Guidance for Industry
Noncontraceptive Estrogen Drug Products for the Treatment of
Vasomotor Symptoms and Vulvar and Vaginal Atrophy Symptoms -
Recommended Prescribing Information for Health Care Providers and
Patient Labeling
(PDF
version of this document)
DRAFT
GUIDANCE
Comments and suggestions regarding
this draft document should be submitted within 60 days of
publication in the Federal Register of the notice announcing
the availability of the draft guidance. Submit comments to the
Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
All comments should be identified with the docket number listed in
the notice of availability that publishes in the Federal Register.
If you have questions on the content
of the draft document contact Margaret Kober at (301) 796-0934.
U.S. Department of
Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
November 2005
Labeling
Revision 4
Guidance
for Industry
Noncontraceptive Estrogen Drug Products for the Treatment of
Vasomotor Symptoms and Vulvar and Vaginal Atrophy Symptoms -
Recommended Prescribing Information for Health Care Providers
and Patient Labeling
Additional copies
of this guidance are available from:
Office of Training and Communications
Division of Drug Information, HFD-240
Center for Drug Evaluation and Research
Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857
(Tel) 301-827-4573
http://www.fda.gov/cder/guidance/index.htm
U.S. Department of
Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
November 2005
Labeling
Revision 4
TABLE OF CONTENTS
I. INTRODUCTION
II. LABELING
FOR HEALTH CARE PROVIDERS
III.
PATIENT INFORMATION
Guidance
for Industry1
Noncontraceptive Estrogen Drug Products for the Treatment of
Vasomotor Symptoms and Vulvar and Vaginal Atrophy Symptoms -
Recommended Prescribing Information
for Health Care Providers and Patient Labeling
This draft
guidance, when finalized, will represent the Food and Drug
Administration's (FDA's) current thinking on this topic. It
does not create or confer any rights for or on any person and
does not operate to bind FDA or the public. You can use an
alternative approach if it satisfies the requirements of the
applicable statutes and regulations. If you want to discuss an
alternative approach, contact the FDA staff responsible for
implementing this guidance. If you cannot identify the
appropriate FDA staff, call the appropriate number listed on
the title page of this guidance. |
I.
INTRODUCTION
This guidance describes, in labeling
format, recommended prescribing information for estrogen drug
products that treat moderate to severe vasomotor symptoms and/or
moderate to severe symptoms of vulvar and vaginal atrophy for new
drug applications (NDAs) and for supplemental new drug applications
(SNDAs). It also provides labeling recommendations for the Patient
Information leaflet. For other indications, such as prevention of
postmenopausal osteoporosis, manufacturers should contact the
appropriate review division in the Office of New Drugs (OND), Center
for Drug Evaluation and Research (CDER).2
For abbreviated new drug
applications (ANDAs), differences between the prescribing
information for the reference listed drug and the prescribing
information for the product covered by the ANDA may exist. These
differences may include the expiration date, formulation,
bioavailability, pharmacokinetics, or omission of an indication or
other aspects of prescribing information protected by patent or
accorded exclusivity under section 505(j)(5)(D) of the Federal Food,
Drug, and Cosmetic Act.
A draft of this guidance was first
issued in October 1998 (63 FR 55399) and revised in September 1999
(64 FR 52100). However, on September 10, 2002, the Agency withdrew
the draft guidance (67 FR 57432) pending consideration of the
results from the National Institutes of Health (NIH) Women's Health
Initiative (WHI) trial.3 A third
draft of this guidance was issued on February 3, 2003 (68 FR 5300)
incorporating the results of the NIH estrogen plus progestin
clinical trial. The fourth draft of this guidance was issued on
February 17, 2004 (69 FR 7492) incorporating the results of the NIH
Women's Health Initiative Memory Study (WHIMS).4
This revised draft of this guidance, incorporating the results of
the NIH estrogen-alone clinical trials, is being made available for
comment.5,6
FDA's guidance documents, including
this guidance, do not establish legally enforceable
responsibilities. Instead, guidances describe the Agency's current
thinking on a topic and should be viewed only as recommendations,
unless specific regulatory or statutory requirements are cited. The
use of the word should in Agency guidances means that
something is suggested or recommended, but not required.
II.
LABELING FOR HEALTH CARE PROVIDERS
We recommend including the
following prescribing information for health care providers:
ESTROGENS
INCREASE THE RISK OF ENDOMETRIAL CANCER
Close clinical surveillance of
all women taking estrogens 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 at equivalent estrogen doses. (See WARNINGS,
Malignant neoplasms, Endometrial cancer.)
CARDIOVASCULAR AND OTHER RISKS
Estrogens with or without
progestins should not be used for the prevention of
cardiovascular disease or dementia. (See WARNINGS,
Cardiovascular disorders and Dementia.)
The Women's Health Initiative
(WHI) study reported increased risks of stroke and deep vein
thrombosis in postmenopausal women (50 to 79 years of age)
during 6.8 years of treatment with oral conjugated estrogens
(CE 0.625 mg) alone per day, relative to placebo. (See
CLINICAL STUDIES and WARNINGS, Cardiovascular disorders.)
The WHI study reported
increased risk of myocardial infarction, stroke, invasive
breast cancer, pulmonary emboli, and deep vein thrombosis in
postmenopausal women (50 to 79 years of age) during 5 years of
treatment with oral conjugated estrogens (CE 0.625 mg)
combined with medroxyprogesterone acetate (MPA 2.5 mg) per
day, relative to placebo. (See CLINICAL STUDIES and
WARNINGS, Cardiovascular disorders and Malignant
neoplasms, Breast cancer.)
