**Guidance For Industry**

**Labeling Guidance for Noncontraceptive Estrogen Drug Products for the
Treatment of Vasomotor Symptoms and Vulvar and Vaginal Atrophy Symptoms
--- Prescribing Information for**

**Health Care Providers**

**and Patient Labeling**

**This guidance document is being distributed for comment purposes
only.**

Comments and suggestions regarding this draft document should be
submitted within 60 days of publication of the *Federal Register* notice
announcing the availability of the draft guidance. Submit comments to
Dockets Management Branch (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) 827-4243.

**U.S. Department of Health and Human Services**

**Food and Drug Administration**

**Center for Drug Evaluation and Research (CDER)**

**January 2003**

**Labeling**

**Guidance For Industry**

**Labeling Guidance for Noncontraceptive Estrogen Drug Products for the
Treatment of Vasomotor Symptoms and Vulvar and Vaginal Atrophy Symptoms
--- Prescribing Information for**

**Health Care Providers**

**and Patient Labeling**

*Additional copies of this Guidance are available from*

*Division of Drug Information (HFD-240)*

*Center for Drug Evaluation and Research*

*Food and Drug Administration*

*5600 Fishers Lane,*

*Rockville, MD 20857*

*(Phone 301-827-4573)*

*Internet: 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)**

**January 2003**

**Labeling**

# Table of Contents {#table-of-contents .TOC-1}

#  {#section .TOC-1}

# I. INTRODUCTION [1](#i.-introduction) {#i.-introduction-1 .TOC-1}

# II. LABELING FOR HEALTH CARE PROVIDERS [2](#ii.-labeling-for-health-care-providers) {#ii.-labeling-for-health-care-providers-2 .TOC-1}

## DESCRIPTION [2](#description) {#description-2 .TOC-2}

## CLINICAL PHARMACOLOGY [2](#clinical-pharmacology) {#clinical-pharmacology-2 .TOC-2}

## INDICATIONS AND USAGE [7](#indications-and-usage) {#indications-and-usage-7 .TOC-2}

## CONTRAINDICATIONS [8](#contraindications) {#contraindications-8 .TOC-2}

## WARNINGS [8](#warnings) {#warnings-8 .TOC-2}

## PRECAUTIONS [12](#precautions) {#precautions-12 .TOC-2}

## ADVERSE REACTIONS [15](#adverse-reactions) {#adverse-reactions-15 .TOC-2}

## OVERDOSAGE [16](#overdosage) {#overdosage-16 .TOC-2}

## DOSAGE AND ADMINISTRATION [16](#dosage-and-administration) {#dosage-and-administration-16 .TOC-2}

## HOW SUPPLIED [17](#how-supplied) {#how-supplied-17 .TOC-2}

# III. PATIENT Information [17](#iii.-patient-information) {#iii.-patient-information-17 .TOC-1}

## What is (Tradename)? [18](#what-is-tradename) {#what-is-tradename-18 .TOC-2}

## What is (Tradename) used for? [18](#what-is-tradename-used-for) {#what-is-tradename-used-for-18 .TOC-2}

## Who should not take (Tradename)? [18](#who-should-not-take-tradename) {#who-should-not-take-tradename-18 .TOC-2}

## How should I take (Tradename)? [19](#how-should-i-take-tradename) {#how-should-i-take-tradename-19 .TOC-2}

## What are the possible side effects of estrogens? [20](#what-are-the-possible-side-effects-of-estrogens) {#what-are-the-possible-side-effects-of-estrogens-20 .TOC-2}

## What can I do to lower my chances of a serious side effect with (Tradename)? [21](#what-can-i-do-to-lower-my-chances-of-a-serious-side-effect-with-tradename) {#what-can-i-do-to-lower-my-chances-of-a-serious-side-effect-with-tradename-21 .TOC-2}

## General information about safe and effective use of (Tradename) [21](#general-information-about-safe-and-effective-use-of-tradename) {#general-information-about-safe-and-effective-use-of-tradename-21 .TOC-2}

## What are the ingredients in (Tradename)? [21](#what-are-the-ingredients-in-tradename) {#what-are-the-ingredients-in-tradename-21 .TOC-2}

**GUIDANCE FOR INDUSTRY**[^1]

**Labeling Guidance for Noncontraceptive Estrogen Drug Products for the
Treatment of Vasomotor Symptoms and Vulvar and Vaginal Atrophy Symptoms
---**

**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. An alternative approach may be used if such
> approach satisfies the requirements of the applicable statutes and
> regulations.

