Estradiol Vaginal Cream

Each gram of Estradiol Vaginal Cream, USP, 0.01% contains 0.1 mg estradiol in a nonliquefying

base containing purified water, propylene glycol, stearyl alcohol, white ceresin wax, mono- and

di-glycerides, hypromellose 2208 (4000 cps), sodium lauryl sulfate, methylparaben, edetate disodium and tertiary-butylhydroquinone. Estradiol is chemically described as estra-1,3,5(10)-

triene-3, 17(beta)-diol. It has an empirical formula of C18H24O2 and molecular weight of 272.37.

The structural formula is:

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

Estrogen drug products are absorbed through the skin, mucous membranes, and the gastrointestinal tract after release from the drug formulation.

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.

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.

Excretion

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

conjugates.

Special Populations

No pharmacokinetic studies were conducted in special populations, including patients with renal

or hepatic impairment.

Drug Interactions

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.

CLINICAL STUDIES

Women’s Health Initiative Studies

The WHI enrolled approximately 27,000 predominantly healthy postmenopausal women in two

substudies to assess the risks and benefits of daily oral CE (0.625 mg)-alone or in combination

with MPA (2.5 mg) compared to placebo in the prevention of certain chronic diseases. The

primary endpoint was the incidence of coronary heart disease (CHD) (defined as nonfatal MI,

silent MI and CHD death), with invasive breast cancer as the primary adverse outcome. A

“global index” included the earliest occurrence of CHD, invasive breast cancer, stroke, PE,

endometrial cancer (only in the CE plus MPA substudy), colorectal cancer, hip fracture, or death

due to other cause. These substudies did not evaluate the effects of CE or CE plus MPA on

menopausal symptoms.

WHI Estrogen-Alone Substudy

The WHI estrogen-alone substudy was stopped early because an increased risk of stroke was

observed, and it was deemed that no further information would be obtained regarding the risks

and benefits of estrogen-alone in predetermined primary endpoints.

Results of the estrogen-alone substudy, which included 10,739 women (average 63 years of age,

range 50 to 79; 75.3 percent White, 15.1 percent Black, 6.1 percent Hispanic, 3.6 percent

Other), after an average follow-up of 7.1 years are presented in Table 1.

TABLE 1 -Relative and Absolute Risk Seen in the Estrogen-Alone Substudy of WHIa

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 CE-alone was 12 more

strokes, while the absolute risk reduction per 10,000 women-years was 7 fewer hip fractures1.

The absolute excess risk of events included in the "global index" was a non-significant 5 events

per 10,000 women-years. There was no difference between the groups in terms of all-cause

mortality.

No overall difference for primary CHD events (nonfatal MI, silent MI and CHD death) and

invasive breast cancer incidence in women receiving CE-alone compared with placebo was

reported in final centrally adjudicated results from the estrogen-alone substudy, after an

average follow-up of 7.1 years.

Centrally adjudicated results for stroke events from the estrogen-alone substudy, after an

average follow-up of 7.1 years, reported no significant differences in distribution of stroke

subtypes or severity, including fatal strokes, in women receiving CE-alone compared to

placebo. Estrogen-alone increased the risk for ischemic stroke, and this excess risk was

present in all subgroups of women examined2.

Timing of the initiation of estrogen-alone therapy relative to the start of menopause may affect

the overall risk benefit profile. The WHI estrogen-alone substudy stratified by age showed in

women 50 to 59 years of age a non-significant trend toward reduced risk for CHD [hazard ratio

(HR) 0.63 (95 percent CI, 0.36-1.09)] and overall mortality [HR 0.71 (95 percent CI, 0.46–

1.11)].

WHI Estrogen Plus Progestin Substudy

The WHI estrogen plus progestin substudy was also stopped early. According to the predefined

stopping rule, after an average follow-up of 5.6 years of treatment, the increased risk of breast

cancer and cardiovascular events exceeded the specified benefits included in the “global

index.” The absolute excess risk of events included in the “global index” was 19 per 10,000

women-years.

For those outcomes included in the WHI “global index” that reached statistical significance after

5.6 years of follow-up, the absolute excess risks per 10,000 women-years in the group treated

with CE plus MPA were 7 more CHD events, 8 more strokes, 10 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.

Results of the CE plus MPA substudy, which included 16,608 women (average 63 years of age,

range 50 to 79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other),

are presented in Table 2. These results reflect centrally adjudicated data after an average follow-up of 5.6 years.

TABLE 2 -Relative and Absolute Risk Seen in the Estrogen Plus Progestin Substudy of

WHI at an Average of 5.6 Yearsa, b

Timing of the initiation of estrogen plus progestin therapy relative to the start of menopause may

affect the overall risk benefit profile. The WHI estrogen plus progestin substudy stratified by age

showed in women 50 to 59 years of age, a non-significant trend toward reduced risk for overall

mortality [HR 0.69 (95 percent CI, 0.44-1.07)].

Women’s Health Initiative Memory Study

The WHIMS estrogen-alone ancillary study of WHI enrolled 2,947 predominantly healthy

hysterectomized postmenopausal women 65 to 79 years of age and older (45 percent were

65 to 69 years of age; 36 percent were 70 to 74 years of age; 19 percent were 75 years of

age and older) to evaluate the effects of daily CE (0.625 mg)-alone on the incidence of

probable dementia (primary outcome) compared to placebo.