The Women's Health Initiative
Memory Study (WHIMS), a substudy of the WHI study, reported
increased risk of developing probable dementia in
postmenopausal women 65 years of age or older during 5.2 years
of treatment with CE 0.625 mg alone and during 4 years of
treatment with CE 0.625 mg combined with MPA 2.5 mg, relative
to placebo. It is unknown whether this finding applies to
younger postmenopausal women. (See CLINICAL STUDIES,
WARNINGS, Dementia, and PRECAUTIONS, Geriatric Use.)
Other doses of oral conjugated
estrogens with medroxyprogesterone acetate, and other
combinations and dosage forms of estrogens and progestins were
not studied in the WHI clinical trials and, in the absence of
comparable data, these risks should be assumed to be similar.
Because of these risks, estrogens with or without progestins
should be prescribed at the lowest effective doses and for the
shortest duration consistent with treatment goals and risks
for the individual woman. |
This should be supplied by the
manufacturer.
Endogenous estrogens are largely
responsible for the development and maintenance of the female
reproductive system and secondary sexual 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 its metabolites,
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
sulfate conjugated form, estrone sulfate, are the most abundant
circulating estrogens in postmenopausal women.
Estrogens act through binding to
nuclear receptors in estrogen-responsive tissues. To date, two
estrogen receptors have been identified. These vary in proportion
from tissue to tissue.
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.
A. Absorption
This section should be specific
for the product in question. If the product in question is an oral
dosage form, we recommend including the following information:
1. The rate and extent of
absorption (e.g., Cmax, Tmax, Cavg,
AUC, fluctuation index, and parent/metabolite ratio) generated
during the clinical pharmacology and biopharmaceutical studies.
2. Dose proportionality data for
the proposed dosing range.
3. The effect of food on the
bioavailability of the product in question.
4. Tables and figures, including
baseline unadjusted levels of estradiol and metabolites. In the
event that baseline adjusted levels are more appropriate, this
fact should be clearly indicated.
If the product in question is a
transdermal delivery system, we recommend including the following
information:
1. The rate and extent of
absorption (e.g., Cmax, Tmax, Cavg,
AUC, fluctuation index, and parent/metabolite ratio) generated
during the clinical pharmacology and biopharmaceutical studies.
2. Data for all the anatomical
application sites that will be proposed in the prescribing
information.
3. Dose proportionality data for
the proposed dosing range.
4. Tables and figures, including
baseline unadjusted levels of estradiol and metabolites. In the
event that baseline adjusted levels are more appropriate, this
fact should be clearly indicated.
5. The nominal mean in vivo delivery
rate.
If the product in question is a
topical dosage form for vaginal administration or administration to
another site and the estrogen is systemically available, we
recommend including the following information:
1. The rate and extent of
absorption (e.g., Cmax, Tmax, Cavg,
AUC, fluctuation index, and parent/metabolite ratio) generated
during the clinical pharmacology and biopharmaceutical studies.
2. Data for all the anatomical
application sites that will be proposed in the prescribing
information (except for vaginally administered products).
3. Dose proportionality data for
the proposed dosing range.
4. Tables and figures, including
baseline unadjusted levels of estradiol and metabolites. In the
event that baseline adjusted levels are more appropriate, this
fact should be clearly indicated.
If the product in question is a
topical dosage form or a dosage form to be administered vaginally
and the estrogen is not systemically available, we recommend stating
this clearly.
B. 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. Estrogens circulate
in the blood largely bound to sex hormone binding globulin (SHBG)
and albumin.
We recommend that additional
protein binding and pharmacokinetic information be specific for the
product in question.
C. 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 intestine followed by reabsorption.
In postmenopausal women, a significant proportion of the circulating
estrogens exist as sulfate conjugates, especially estrone sulfate,
which serves as a circulating reservoir for the formation of more
active estrogens.
We recommend that additional
metabolic and pharmacokinetic information be specific for the
product in question.
D. Excretion
Estradiol, estrone, and estriol are
excreted in the urine along with glucuronide and sulfate conjugates.
We recommend that additional
pharmacokinetic information (e.g., apparent half-life(s) and
clearance) be specific for the product in question.
E. Special Populations
This section should be specific
for the product in question.
F. Drug Interactions
We recommend including the
following information:
In vitro and in vivo studies have
shown that estrogens are metabolized partially by cytochrome P450
3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect
estrogen drug metabolism. Inducers of CYP3A4, such as St. John's
Wort preparations (Hypericum perforatum), phenobarbital,
carbamazepine, and rifampin, may reduce plasma concentrations of
estrogens, possibly resulting in a decrease in therapeutic effects
and/or changes in the uterine bleeding profile. Inhibitors of
CYP3A4, such as erythromycin, clarithromycin, ketoconazole,
itraconazole, ritonavir, and grapefruit juice, may increase plasma
concentrations of estrogens and result in side effects.
This section should be specific
for the product in question. If the product in question is a
transdermal delivery system, we recommend adding the following
section on adhesion:
G. Adhesion
Since the adhesion or lack of
adhesion of transdermal systems to the skin is a critical factor
directly related to drug delivery, therapeutic effect, and possibly
to compliance, we recommend including in vivo adhesion information
on the percentage of systems that lifted and/or were detached and
replaced during the pharmacokinetic and clinical studies. Adhesion
information should be specific for the transdermal product in
question.