# I. INTRODUCTION

This guidance describes recommended prescribing information for estrogen
drug products that treat moderate to severe vasomotor symptoms and/or
moderate to severe symptoms of vulvar vaginal atrophy for new drug
applications (NDAs). It also provides labeling recommendations for the
Patient Information leaflet. For other indications, such as prevention
of osteoporosis, sponsors are asked to direct inquiries to the
appropriate CDER Office of New Drugs review division.[^2]

A draft of this guidance was first issued 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.[^3] This
second draft is being made available for comment.

For ANDAs, differences between the prescribing information for the
reference listed drug and the prescribing information for the product
covered by the ANDA may exist, including differences in 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.

# II. LABELING FOR HEALTH CARE PROVIDERS

*We recommend the following prescribing information be included for
health care providers*:

## 

## DESCRIPTION

*Supplied by manufacturer*

## CLINICAL PHARMACOLOGY

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.

**Pharmacokinetics**

***Absorption***

*This section will be specific for the product in question. If the
product in question is an oral dosage form, we recommend the following
information be included:*

1\. The rate and extent of absorption (e.g., C~max~, T~max~ C~avg~, 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 should include 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 the following information be included:*

1\. The rate and extent of absorption (e.g., C~max~,T~max~ C~avg~, AUC,
Fluctuation index, and parent/metabolite ratio) generated during the
pivotal 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, with this fact 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 the following information be
included:*

1\. The rate and extent of absorption (e.g., C~max~,T~max~ C~avg~, AUC,
Fluctuation index, and parent/metabolite ratio) generated during the
pivotal 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, with this fact 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 this be clearly stated.*

***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.*

***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 gut 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 additional metabolic and pharmacokinetic information be
specific for the product in question.*

***Excretion***

Estradiol, estrone, and estriol are excreted in the urine along with
glucuronide and sulfate conjugates.

*We recommend additional pharmacokinetic information (e.g., apparent
half life(s) and clearance) be specific for the product in question.*

***Special Populations***

*This section will be specific for the product in question.*

***Drug Interactions***

*We recommend that the following information be included:*

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 may result in side effects.

*If the product in question is a transdermal delivery system, we
recommend the following section on adhesion be added:*

***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 that in vivo adhesion
information on the percentage of systems that lifted and/or were
detached and replaced during the pharmacokinetic and clinical studies be
included. Adhesion information would be specific for the transdermal
product in question.*

**Clinical Studies**

*This section will be specific for the product in question and would
include information concerning the appropriate endpoints to assess the
efficacy for the indication sought. A concise and objective description
of the pivotal efficacy studies would 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 that a table of results be included that provides
the sample size, the mean number (SD) of hot flashes per week at
baseline and at weeks 4, 8, and 12 for each treatment group, and the
mean change (SD) from baseline at weeks 4,8, and 12 for each treatment
group.*

*For the indication of treatment of moderate to severe symptoms of
vulvar and vaginal atrophy, description of the study results should be
included in the text.*

*We recommend that results from individual studies be reported
separately.*

**Women's Health Initiative Studies.**

The Women's Health Initiative (WHI) enrolled a total of 27,000
predominantly healthy postmenopausal women to assess the risks and
benefits of either the use of 0.625 mg conjugated equine estrogens (CE)
per day alone or the use of 0.625 mg conjugated equine estrogens 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 or CE/MPA
on menopausal symptoms.

