precautions, Pregnancy, Nursing, Abuse - Norethindrone acetate and ethinyl estradiol
WARNINGS
See BOXED WARNING.
Women’s Health Initiative Studies.
A substudy of the Women’s Health Initiative (WHI) enrolled
a total of 16,608 predominantly healthy postmenopausal women (average age of
63 years, range 50 to 79; 83.9% White, 6.5% Black, 5.5% Hispanic) to assess
the risks and benefits of the use of 0.625 mg conjugated equine estrogens (CE)
plus 2.5 mg medroxyprogesterone acetate (MPA) per day compared to placebo in
the prevention of certain chronic diseases. The primary endpoint was the incidence
of coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death),
with invasive breast cancer as the primary adverse outcome studied. A "global
index" included the earliest occurrence of CHD, invasive breast cancer,
stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip
fracture, or death due to other cause. The study did not evaluate the effects
of CE/MPA on menopausal symptoms. The CE/MPA substudy was stopped early because,
according to the predefined stopping rule, the increased risk of breast cancer
and cardiovascular events exceeded the specified benefits included in the "global
index." Results of the CE/MPA substudy, after an average follow-up of 5.2
years are presented in Table 4 below:
|
Table 4. RELATIVE AND ABSOLUTE RISK SEEN IN THE PREMPROTM
(conjugated estrogens/medroxyprogesterone) SUBSTUDY OF WHIa
|
|
Eventc
|
Relative Risk CE/MPA vs placebo at 5.2 Years (95% CI*)
|
Placebo n = 8102
|
CE/MPA N = 8506
|
|
|
Absolute Risk per 10,000 Person-years
|
|
|
CHD events
|
1.29 (1.02-1.63)
|
30
|
37
|
|
Non-fatal MI
|
1.32 (1.02-1.72)
|
23
|
30
|
|
CHD death
|
1.18 (0.70-1.97)
|
6
|
7
|
|
Invasive breast cancerb
|
1.26 (1.00-1.59)
|
30
|
38
|
|
Stroke
|
1.41 (1.07-1.85)
|
21
|
29
|
|
Pulmonary embolism
|
2.13 (1.39-3.25)
|
8
|
16
|
|
Colorectal cancer
|
0.63 (0.43-0.92)
|
16
|
10
|
|
Endometrial cancer
|
0.83 (0.47-1.47)
|
6
|
5
|
|
Hip fracture
|
0.66 (0.45-0.98)
|
15
|
10
|
|
Death due to causes other than the events above
|
0.92 (0.74-1.14)
|
40
|
37
|
|
Global Index c
|
1.15 (1.03-1.28)
|
151
|
170
|
| |
|
|
|
|
Deep vein thrombosis d
|
2.07 (1.49-2.87)
|
13
|
26
|
|
Vertebral fractures d
|
0.66 (0.44-0.98)
|
15
|
9
|
|
Other osteoporotic fractures d
|
0.77 (0.69-0.86)
|
170
|
131
|
|
a adapted from JAMA, 2002; 288:321-333
|
|
b includes metastatic and non-metastatic breast
cancer with the exception of in situ breast cancer
|
|
c a subset of the events was combined in a
"global index", defined as the earliest occurrence of CHD events,
invasive breast cancer, stroke, pulmonary embolism, endometrial cancer,
colorectal cancer, hip fracture, or death due to other causes
|
|
d not included in Global Index
|
|
* nominal confidence intervals unadjusted for multiple
looks and multiple comparisons
|
For those outcomes included in the "global index," absolute
excess risks per 10,000 person-years in the group treated with CE/MPA were 7
more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers,
while absolute risk reductions per 10,000 person-years were 6 fewer colorectal
cancers and 5 fewer hip fractures. The absolute excess risk of events included
in the "global index" was 19 per 10,000 person-years. There was no
difference between the groups in terms of all-cause mortality (See BOXED
WARNING).
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, estrogen/progestin therapy 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 WHI, an increased risk of 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.
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-0.625mg/2.5mg 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 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.
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.
Five epidemiologic studies have found an increased risk of
VTE in users of estrogen therapy (ET) who did not have predisposing conditions
for VTE, such as a past history of cardiovascular disease or a recent history
of pregnancy, surgery, trauma, or serious illness. The increased risk was found
only in current ET users; it did not persist in former users. The risk appeared
to be higher in the first year of use and decreased thereafter. The findings
were similar for ET alone or with added progestin and pertain to commonly used
oral and transdermal doses, with a possible dose-dependent effect on risk. The
studies found the VTE risk to be about one case per 10,000 women per year among
women not using ET and without predisposing conditions. The risk in current
ET users was increased to 2-3 cases per 10,000 women per year.
If feasible, estrogens should be discontinued at least 4-6
weeks before surgery of the type associated with an increased risk of thromboembolism,
or during periods of prolonged immobilization.
