Evamist (Page 5 of 8)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Evamist should not be used during pregnancy [see Contraindications (4)]. There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins as an oral contraceptive inadvertently during early pregnancy.

8.3 Nursing Mothers

Evamist should not be used during lactation. Estrogen administration to nursing women has been shown to decrease the quantity and quality of the breast milk. Detectable amounts of estrogens have been identified in the milk of women receiving estrogen-alone therapy. Caution should be exercised when Evamist is administered to a nursing woman.

8.4 Pediatric Use

Evamist is not intended in children. Clinical studies have not been conducted in the pediatric population.

8.5 Geriatric Use

There have not been sufficient numbers of geriatric women involved in studies utilizing Evamist to determine whether those over 65 years of age differ from younger subjects in their response to Evamist.

The Women’s Health Initiative Studies

In the WHI estrogen-alone substudy (daily CE [0.625 mg]-alone versus placebo), there was a higher relative risk of stroke in women greater than 65 years of age [see Clinical Studies (14.2)].

In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age [see Clinical Studies (14.2)].

The Women’s Health Initiative Memory Study

In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen-alone or estrogen plus progestin when compared to placebo [see Warnings and Precautions (5.3), and Clinical Studies (14.3)].

Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women8 [see Warnings and Precautions (5.3), and Clinical Studies (14.3)].

8.6 Renal Impairment

The effect of renal impairment on the pharmacokinetics of Evamist has not been studied.

8.7 Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of Evamist has not been studied.

10 OVERDOSAGE

Overdosage of estrogen may cause nausea and vomiting, breast tenderness, abdominal pain, drowsiness and fatigue, and withdrawal bleeding may occur in women. Treatment of overdose consists of discontinuation of Evamist together with institution of appropriate symptomatic care.

11 DESCRIPTION

Evamist (estradiol transdermal spray) is designed to deliver estradiol to the blood circulation following topical application to the skin of a rapidly drying solution from a metered-dose pump.

Evamist is a homogeneous solution of 1.7% estradiol USP (active ingredient) in alcohol USP and octisalate USP formulated to provide sustained release of the active ingredient into the systemic circulation.

Estradiol USP is a white crystalline powder, chemically described as estra-1,3,5(10)-triene-3,17β-diol. It has an empirical formula of C18 H24 O2 ·1/2 H2 O and molecular weight of 281.4. The structural formula is:

Structural Formula
(click image for full-size original)

Each metered-dose pump contains 8.1 mL and is designed to deliver 56 sprays of 90 mcL each after priming. One spray of Evamist contains 1.53 mg estradiol. The metered-dose pump should be held upright and vertical for spraying. Before a new applicator is used for the first time, the pump should be primed by spraying 3 times into the cover.

One, two or three sprays are applied daily each morning to adjacent non-overlapping 20 cm2 areas on the inner surface of the arm between the elbow and the wrist and allowed to dry.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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 in the 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 FSH, through a negative feed back mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.

12.2 Pharmacodynamics

There are no pharmacodynamic data for Evamist.

12.3 Pharmacokinetics

Absorption

In a multiple-dose study, 72 postmenopausal women were treated for 14 days with Evamist to the inner forearm. Serum concentrations of estradiol appeared to reach steady state after 7 to 8 days of application of one, two, or three 90 mcL sprays of Evamist per day (Figure 1).

Figure 1
(click image for full-size original)

Figure 1. Mean (±SD) Serum Estradiol Concentrations on Day 14 Following Topical Application for 14 Days of One, Two or Three Sprays of Evamist (Unadjusted for Baseline)

Pharmacokinetics parameters for estradiol from one, two, or three 90 mcL sprays of Evamist, as assessed on Day 14 of this study, are described in Table 2.

Table 2. Estradiol Pharmacokinetic Parameters on Day 14 (Unadjusted for Baseline)
PK Parameter Number of Daily Sprays of Evamist
1 Spray (N = 24) 2 Spray (N = 23) 3 Spray (N = 24)
1 Values expressed are arithmetic means (%CV)2 Values expressed are medians (minimum-maximum)

Cmax (pg/mL)1 Cmin (pg/mL)1 Cavg (pg/mL)1 AUC0-24 (pg*hr/mL)1 Tmax (hours)2

36.4 (62) 11.3 (52) 19.6 (49) 471 (49) 20 (0-24)

57.4 (94) 18.1 (51) 30.7 (43) 736 (43) 18 (0-24)

54.1 (50) 19.6 (27) 30.9 (30) 742 (30) 20 (0-24)

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 blood largely bound to 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 a 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.

Excretion

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

Use in Specific Populations

No pharmacokinetic studies were conducted with Evamist in specific populations, including women with renal or hepatic impairment.

Potential for Estradiol Transfer

The effect of estradiol transfer was evaluated in 20 healthy postmenopausal women who applied three 90-mcL sprays of Evamist to the inner forearm once daily. One hour after applying Evamist, subjects held the dosed forearm against the inner forearm of a non-dosed (recipient) male subject for one 5-minute period of continual contact. A 4% increase in serum estradiol exposure was observed in persons who came in contact with the application site. The possibility of unintentional secondary exposure to Evamist should be brought to the attention of physicians and Evamist users.

All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.

This site is provided for educational and informational purposes only, in accordance with our Terms of Use, and is not intended as a substitute for the advice of a medical doctor, nurse, nurse practitioner or other qualified health professional.

Privacy Policy | Copyright © 2021. All Rights Reserved.