The CE-only substudy is continuing and results have not been reported.
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% White, 6.5% Black,
5.5% Hispanic), after an average follow-up of 5.2 years are presented in
Table *(insert number)* below:

+----------------------+-----------------+-------------+--------------+
| **Table** *(insert   |                 |             |              |
| number)***. RELATIVE |                 |             |              |
| AND ABSOLUTE RISK    |                 |             |              |
| SEEN IN THE CE/MPA   |                 |             |              |
| SUBSTUDY OF WHI^a^** |                 |             |              |
+----------------------+-----------------+-------------+--------------+
| Event^c^             | Relative Risk\  | Placebo\    | CE/MPA       |
|                      | CE/MPA vs       | n = 8102    |              |
|                      | placebo\        |             | n = 8506     |
|                      | at 5.2 Years    |             |              |
|                      |                 |             |              |
|                      | (95% CI\*)      |             |              |
+----------------------+-----------------+-------------+--------------+
|                      |                 | Absolute    |              |
|                      |                 | Risk per    |              |
|                      |                 | 10,000      |              |
|                      |                 | P           |              |
|                      |                 | erson-years |              |
+----------------------+-----------------+-------------+--------------+
| CHD events           | 1.29            | 30          | 37           |
|                      | (1.02-1.63)     |             |              |
+----------------------+-----------------+-------------+--------------+
| *Non-fatal MI*       | *1.32           | *23*        | *30*         |
|                      | (1.02-1.72)*    |             |              |
+----------------------+-----------------+-------------+--------------+
| *CHD death*          | *1.18           | *6*         | *7*          |
|                      | (0.70-1.97)*    |             |              |
+----------------------+-----------------+-------------+--------------+
| Invasive breast      | 1.26            | 30          | 38           |
| cancer^b^            | (1.00-1.59)     |             |              |
+----------------------+-----------------+-------------+--------------+
| Stroke               | 1.41            | 21          | 29           |
|                      | (1.07-1.85)     |             |              |
+----------------------+-----------------+-------------+--------------+
| Pulmonary embolism   | 2.13            | 8           | 16           |
|                      | (1.39-3.25)     |             |              |
+----------------------+-----------------+-------------+--------------+
| Colorectal cancer    | 0.63            | 16          | 10           |
|                      | (0.43-0.92)     |             |              |
+----------------------+-----------------+-------------+--------------+
| Endometrial cancer   | 0.83            | 6           | 5            |
|                      | (0.47-1.47)     |             |              |
+----------------------+-----------------+-------------+--------------+
| Hip fracture         | 0.66            | 15          | 10           |
|                      | (0.45-0.98)     |             |              |
+----------------------+-----------------+-------------+--------------+
| Death due to causes  | 0.92            | 40          | 37           |
| other than the       | (0.74-1.14)     |             |              |
| events above         |                 |             |              |
+----------------------+-----------------+-------------+--------------+
| Global Index ^c^     | 1.15            | 151         | 170          |
|                      | (1.03-1.28)     |             |              |
+----------------------+-----------------+-------------+--------------+
|                      |                 |             |              |
+----------------------+-----------------+-------------+--------------+
| Deep vein thrombosis | 2.07            | 13          | 26           |
| ^d^                  | (1.49-2.87)     |             |              |
+----------------------+-----------------+-------------+--------------+
| Vertebral fractures  | 0.66            | 15          | 9            |
| ^d^                  | (0.44-0.98)     |             |              |
+----------------------+-----------------+-------------+--------------+
| Other osteoporotic   | 0.77            | 170         | 131          |
| fractures ^d^        | (0.69-0.86)     |             |              |
+----------------------+-----------------+-------------+--------------+

^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 WARNINGS, WARNINGS,** and
**PRECAUTIONS**.)

## INDICATIONS AND USAGE

*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
the menopause.

2\. Treatment of moderate to severe symptoms of vulvar and vaginal
atrophy associated with the menopause. When prescribing solely for the
treatment of symptoms of vulvar and vaginal atrophy, topical vaginal
products should be considered.

## CONTRAINDICATIONS

Estrogens should not be used in individuals with any of the following
conditions:

1.  Undiagnosed abnormal genital bleeding.

2.  Known, suspected, or history of cancer of the breast except in
    appropriately selected patients being treated for metastatic
    disease.

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.  (Tradename) should not be used in patients with known
    hypersensitivity to its ingredients.

7.  Known or suspected pregnancy. There is no indication for (Tradename)
    in pregnancy. There appears to be little or no increased risk of
    birth defects in women who have used estrogens and progestins from
    oral contraceptives inadvertently during early pregnancy (See
    PRECAUTIONS).