This section should be specific
for the product in question and should include information
concerning the appropriate endpoints to assess the effectiveness for
the indication sought. A concise and objective description of the
studies that provide primary support for effectiveness should
include brief summaries of the following:
a. Study designs
b. Demographics of the
intent-to-treat study populations
c. Study results
For the indication of treatment
of moderate to severe vasomotor symptoms, we recommend including a
table of results (number and severity of vasomotor symptoms combined
in a single table or reported in separate tables) that provides the
sample size, the mean number (standard deviation (SD)) or mean
severity (SD) of hot flashes per day or per week at baseline and at
weeks 4 and 12 for each treatment group, the mean change (SD) for
number and severity from baseline at weeks 4 and 12 for each
treatment group, and the P-value versus placebo for number and
severity at weeks 4 and 12 for each treatment group.
For the indication of treatment
of moderate to severe symptoms of vulvar and vaginal atrophy, a
description of the study results should be included in the text.
We recommend reporting results
from individual studies separately.
Women's Health Initiative Studies
The WHI enrolled a total of 27,000
predominantly healthy postmenopausal women to assess the risks and
benefits of either the use of oral conjugated estrogens (CE 0.625
mg) alone per day or the use of oral conjugated estrogens (CE 0.625
mg) plus medroxyprogesterone acetate (MPA 2.5 mg) 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 or CE/MPA on menopausal symptoms.
The estrogen-alone substudy was
stopped early because an increased risk of stroke was observed.
Results of the estrogen-alone substudy, which included 10,739 women
(average age of 63 years, range 50 to 79; 75.3 percent white, 15
percent black, 6.1 percent Hispanic), after an average follow-up of
6.8 years are presented in Table (insert number).
Table
(insert number) RELATIVE AND ABSOLUTE RISK SEEN IN THE
ESTROGEN-ALONE SUBSTUDY OF WHIa |
Eventc |
Relative Risk*
Premarin vs. Placebo
at 6.8 Years
(95% CI) |
Placebo
n = 5,429 |
Premarin
n = 5,310 |
|
|
Absolute Risk per
10,000
Women-Years |
CHD
events |
0.91 (0.75-1.12) |
54 |
49 |
Nonfatal MI |
0.89
(0.70-1.12) |
41 |
37 |
CHD
death |
0.94
(0.65-1.36) |
16 |
15 |
Invasive breast cancer |
0.77 (0.59-1.01) |
33 |
26 |
Stroke |
1.39 (1.10-1.77) |
32 |
44 |
Pulmonary embolism |
1.34 (0.87-2.06) |
10 |
13 |
Colorectal cancer |
1.08 (0.75-1.55) |
16 |
17 |
Hip
fracture |
0.61 (0.41-0.91) |
17 |
11 |
Death
due to causes other than the events above |
1.08 (0.88-1.32) |
50 |
53 |
Global
indexb |
1.01 (0.91-1.12) |
190 |
192 |
|
Deep
vein thrombosisc |
1.47 (1.04-2.08) |
15 |
21 |
Vertebral fracturesc |
0.62 (0.42-0.93) |
17 |
11 |
Total
fracturesc |
0.70 (0.63-0.79) |
195 |
139 |
a Adapted from JAMA,
2004; 291:1701-1712
b 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
c Not included in global
index
* Nominal confidence
intervals unadjusted for multiple looks and multiple comparisons
For those outcomes included in the
WHI "global index" that reached statistical significance, the
absolute excess risk per 10,000 women-years in the group treated
with Premarin alone was 12 more strokes, while the absolute risk
reduction per 10,000 women-years was 6 fewer hip fractures. The
absolute excess risk of events included in the "global index" was a
nonsignificant 2 events per 10,000 women-years. There was no
difference between the groups in terms of all-cause mortality. (See
BOXED WARNINGS, WARNINGS, and PRECAUTIONS.)
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, which included 16,608 women (average age of 63
years, range 50 to 79; 83.9 percent white, 6.5 percent black, 5.5
percent Hispanic), after an average follow-up of 5.2 years are
presented in Table (insert number).
Table
(insert number) RELATIVE AND ABSOLUTE RISK SEEN IN THE
CE/MPA SUBSTUDY OF WHIa |
Eventc |
Relative Risk
CE/MPA vs. placebo
at 5.2 Years
(95% CI*) |
Placebo
n = 8,102 |
CE/MPA
n = 8,506 |
|
|
Absolute Risk per
10,000
Women-Years |
CHD
events |
1.29 (1.02-1.63) |
30 |
37 |
Nonfatal 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
indexc |
1.15 (1.03-1.28) |
151 |
170 |
|
Deep
vein thrombosisd |
2.07 (1.49-2.87) |
13 |
26 |
Vertebral fracturesd |
0.66 (0.44-0.98) |
15 |
9 |
Other
osteoporotic fracturesd |
0.77 (0.69-0.86) |
170 |
131 |
a Adapted from JAMA,
2002; 288:321-333
b Includes metastatic and
nonmetastatic 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," the absolute excess risks per 10,000 women-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 the
absolute risk reductions per 10,000 women-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
women-years. There was no difference between the groups in terms of
all-cause mortality. (See BOXED WARNINGS, WARNINGS,
and PRECAUTIONS.)
Women's Health Initiative Memory
Study
The estrogen-alone WHIMS, a substudy
of the WHI study, enrolled 2,947 predominantly healthy
postmenopausal women 65 years of age and older (45 percent were aged
65 to 69 years, 36 percent were 70 to 74 years, and 19 percent were
75 years of age and older) to evaluate the effects of conjugated
estrogens (CE 0.625 mg) on the incidence of probable dementia
(primary outcome) compared with placebo.