After an average follow-up of 5.2 years, the relative risk of probable dementia for CE-alone

versus placebo was 1.49 (95 percent CI, 0.83-2.66). The absolute risk of probable dementia for

CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years. Probable dementia

as defined in this study included Alzheimer’s disease (AD), vascular dementia (VaD) and mixed

types (having features of both AD and VaD). The most common classification of probable

dementia in the treatment group and the placebo group was AD. Since the ancillary study was

conducted in women 65 to 79 years of age, it is unknown whether these findings apply to

younger postmenopausal women [see BOXED WARNINGS, WARNINGS, Probable

Dementia and PRECAUTIONS, Geriatric Use].

The WHIMS estrogen plus progestin ancillary study of WHI enrolled 4,532 predominantly

healthy postmenopausal women 65 years of age and older (47 percent were 65 to 69 years of

age; 35 percent were 70 to 74 years; 18 percent were 75 years of age and older) to evaluate

the effects of daily CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia

(primary outcome) compared to placebo.

After an average follow-up of 4 years, the relative risk of probable dementia for CE plus MPA

versus placebo was 2.05 (95 percent CI, 1.21-3.48). The absolute risk of probable dementia for

CE plus MPA versus placebo was 45 versus 22 per 10,000 women-years. Probable dementia as

defined in this study included AD, VaD and mixed types (having features of both AD and

VaD). The most common classification of probable dementia in the treatment group and the

placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of

age, it is unknown whether these findings apply to younger postmenopausal women [see

WARNINGS, Probable Dementia and PRECAUTIONS, Geriatric Use].

When data from the two populations were pooled as planned in the WHIMS protocol, the

reported overall relative risk for probable dementia was 1.76 (95 percent CI, 1.19-2.60).

Differences between groups became apparent in the first year of treatment. It is unknown

whether these findings apply to younger postmenopausal women [see WARNINGS, Probable

Dementia and PRECAUTIONS, Geriatric Use].

Estradiol Vaginal Cream, USP, 0.01% 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 DVT, PE or history of these conditions.

5. Active arterial thromboembolic disease (for example, stroke, MI) or a history of these

conditions.

6. Known anaphylactic reaction or angioedema to Estradiol Vaginal Cream, USP,

0.01%.

7. Known liver dysfunction or disease.

8. Known protein C, protein S, or antithrombin deficiency, or other known

thrombophilic disorders.

9. Known or suspected pregnancy.

See BOXED WARNINGS, WARNINGS and PRECAUTIONS.

Systemic absorption may occur with the use of Estradiol Vaginal Cream, USP, 0.01%. The

warnings, precautions, and adverse reactions associated with oral estrogen treatment should

be taken into account.

The following adverse reactions have been reported with estrogen and/or progestin therapy.

1. Genitourinary System

Abnormal uterine bleeding or spotting; dysmenorrhea or pelvic pain, increase in size of uterine

leiomyomata; vaginitis, including vaginal candidiasis; change in cervical secretion; cystitis-like

syndrome; application site reactions of vulvovaginal discomfort including burning and irritation;

genital pruritus; ovarian cancer; endometrial hyperplasia; endometrial cancer.

2. Breasts

Tenderness, enlargement, pain, nipple discharge, fibrocystic breast changes; breast cancer.

3. Cardiovascular

Deep and superficial venous thrombosis; pulmonary embolism; myocardial infarction; stroke;

increase in blood pressure.

4. Gastrointestinal

Nausea, vomiting; abdominal cramps, bloating; increased incidence of gallbladder disease.

5. Skin

Chloasma that may persist when drug is discontinued; loss of scalp hair; hirsutism; rash.

6. Eyes

Retinal vascular thrombosis, intolerance to contact lenses.

7. Central Nervous System

Headache; migraine; dizziness; mental depression; nervousness; mood disturbances; irritability;

dementia.

8. Miscellaneous

Increase or decrease in weight; glucose intolerance; edema; arthralgias; leg cramps; changes in

libido; urticaria; exacerbation of asthma; increased triglycerides; hypersensitivity (including

erythema multiforme).

Use of Estradiol Vaginal Cream, USP, 0.01% alone or in combination with a progestin, should be

limited to the shortest duration consistent with treatment goals and risks for the individual

woman. Postmenopausal women should reevaluate periodically as clinically appropriate to

determine if treatment is still necessary. For treatment of vulvar and vaginal atrophy associated

with the menopause, the lowest dose and regimen that will control symptoms should be chosen

and medication should be discontinued as promptly as possible. For women who have a uterus,

adequate diagnostic measures, including directed and random endometrial sampling when

indicated, should be undertaken to rule out malignancy in cases of undiagnosed persistent or

recurring abnormal genital bleeding.

Usual Dosage: The usual dosage range is 2 to 4 g (marked on the applicator) daily for one or two

weeks, then gradually reduced to one half initial dosage for a similar period. A maintenance

dosage of 1 g, one to three times a week, may be used after restoration of the vaginal mucosa has

been achieved.

NOTE: The number of doses per tube will vary with dosage requirements and patient

handling.

Estradiol Vaginal Cream USP 0.01% UNSCENTED, 42.5 g Carton Text

NDC 0093-3541-43

Estradiol Vaginal Cream USP

0.01%

UNSCENTED

Each gram contains 0.1 mg estradiol in a nonliquefying base.

Usual Dosage: See enclosed Package Insert for Full Prescribing Information.

CAUTION: Keep this and all medications out of the reach of children.

CALIBRATED APPLICATOR ENCLOSED

This product also contains purified water, propylene glycol, stearyl alcohol,

white ceresin wax, mono- and di-glycerides, hypromellose, sodium lauryl

sulfate, methylparaben, edetate disodium, and t-butylhydroquinone.

Read Accompanying Information For The Patient

SHAPING

WOMEN’S HEALTH®

Rx only

NET WT 1 ½ OZ *42.5 G) TUBE

TEVA