## WARNINGS

**See BOXED WARNINGS.**

The use of unopposed estrogens in women who have a uterus is associated
with an increased risk of endometrial cancer.

1\. Cardiovascular disorders.

Estrogen and 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 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 Women's Health Initiative study (WHI), an increase in the number
of myocardial infarctions and strokes has been observed in women
receiving CE compared to placebo. These observations are preliminary,
and the study is continuing*.* (See **CLINICAL PHARMACOLOGY, Clinical
Studies**.)

In the CE/MPA substudy of 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.

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 Women's Health Initiative study (WHI), an increase in VTE has
been observed in women receiving CE compared to placebo. These
observations are preliminary, and the study is continuing. (See
**CLINICAL PHARMACOLOGY, Clinical Studies**.)

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.

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-fold greater than in non-users, 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 one year.
The greatest risk appears 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. 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**

Estrogen and 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 estrogens 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**.)

In the WHI, no increased risk of breast cancer in CE-treated women
compared to placebo was reported after an average of 5.2 years of
therapy. These data are preliminary and that substudy of WHI is
continuing.

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 self-examinations.
In addition, mammography examinations should be scheduled based on
patient age and risk factors.

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

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.

5\. 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\. 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**

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. 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**

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
T~4~ and T~3~ 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 may cause some degree of fluid retention, patients
with 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**

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.

**9. Exacerbation of endometriosis**

Endometriosis may be exacerbated with administration of estrogens.

**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 (Tradename).

**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 will 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 thyroid-binding globulin (TBG) leading to increased
circulating total thyroid hormone levels as measured by protein-bound
iodine (PBI), T~4~ levels (by column or by radioimmunoassay) or T~3~
levels by radioimmunoassay. T~3~ resin uptake is decreased, reflecting
the elevated TB~6~. 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), sex hormone‑binding globulin
(SHBG)) leading to increased circulating corticosteroids and sex
steroids, respectively. Free or biologically active hormone
concentrations are unchanged. Other plasma proteins may be increased
(angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).

4\. Increased plasma HDL and HDL~2~ subfraction concentrations, reduced
LDL cholesterol concentration, increased triglycerides levels.

5.  Impaired glucose tolerance.

6.  Reduced response to metyrapone test.

**E**. **CARCINOGENESES, MUTAGENESIS, AND 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
WARNINGS, CONTRAINDICATIONS, and WARNINGS.)**

**F. PREGNANCY**

(Tradename) 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 (Tradename) is administered to a nursing woman.

**H**. **PEDIATRIC USE**

*Complete as appropriate in accordance with 21 CFR 201.57(f)(9)*

### **GERIATRIC USE**

*Complete as appropriate in accordance with 21 CFR 201.57(f)(10)*

## ADVERSE REACTIONS

*Revise 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% with Trademark:*

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 the following:*

The following additional adverse reactions have been reported with
estrogens. (See **BOXED WARNINGS, WARNINGS** and **PRECAUTIONS**.)

**1. Genitourinary system**

Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or
flow; breakthrough bleeding; spotting; 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 gall bladder disease; pancreatitis.

**5. Skin**

Chloasma or melasma, which may persist when drug is discontinued;
erythema multiforme; erythema nodosum; hemorrhagic eruption; loss of
scalp hair; hirsutism; pruritus, rash.

# 6. Eyes {#eyes .TOC-1}

Retinal vascular thrombosis, steepening of corneal curvature,
intolerance to contact lenses.

**7. Central nervous system**

Headache; migraine; dizziness; mental depression; chorea; nervousness;
mood disturbances; irritability; exacerbation of epilepsy.

**8. Miscellaneous**

Increase or decrease in weight; reduced carbohydrate tolerance;
aggravation of porphyria; edema; arthalgias; leg cramps; changes in
libido; 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 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 limited to
the shortest duration consistent with treatment goals and risks for the
individual woman. Patients should be reevaluated 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.

*Manufacturer to 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 the
menopause.*

*For products with multiple doses:*

Patients should be started at the lowest dose.