After an average follow-up of 5.2
years, 28 women in the estrogen-alone group (37 per 10,000
women-years) and 19 in the placebo group (25 per 10,000 women-years)
were diagnosed with probable dementia. The relative risk of probable
dementia in the estrogen-alone group was 1.49 (95 percent confidence
interval (CI), 0.83-2.66) compared to placebo. It is unknown whether
these findings apply to younger postmenopausal women. (See BOXED
WARNINGS, WARNINGS, Dementia, and PRECAUTIONS,
Geriatric Use.)
The estrogen plus progestin WHIMS
substudy enrolled 4,532 predominantly healthy postmenopausal women
65 years of age and older (47 percent were aged 65 to 69 years, 35
percent were 70 to 74 years, and 18 percent were 75 years of age and
older) to evaluate the effects of conjugated estrogens (CE 0.625 mg)
plus medroxyprogesterone acetate (MPA 2.5 mg) on the incidence of
probable dementia (primary outcome) compared with placebo.
After an average follow-up of 4
years, 40 women in the estrogen/progestin group (45 per 10,000
women-years) and 21 in the placebo group (22 per 10,000 women-years)
were diagnosed with probable dementia. The relative risk of probable
dementia in the hormone therapy group was 2.05 (95 percent CI,
1.21-3.48) compared to placebo. Differences between groups became
apparent in the first year of treatment. It is unknown whether these
findings apply to younger postmenopausal women. (See BOXED
WARNING, WARNINGS, Dementia, and PRECAUTIONS,
Geriatric Use.)
INDICATIONS AND USAGE
(Trade Name) is indicated in the:
Depending on the specific drug,
dosage form, and clinical trials performed, the prescribing
information can include appropriate indications from those listed
here.
1. Treatment of moderate to
severe vasomotor symptoms associated with menopause.
2. Treatment of moderate to
severe symptoms of vulvar and vaginal atrophy associated with
menopause. When prescribing solely for the treatment of symptoms
of vulvar and vaginal atrophy, topical vaginal products should
be considered.
CONTRAINDICATIONS
(Trade Name) should not be used in
women with any of the following conditions:
1. Undiagnosed abnormal genital
bleeding.
2. Known, suspected, or history
of cancer of the breast.
3. Known or suspected
estrogen-dependent neoplasia.
4. Active deep vein thrombosis,
pulmonary embolism, or history of these conditions.
5. Active or recent (e.g.,
within the past year) arterial thromboembolic disease (e.g.,
stroke, myocardial infarction).
6. Liver dysfunction or disease.
7. Known hypersensitivity to the
ingredients of (Trade Name).
8. Known or suspected pregnancy.
There is no indication for (Trade Name) in pregnancy. There
appears to be little or no increased risk of birth defects in
children born to women who have used estrogens and progestins
from oral contraceptives inadvertently during early pregnancy.
(See PRECAUTIONS.)
WARNINGS
See BOXED WARNINGS.
1. Cardiovascular disorders
Estrogen and estrogen/progestin
therapies have 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 (VTE)). Should any of these occur or be suspected,
estrogens should be discontinued immediately.
Risk factors for arterial vascular
disease (e.g., hypertension, diabetes mellitus, tobacco use,
hypercholesterolemia, and obesity) and/or venous thromboembolism
(e.g., personal history or family history of VTE, obesity, and
systemic lupus erythematosus) should be managed appropriately.
a. Coronary heart disease and
stroke
In the WHI estrogen-alone substudy,
an increased risk of stroke was observed in women receiving CE
compared to placebo (44 versus 32 per 10,000 women-years). The
increase in risk was observed in year 1 and persisted. (See
CLINICAL STUDIES.)
In the CE/MPA substudy of the WHI
study, an increased risk of CHD events (defined as nonfatal
myocardial infarction and CHD death) was observed in women receiving
CE/MPA compared to women receiving placebo (37 versus 30 per 10,000
women-years). The increase in risk was observed in year 1 and
persisted. In the same substudy of the WHI study, an increased risk
of stroke was observed in women receiving CE/MPA compared to women
receiving placebo (29 versus 21 per 10,000 women-years). The
increase in risk was observed after the first year and persisted.
(See CLINICAL STUDIES.)
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.
Participation in an open label extension of the original HERS trial
(HERS II) was agreed to by 2,321 women. 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 risk of nonfatal
myocardial infarction, pulmonary embolism, and thrombophlebitis.
b. Venous thromboembolism
In the WHI estrogen-alone substudy,
an increased risk of deep vein thrombosis was observed in women
receiving CE compared to placebo (21 versus 15 per 10,000
women-years). The increase in deep vein thrombosis risk was observed
during the first year. (See CLINICAL STUDIES.)
In the CE/MPA substudy of the WHI
study, a twofold 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 women-years in the CE/MPA group compared to 16 per 10,000
women-years in the placebo group. The increase in VTE risk was
observed during the first year and persisted. (See 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. Endometrial cancer
The use of unopposed estrogens in
women with intact uteri has been associated with an increased risk
of endometrial cancer. The reported endometrial cancer risk among
unopposed estrogen users is about 2 to 12 times greater than in
nonusers, and appears dependent on duration of treatment and on
estrogen dose. Most studies show no significant increased risk
associated with use of estrogens for less than 1 year. The greatest
risk appears associated with prolonged use, with an increased risk
of 15- to 24-fold for 5 to 10 years or more. 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. Adding a progestin to estrogen therapy has
been shown to reduce the risk of endometrial hyperplasia, which may
be a precursor to endometrial cancer.
b. Breast cancer
The use of estrogens and progestins
by postmenopausal women has been reported to increase the risk of
breast cancer. The most important randomized clinical trial
providing information about this issue is the CE/MPA substudy of the
WHI study (see CLINICAL STUDIES). The results from
observational studies are generally consistent with those of the WHI
clinical trial and report no significant variation in the risk of
breast cancer among different estrogens or progestins, doses, or
routes of administration.
