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

DRAFT GUIDANCE 

This guidance document is being distributed for comment purposes only.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 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

J:\!GUIDANC\6932dftcln2.doc 

11/07/05
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............................................................................................................. 1

II. LABELING FOR HEALTH CARE PROVIDERS....................................................... 3

DESCRIPTION ......................................................................................................................................4

CLINICAL PHARMACOLOGY .........................................................................................................4

CLINICAL STUDIES............................................................................................................................7

INDICATIONS AND USAGE.............................................................................................................10

CONTRAINDICATIONS....................................................................................................................10

WARNINGS..........................................................................................................................................11

PRECAUTIONS...................................................................................................................................14

ADVERSE REACTIONS ....................................................................................................................18

OVERDOSAGE....................................................................................................................................19

DOSAGE AND ADMINISTRATION ................................................................................................20

HOW SUPPLIED .................................................................................................................................20

III. PATIENT INFORMATION.......................................................................................... 21

What is (Trade Name)?........................................................................................................................21

What is (Trade Name) used for?.........................................................................................................21

Who should not take (Trade Name)?..................................................................................................22

What are the ingredients in (Trade Name)? ......................................................................................23

How should I take (Trade Name)?......................................................................................................23

What are the possible side effects of estrogens? ................................................................................23

What can I do to lower my chances of a serious side effect with (Trade Name)?...........................25

General information about safe and effective use of (Trade Name)................................................25
Contains Nonbinding Recommendations

Draft — Not for Implementation 

Guidance for Industry1 1 

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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 

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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. 

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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 

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. 

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 Drugs for the prevention or treatment of postmenopausal osteoporosis are reviewed by the Division of Metabolism

and Endocrinology Products, OND, CDER. 

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Contains Nonbinding Recommendations

Draft — Not for Implementation 

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).

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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. 

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 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. 

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 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.

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 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.

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 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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54 II. LABELING FOR HEALTH CARE PROVIDERS 

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We recommend including the following prescribing information for health care providers: 

58 ESTROGENS INCREASE THE RISK OF ENDOMETRIAL CANCER 

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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.) 

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67 CARDIOVASCULAR AND OTHER RISKS

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Estrogens with or without progestins should not be used for the prevention of cardiovascular 

disease or dementia. (See WARNINGS, Cardiovascular disorders and Dementia.)

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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.)

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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.) 

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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.) 

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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.

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This should be supplied by the 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. 

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: 

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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. 

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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:

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231 G. Adhesion

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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.

CLINICAL STUDIES

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, 

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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 ESTROGENALONE SUBSTUDY OF WHIa

Placebo 

n = 5,429 

Premarin 

n = 5,310 

Eventc Relative Risk* 

Premarin vs. Placebo 

at 6.8 Years 

(95% CI) 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 fractures

c 0.70 (0.63-0.79) 195 139 

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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 

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 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 allcause 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). 

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Table (insert number) RELATIVE AND ABSOLUTE RISK SEEN IN THE CE/MPA 

SUBSTUDY OF WHIa

Placebo 

n = 8,102 

CE/MPA 

n = 8,506 

Eventc Relative Risk 

CE/MPA vs. placebo 

at 5.2 Years 

(95% CI*) 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

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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 womenyears 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. 

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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 

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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. 

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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, 

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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/MPAtreated 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 

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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. 

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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. 

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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 

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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 posthysterectomy 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. 

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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. 

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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 

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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 estrogencontaining drug products by young children. Overdosage of estrogen may cause nausea and 

vomiting, and withdrawal bleeding may occur in females. 

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782 DOSAGE AND ADMINISTRATION 

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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.

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819 III. PATIENT INFORMATION 

820 

821 

822 

The recommended text for the Patient Information leaflet is as follows: 

823 PATIENT INFORMATION

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826 

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834 

(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)? 

835 

836 

837 

838 • Estrogens increase the chance of getting cancer of the uterus. 

839 

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. 

840 

841 

842 

843 

• Do not use estrogens with or without progestins to prevent heart disease, heart attacks, or 

strokes. 

844 

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846 

Using estrogens with or without progestins may increase your chance of getting heart attacks, 

strokes, breast cancer, and blood clots. 

847 

848 

849 

850 • Do not use estrogens with or without progestins to prevent dementia. 

851 

852 Using estrogens with or without progestins may increase your risk of dementia. 

853 

You and your health care provider should talk regularly about whether you still need treatment 

with (Trade Name). 

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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. 

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(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 “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 (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

See the end of this leaflet for a list of ingredients in (Trade Name).

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911 • Think you may be pregnant 

912 

913 

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Tell your health care provider: 

• If you are breastfeeding 

The hormone in (Trade Name) 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; 

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

You may need to stop taking estrogens. 

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?

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Contains Nonbinding Recommendations

Draft — Not for Implementation 

957 Less common but serious side effects include: 

958 

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• 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 (“fibroids”) 

• Vaginal yeast infection

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Contains Nonbinding Recommendations

Draft — Not for Implementation 

25

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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).