2. Induction of 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
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 estrogens and/or estrogen with progestins had a higher relative risk for
breast cancer associated with CE/MPA than those who had never used these hormones.
Epidemiologic studies have reported an increased risk of breast
cancer in association with increasing duration of postmenopausal treatment with
estrogens with or without 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 healthcare provider and perform monthly self-examinations. In addition, mammography
examinations should be scheduled 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 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 1 year. The
greatest risk appears associated with prolonged use, with increased risks of
15- to 24-fold for use of 5 to 10 years or more, and this risk has been shown
to persist for at least 15 years after cessation of estrogen treatment. Results
from a 2-year clinical study of the effects of femhrt 1/5 on endometrial
hyperplasia are shown in the Clinical Studies section of this label.
Clinical surveillance of all women taking progestin/estrogen 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
"natural" estrogens are more or less hazardous than "synthetic"
estrogens at equivalent doses.
3. Gallbladder Disease
A 2- to 4-fold increase in the risk of gallbladder disease
requiring surgery in women receiving postmenopausal estrogen has been
reported.
4. Hypercalcemia
Administration of estrogens may lead to severe hypercalcemia
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. Visual Disturbances
Medication should be discontinued pending examination if there
is a sudden partial or complete loss of vision, or if there is a sudden onset
of proptosis, diplopia or migraine. If examination reveals papilledema or retinal
vascular lesions, medication should be withdrawn.
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 treatment.
These include: a. A possible increased risk of breast cancer b. Adverse effects
on lipoprotein metabolism (e.g., lowering HDL, raising LDL) c. Impairment of
glucose tolerance
2. Elevated Blood Pressure
Occasional blood pressure increases during estrogen 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 nonusers. Two other studies showed
slightly lower blood pressure among estrogen users compared to nonusers. Blood
pressure should be monitored at regular intervals with estrogen use.
3. Use in Hysterectomized Women
Existing data do not support the use of the combination of
progestin and estrogen in postmenopausal women without a uterus.
4. Physical Examination
A complete medical and family history should be taken prior
to the initiation of femhrt 1/5 and annually thereafter. These examinations
should include special reference to blood pressure, breasts, abdomen, and pelvic
organs, and should include a Papanicolaou smear.
5. Fluid Retention
Progestin/estrogen therapy may cause some degree of fluid retention.
Conditions which might be exacerbated by this factor, such as asthma, epilepsy,
migraine, and cardiac or renal dysfunction, require careful observation.
6. Hypocalcemia
Estrogens should be used with caution in individuals with severe
hypocalcemia
7. 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 combined
estrogen/progestin therapy in postmenopausal women.
8. Exacerbation of endometriosis
Endometriosis may be exacerbated with administration of estrogens.
9. Uterine Bleeding and Mastodynia
Certain patients may develop undesirable manifestations of
estrogenic stimulation, such as abnormal uterine bleeding and mastodynia. In
cases of undiagnosed abnormal uterine bleeding, adequate diagnostic measures
are indicated (see WARNINGS).
10. Impaired Liver Function
Estrogens and progestins 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.
11. Pathology Specimens
The pathologist should be advised of progestin/estrogen therapy
when relevant specimens are submitted.
12. 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.
13. Hypercoagulability
Some studies have shown that women taking estrogen therapy
have hypercoagulability, primarily related to decreased antithrombin 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 coagulation parameters at baseline compared to premenopausal
women. There is some suggestion that low dose postmenopausal mestranol may increase
the risk of thromboembolism, although the majority of studies (of primarily
conjugated estrogen users) report no such increase. There is insufficient information
on hypercoagulability in women who have had previous thromboembolic disease,
therefore, femhrt 1/5 is contraindicated in such women.
14. Familial Hyperlipoproteinemia
Estrogen therapy may be associated with massive elevations
of plasma triglycerides leading to pancreatitis and other complications in patients
with familial defects of lipoprotein metabolism.
15.Depression
Patients who have a history of depression should be carefully
observed and the drug discontinued if the depression recurs to a serious degree.
16. Impaired Glucose Tolerance
Diabetic patients should be carefully observed while receiving
progestin/estrogen therapy. The effects of femhrt 1/5 on glucose tolerance
have not been studied.
B. INFORMATION FOR PATIENT
Physicians are advised to discuss the contents of the Patient
Information leaflet with patients for whom they prescribe femhrt 1/5. See text
of Patient Information which appears after
the HOW SUPPLIED section.
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).
F. Pregnancy
Estrogens/progestins should not be used during pregnancy (see
CONTRAINDICATIONS).
G. Nursing Mothers
As a general principle, the administration of any drug to nursing
mothers should be done only when clearly necessary since many drugs are excreted
in human milk. Estrogen administration to nursing mothers has been shown to
decrease the quantity and quality of the milk. Detectable amounts of drug have
been identified in the milk of mothers receiving progestational drugs. The effect
of this on the nursing infant has not been determined. Caution should be exercised
when femhrt 1/5 is administered to nursing mothers.
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