The CE/MPA substudy of the WHI study
reported an increased risk of breast cancer in women who took CE/MPA
for a mean follow-up of 5.6 years. Observational studies have also
reported an increased risk for estrogen/progestin combination
therapy, and a smaller increased risk for estrogen-alone therapy,
after several years of use. In the WHI trial and from observational
studies, the excess risk increased with duration of use. From
observational studies, the risk appeared to return to baseline in
about 5 years after stopping treatment. In addition, observational
studies suggest that the risk of breast cancer was greater, and
became apparent earlier, with estrogen/progestin combination therapy
as compared to estrogen-alone therapy.
In the CE/MPA substudy, 26 percent
of the women reported prior use of estrogen-alone and/or
estrogen/progestin combination hormone therapy. After a mean
follow-up of 5.6 years during the clinical trial, the overall
relative risk of invasive breast cancer was 1.24 (95 percent CI,
1.01-1.54), and the overall absolute risk was 41 versus 33 cases per
10,000 women-years, for CE/MPA compared with placebo. Among women
who reported prior use of hormone therapy, the relative risk of
invasive breast cancer was 1.86, and the absolute risk was 46 versus
25 cases per 10,000 women-years, for CE/MPA compared with placebo.
Among women who reported no prior use of hormone therapy, the
relative risk of invasive breast cancer was 1.09, and the absolute
risk was 40 versus 36 cases per 10,000 women-years, for CE/MPA
compared with placebo. In the same substudy, invasive breast cancers
were larger and diagnosed at a more advanced stage in the CE/MPA
group compared with the placebo group. Metastatic disease was rare
with no apparent difference between the two groups. Other prognostic
factors such as histologic subtype, grade, and hormone receptor
status did not differ between the groups.
The use of estrogen plus progestin
has been reported to result in an increase in abnormal mammograms
requiring further evaluation. All women should receive yearly breast
examinations by a health care provider and perform monthly breast
self-examinations. In addition, mammography examinations should be
scheduled based on patient age, risk factors, and prior mammogram
results.
3. Dementia
In the estrogen-alone WHIMS, a
population of 2,947 hysterectomized women aged 65 to 79 years was
randomized to CE or placebo. In the estrogen plus progestin WHIMS, a
population of 4,532 postmenopausal women aged 65 to 79 years was
randomized to CE/MPA or placebo.
In the estrogen-alone substudy,
after an average follow-up of 5.2 years, 28 women in the
estrogen-alone group and 19 women in the placebo group were
diagnosed with probable dementia. The relative risk of probable
dementia for estrogen alone versus placebo was 1.49 (95 percent CI,
0.83-2.66). The absolute risk of probable dementia for estrogen
alone versus placebo was 37 versus 25 cases per 10,000 women-years.
It is unknown whether these findings apply to younger postmenopausal
women. (See CLINICAL STUDIES and PRECAUTIONS, Geriatric
Use.)
After an average follow-up of 4
years, 40 women being treated with CE/MPA (1.8 percent, n = 2,229)
and 21 women in the placebo group (0.9 percent, n = 2,303) received
diagnoses of probable dementia. The relative risk for CE/MPA versus
placebo was 2.05 (95 percent CI, 1.21-3.48), and was similar for
women with and without histories of menopausal hormone use before
WHIMS. The absolute risk of probable dementia for CE/MPA versus
placebo was 45 versus 22 cases per 10,000 women-years, and the
absolute excess risk for CE/MPA was 23 cases per 10,000 women-years.
It is unknown whether these findings apply to younger postmenopausal
women. (See CLINICAL STUDIES and PRECAUTIONS, Geriatric
Use.)
4. Gallbladder disease
A two- to fourfold increase in the
risk of gallbladder disease requiring surgery in postmenopausal
women receiving estrogens has been reported.
5. Hypercalcemia
Estrogen administration may lead to
severe hypercalcemia in patients with breast cancer and bone
metastases. If hypercalcemia occurs, use of the drug should be
stopped and appropriate measures taken to reduce the serum calcium
level.
6. 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 permanently 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 estrogens
on blood pressure was not seen. Blood pressure should be monitored
at regular intervals with estrogen use.
3. Hypertriglyceridemia
In patients with preexisting
hypertriglyceridemia, estrogen therapy may be associated with
elevations of plasma triglycerides leading to pancreatitis and other
complications.
4. Impaired liver function and
past history of cholestatic jaundice
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 to maintain their free thyroid hormone levels in
an acceptable range.
6. Fluid retention
Estrogens may cause some degree of
fluid retention. Because of this, patients who have conditions that
might be influenced by this factor, such as a 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
The CE/MPA substudy of the WHI study
reported that estrogen plus progestin increased the risk of ovarian
cancer. After an average follow-up of 5.6 years, the relative risk
for ovarian cancer for CE/MPA versus placebo was 1.58 (95 percent
CI, 0.77-3.24) but was not statistically significant. The absolute
risk for CE/MPA versus placebo was 4.2 versus 2.7 cases per 10,000
women-years. In some epidemiologic studies, the use of estrogen
alone, in particular for 10 or more years, has been associated with
an increased risk of ovarian cancer. Other epidemiologic studies
have not found these associations.
9. Exacerbation of endometriosis
Endometriosis may be exacerbated
with administration of estrogens. A few cases of malignant
transformation of residual endometrial implants have been reported
in women treated post-hysterectomy with estrogen-alone therapy. For
patients known to have residual endometriosis post-hysterectomy, the
addition of progestin should be considered.