## HOW SUPPLIED

*Manufacturer to supply information on available dosage forms, potency,
color, and packaging.*

*Manufacturer to include statement such as "Keep out of reach of
children" to both the instructions and dispenser.*

# III. PATIENT Information 

*The recommended text of the PATIENT INFORMATION leaflet is as follows:*

**[PATIENT INFORMATION]{.underline}**

(Updated *insert full date*)

**Tradename**

(*Insert chemical name*)

Read this PATIENT INFORMATION before you start taking (Tradename) and
read what you get each time you refill (Tradename). 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 (Tradename)?

(Tradename) is a medicine that contains estrogen hormones.

## What is (Tradename) used for?

*Include only approved indications.*

(Tradename) 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 "change of life" 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 "surgical menopause."
>
> 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 ("hot
> flashes" or "hot flushes"). 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 (Tradename).

-   **treat moderate to severe dryness, itching, and burning in or
    around the vagina**

> You and your health care provider should talk regularly about whether
> you still need treatment with (Trademark) to control these problems.

## Who should not take (Tradename)?

Do not start taking (Tradename) if you:

-   **have unusual vaginal bleeding**

```{=html}
<!-- -->
```
-   **currently have or have had certain cancers**

> Estrogens may increase the chances of getting certain types of
> cancers, including cancer of the breast or uterus. If you have or had
> cancer, talk with your health care provider about whether you should
> take (Tradename).

-   **had a stroke or heart attack in the past year**

```{=html}
<!-- -->
```
-   **currently have or have had blood clots**

```{=html}
<!-- -->
```
-   **are allergic to (Tradename) or any of its ingredients**

> See the end of this leaflet for a list of ingredients in (Tradename).

-   **think you may be pregnant**

> Tell your health care provider:

-   if you are breastfeeding

> The hormone in (Tradename) can pass into your milk.

-   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, or problems with your heart,
> liver, thyroid, 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 (Tradename)
> works. (Tradename) may also affect how your other medicines work.

-   **if you are going to have surgery or will be on bed rest.**

> You may need to stop taking estrogens.

## 

## 

## How should I take (Tradename)?

*Provide instructions on how to take (Tradename).* *If (Tradename) comes
in several strengths, include #1.*

1\. Start at the lowest dose and talk to your health care provider how
well that dose is working for you.

2\. Estrogens should be used only as long as needed. You and your health
care provider should talk regularly (for example, every 3 to 6 months)
about whether you still need treatment with (*Tradename*).

## 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

-   Gallbladder disease

-   Ovarian cancer

These are some of the warning signs of serious side effects:

-   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 ("fibroids")

-   Vaginal yeast infection

These are not all the possible side effects of (Tradename). For more
information, ask your health care provider or pharmacist.

## 

## What can I do to lower my chances of a serious side effect with (Tradename)?

Talk with your health care provider regularly about whether you should
continue taking (Tradename). See your health care provider right away if
you get vaginal bleeding while taking (Tradename). Have a breast exam
and mammogram (breast X-ray) every year unless your health care provider
tells you something else. 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 higher chances for getting heart
disease. Ask your health care provider for ways to lower your chances
for getting heart disease.

## General information about safe and effective use of (Tradename)

Medicines are sometimes prescribed for conditions that are not mentioned
in patient information leaflets. Do not take (Tradename) for conditions
for which it was not prescribed. Do not give (Tradename) to other
people, even if they have the same symptoms you have. It may harm them.
Keep (Tradename) out of the reach of children.

This leaflet provides a summary of the most important information about
(Tradename). If you would like more information, talk with your health
care provider or pharmacist. You can ask for information about
(Tradename) that is written for health professionals. You can get more
information by calling the toll free number (*add number here)*.

## 

## What are the ingredients in (Tradename)?

*Provide a list of all ingredients, active and nonactive.*

[^1]: This guidance has been prepared by the Division of Reproductive
    and Urologic Drug Products in the Center for Drug Evaluation and
    Research (CDER) at the Food and Drug Administration.

[^2]: Drugs for the prevention or treatment of osteoporosis are reviewed
    by the Division of Metabolic and Endocrine Drug Products, Office of
    New Drugs, CDER.

[^3]: The results of the NIH Women\'s Health Initiative trial were
    reported in the Journal of the American Medical Association,
    2002;288:321-333.