10. Exacerbation of other
conditions
Estrogens may cause an exacerbation
of asthma, diabetes mellitus, epilepsy, migraine or porphyria,
systemic lupus erythematosus, and hepatic hemangiomas and should be
used with caution in women with these conditions.
B. Information for Patients
Physicians are advised to discuss
the Patient Information leaflet with patients for whom they
prescribe (Trade Name).
C. Laboratory Tests
Estrogen administration should be
initiated at the lowest dose approved for the indication and then
guided by clinical response rather than by serum hormone levels
(e.g., estradiol, FSH).
This section should be specific
for the product in question.
D. Drug/laboratory Test
Interactions
1. Accelerated prothrombin time,
partial thromboplastin time, and platelet aggregation time;
increased platelet count; increased factors II, VII antigen,
VIII antigen, VIII coagulant activity, IX, X, XII, VII-X
complex, II-VII-X complex, and beta-thromboglobulin; decreased
levels of antifactor Xa and antithrombin III, decreased
antithrombin III activity; increased levels of fibrinogen and
fibrinogen activity; increased plasminogen antigen and activity.
2. Increased TBG levels leading
to increased circulating total thyroid hormone levels as
measured by protein-bound iodine (PBI), T4 levels (by
column or by radioimmunoassay), or T3 levels by
radioimmunoassay. T3 resin uptake is decreased,
reflecting the elevated TBG. Free T4 and free T3
concentrations are unaltered. Patients on thyroid replacement
therapy may require higher doses of thyroid hormone.
3. Other binding proteins may be
elevated in serum (i.e., corticosteroid binding globulin (CBG),
SHBG) leading to increased total circulating corticosteroids and
sex steroids, respectively. Free hormone concentrations may be
decreased. Other plasma proteins may be increased (angiotensinogen/renin
substrate, alpha-1-antitrypsin, ceruloplasmin).
4. Increased plasma HDL and HDL2
cholesterol subfraction concentrations, reduced LDL cholesterol
concentration, increased triglycerides levels.
5. Impaired glucose tolerance.
6. Reduced response to
metyrapone test.
E. Carcinogenesis,
Mutagenesis, Impairment of Fertility
Long-term continuous administration
of estrogen, with or without progestin, in women with or without a
uterus, has shown an increased risk of endometrial cancer, breast
cancer, and ovarian cancer. (See BOXED WARNINGS, WARNINGS,
and PRECAUTIONS.)
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.
This section should be specific
for the product in question.
F. Pregnancy
(Trade Name) 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 have been identified in the
milk of mothers receiving this drug. Caution should be exercised
when (Trade Name) is administered to a nursing woman.
H. Pediatric Use
Complete as appropriate in
accordance with 21 CFR 201.57(f)(9).
I. Geriatric Use
Complete as appropriate in
accordance with 21 CFR 201.57(f)(10).
Of the total number of subjects in
the estrogen-alone substudy of the WHI study, 46 percent (n = 4,943)
were 65 years and older, while 7.1 percent (n = 767) were 75 years
and older. There was a higher relative risk (CE versus placebo) of
stroke in women less than 75 years of age compared to women 75 years
and older.
In the estrogen-alone substudy of
the WHIMS, a population of 2,947 hysterectomized women, aged 65 to
79 years, was randomized to estrogen alone (CE 0.625 mg) or placebo.
In the estrogen-alone group, after an average follow-up of 5.2
years, the relative risk (CE versus placebo) of probable dementia
was 1.49 (95 percent CI, 0.83-2.66).
Of the total number of subjects in
the estrogen plus progestin substudy of the WHI study, 44 percent (n
= 7,320) were 65 years and older, while 6.6 percent (n = 1,095) were
75 years and older. There was a higher relative risk (CE/MPA versus
placebo) of stroke and invasive breast cancer in women 75 and older
compared to women less than 75 years of age.
In the estrogen plus progestin
substudy of WHIMS, a population of 4,532 postmenopausal women, aged
65 to 70 years, was randomized to conjugated estrogens (CE 0.625 mg)
plus medroxyprogesterone acetate (MPA 2.5 mg) or placebo. In the
estrogen plus progestin group, after an average follow-up of 4
years, the relative risk (CE/MPA versus placebo) of probable
dementia was 2.05 (95 percent CI, 1.21-3.48).
Pooling the events in women
receiving CE or CE/MPA in comparison to those in women on placebo,
the overall relative risk of probable dementia was 1.76 (95 percent
CI, 1.19-2.60). Since both substudies were conducted in women aged
65 to 79 years, it is unknown whether these findings apply to
younger postmenopausal women. (See BOXED WARNINGS and
WARNINGS, Dementia.)
ADVERSE
REACTIONS
See BOXED WARNINGS,
WARNINGS, and PRECAUTIONS.
This section should be revised to
state the following when including a table of all treatment emergent
adverse events regardless of drug relationship reported as a
frequency of greater than or equal to 5 percent with Trade Name.
Because clinical trials are
conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly
compared to rates in the clinical trials of another drug and may not
reflect the rates observed in practice. The adverse reaction
information from clinical trials does, however, provide a basis for
identifying the adverse events that appear to be related to drug use
and for approximating rates.
We recommend including the
following:
The following additional adverse
reactions have been reported with estrogen and/or progestin therapy.
1. Genitourinary system
Changes in vaginal bleeding pattern
and abnormal withdrawal bleeding or flow; breakthrough bleeding;
spotting; dysmenorrhea, increase in size of uterine leiomyomata;
vaginitis, including vaginal candidiasis; change in amount of
cervical secretion; changes in cervical ectropion; ovarian cancer;
endometrial hyperplasia; endometrial cancer.
2. Breasts
Tenderness, enlargement, pain,
nipple discharge, galactorrhea; fibrocystic breast changes; breast
cancer.
3. Cardiovascular
Deep and superficial venous
thrombosis; pulmonary embolism; thrombophlebitis; myocardial
infarction; stroke; increase in blood pressure.
4. Gastrointestinal
Nausea, vomiting; abdominal cramps,
bloating; cholestatic jaundice; increased incidence of gallbladder
disease; pancreatitis, enlargement of hepatic hemangiomas.
5. Skin
Chloasma or melasma that may persist
when drug is discontinued; erythema multiforme; erythema nodosum;
hemorrhagic eruption; loss of scalp hair; hirsutism; pruritus, rash.
6. Eyes
Retinal vascular thrombosis,
intolerance to contact lenses.
7. Central nervous system
Headache; migraine; dizziness;
mental depression; chorea; nervousness; mood disturbances;
irritability; exacerbation of epilepsy, dementia.
8. Miscellaneous
Increase or decrease in weight;
reduced carbohydrate tolerance; aggravation of porphyria; edema;
arthalgias; leg cramps; changes in libido; urticaria, angioedema,
anaphylactoid/anaplylactic reactions; hypocalcemia; exacerbation of
asthma; increased triglycerides.
OVERDOSAGE
Serious ill effects have not been
reported following acute ingestion of large doses of
estrogen-containing drug products by young children. Overdosage of
estrogen may cause nausea and vomiting, and withdrawal bleeding may
occur in females.
DOSAGE AND
ADMINISTRATION
Depending on the specific drug
and dosage form, the prescribing information can include appropriate
dosage and administration from those listed here.
When estrogen is prescribed for a
postmenopausal woman with a uterus, a progestin should also be
initiated to reduce the risk of endometrial cancer. A woman without
a uterus does not need progestin. Use of estrogen, alone or in
combination with a progestin, should be with the lowest effective
dose and for the shortest duration consistent with treatment goals
and risks for the individual woman. Patients should be re-evaluated
periodically as clinically appropriate (e.g., 3-month to 6-month
intervals) to determine if treatment is still necessary (see
BOXED WARNINGS and WARNINGS). For women who have a
uterus, adequate diagnostic measures, such as endometrial sampling,
when indicated, should be undertaken to rule out malignancy in cases
of undiagnosed persistent or recurring abnormal vaginal bleeding.
The manufacturer should supply
specific dosage information for treatment of moderate to severe
vasomotor symptoms and for treatment of moderate to severe symptoms
of vulvar and vaginal atrophy associated with menopause.
For products with multiple doses:
Patients should be started at the
lowest dose.
We recommend that manufacturers
whose clinical development program did not identify the lowest
effective dose include:
The lowest effective dose of (Trade
Name) has not been determined.
HOW
SUPPLIED
The manufacturer should supply
information on available dosage forms, potency, color, and
packaging. The manufacturer should also provide a storage statement.
The manufacturer should include a
statement such as "Keep out of reach of children" in both the
instructions and the dispenser.
III. PATIENT INFORMATION
The recommended text for the
Patient Information leaflet is as follows:
PATIENT
INFORMATION
(Updated insert
full date)
Trade Name
(Insert chemical
name)
Read this Patient Information
leaflet before you start taking (Trade Name) and read what you get
each time you refill (Trade Name). There may be new information.
This information does not take the place of talking to your health
care provider about your medical condition or your treatment.
WHAT IS THE
MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT (TRADE NAME)
(AN ESTROGEN HORMONE)?
- Estrogens increase
the chance of getting cancer of the uterus.
Report any unusual vaginal
bleeding right away while you are taking estrogens. Vaginal
bleeding after menopause may be a warning sign of cancer of
the uterus (womb). Your health care provider should check any
unusual vaginal bleeding to find out the cause.
- Do not use estrogens with
or without progestins to prevent heart disease, heart
attacks, or strokes.
Using estrogens with or
without progestins may increase your chance of getting heart
attacks, strokes, breast cancer, and blood clots.
- Do not use estrogens with
or without progestins to prevent dementia.
Using estrogens with or
without progestins may increase your risk of dementia.
You and your health care
provider should talk regularly about whether you still need
treatment with (Trade Name). |
What is (Trade Name)?
(Trade Name) is a medicine that
contains estrogen hormones.
What is (Trade Name)
used for?
We recommend including only
approved indications.
(Trade Name) is used after menopause
to:
- Reduce moderate to severe hot
flashes
Estrogens are hormones made by a
woman's ovaries. The ovaries normally stop making estrogens when
a woman is between 45 to 55 years old. This drop in body
estrogen levels causes the 93change of life94 or menopause (the
end of monthly menstrual periods). Sometimes, both ovaries are
removed during an operation before natural menopause takes
place. The sudden drop in estrogen levels causes 93surgical
menopause.94
When the estrogen levels begin
dropping, some women develop very uncomfortable symptoms, such
as feelings of warmth in the face, neck, and chest, or sudden
strong feelings of heat and sweating (93hot flashes94 or 93hot
flushes94). In some women, the symptoms are mild, and they will
not need estrogens. In other women, symptoms can be more severe.
You and your health care provider should talk regularly about
whether you still need treatment with (Trade Name).
- Treat moderate to severe
dryness, itching, and burning in and around the vagina
You and your health care
provider should talk regularly about whether you still need
treatment with (Trade Name) to control these problems. If you
use (Trade Name) only to treat your dryness, itching, and
burning in and around your vagina, talk with your health care
provider about whether a topical vaginal product would be better
for you.
Who should not take (Trade Name)?
Do not start taking (Trade Name) if
you:
- Have unusual vaginal bleeding
- Currently have or have had
certain cancers
Estrogens may increase the
chance of getting certain types of cancers, including cancer of
the breast or uterus. If you have or have had cancer, talk with
your health care provider about whether you should take (Trade
Name).
- Had a stroke or heart attack
in the past year
- Currently have or have had
blood clots
- Currently have or have had
liver problems
- Are allergic to (Trade Name)
or any of its ingredients
- Think you may be pregnant
Tell your health care provider:
- If you are breastfeeding
- About all of your medical
problems
Your health care provider may
need to check you more carefully if you have certain conditions,
such as asthma (wheezing); epilepsy (seizures); migraine;
endometriosis; lupus; problems with your heart, liver, thyroid,
or kidneys; or have high calcium levels in your blood.
- About all the medicines you
take
This includes prescription and
nonprescription medicines, vitamins, and herbal supplements.
Some medicines may affect how (Trade Name) works. (Trade Name)
may also affect how your other medicines work.
- If you are going to have
surgery or will be on bed rest
What are the ingredients in
(Trade Name)?
We recommend providing a list of
all active and nonactive ingredients.
How should I take (Trade Name)?
We recommend providing
instructions on how to take (Trade Name). If (Trade Name) comes in
several strengths, include #1.
1. Start at the lowest dose and
talk to your health care provider about how well that dose is
working for you.
2. Estrogens should be used at the
lowest dose possible for your treatment only as long as needed.
(Sponsors whose clinical development program did not identify the
lowest effective dose are recommended to include: The lowest
effective dose of (Trade Name) has not been determined. You and
your health care provider should talk regularly (e.g., every 3 to
6 months) about the dose you are taking and whether you still need
treatment with (Trade Name)).
What are the
possible side effects of estrogens?
Less common but serious side
effects include:
- Breast cancer
- Cancer of the uterus
- Stroke
- Heart attack
- Blood clots
- Dementia
- Gallbladder disease
- Ovarian cancer
Some of the warning signs of
serious side effects include:
- Breast lumps
- Unusual vaginal bleeding
- Dizziness and faintness
- Changes in speech
- Severe headaches
- Chest pain
- Shortness of breath
- Pains in your legs
- Changes in vision
- Vomiting
Call your health care provider right
away if you get any of these warning signs, or any other unusual
symptom that concerns you.
Common side effects include:
- Headache
- Breast pain
- Irregular vaginal bleeding or
spotting
- Stomach/abdominal cramps,
bloating
- Nausea and vomiting
- Hair loss
Other side effects include:
- High blood pressure
- Liver problems
- High blood sugar
- Fluid retention
- Enlargement of benign tumors
of the uterus (93fibroids94)
- Vaginal yeast infection
These are not all the possible side
effects of (Trade Name). For more information, ask your health care
provider or pharmacist.
What can I do to
lower my chances of a serious side effect with (Trade Name)?
Talk with your health care provider
regularly about whether you should continue taking (Trade Name). If
you have a uterus, talk to your health care provider about whether
the addition of a progestin is right for you. In general, the
addition of a progestin is recommended for women with a uterus to
reduce the chance of getting cancer of the uterus. See your health
care provider right away if you get vaginal bleeding while taking
(Trade Name). Have a breast exam and mammogram (breast X-ray) every
year unless your health care provider tells you otherwise. If
members of your family have had breast cancer or if you have ever
had breast lumps or an abnormal mammogram, you may need to have
breast exams more often. If you have high blood pressure, high
cholesterol (fat in the blood), diabetes, are overweight, or if you
use tobacco, you may have a higher chance of getting heart disease.
Ask your health care provider for ways to lower your chance of
getting heart disease.
Have an annual gynecologic exam
General information about safe and effective use of (Trade Name)
Medicines are sometimes prescribed
for conditions that are not mentioned in patient information
leaflets. Do not take (Trade Name) for conditions for which it was
not prescribed. Do not give (Trade Name) to other people, even if
they have the same symptoms you have. It may harm them.
Keep (Trade Name) out of the
reach of children
This leaflet provides a summary of
the most important information about (Trade Name). If you would like
more information, talk with your health care provider or pharmacist.
You can ask for information about (Trade Name) that is written for
health professionals. You can get more information by calling the
toll-free number (add number here).
1 This guidance has been prepared by
the Division of Reproductive and Urologic Products in the Center for
Drug Evaluation and Research (CDER) at the Food and Drug
Administration.
2 Drugs for the prevention or
treatment of postmenopausal osteoporosis are reviewed by the
Division of Metabolism and Endocrinology Products, OND, CDER.
3 The results of the NIH Women's
Health Initiative estrogen plus progestin clinical trial were
reported in the Journal of the American Medical Association,
2002; 288:321-333.
4 The results of the NIH Women's
Health Initiative Memory Study estrogen plus progestin clinical
trial were reported in the Journal of the American Medical
Association, 2003; 289:2651-2662.
5 The results of the NIH Women's
Health Initiative estrogen-alone clinical trial were reported in the
Journal of the American Medical Association, 2004;
291:1701-1712.
6 The results of the NIH Women's
Health Initiative Memory Study estrogen-alone clinical trial were
reported in the Journal of the American Medical Association,
2004; 291:2947-2958.
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Date created: November 15, 2005 |