Estradiol 10 ug Insert, 8-count — NDC 0093-3223-08 (Billing 00093-3223-08)

12 CLINICAL PHARMACOLOGY

12.1Mechanism 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 feedback mechanism.

Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.

12.2Pharmacodynamics Generally, a serum concentration does not predict an individual woman’s therapeutic response to estradiol vaginal inserts nor her risk for adverse outcomes. Likewise, exposure comparisons across different estrogen products to infer efficacy or safety for the individual woman may not be valid.

12.3Pharmacokinetics Absorption Estrogen drug products are well absorbed through the skin, mucous membranes, and the gastrointestinal tract. The vaginal delivery of estrogens circumvents first-pass metabolism. In a single-center, randomized, open-label, multiple-dose study conducted in 29 patients, estradiol vaginal inserts 10 mcg demonstrated a mean estradiol (E2) C ave at Day 83 of 5.5 pg/mL after 12 weeks of treatment (see Table 2).

Table 2: Arithmetic Means of Estradiol (E2), Estrone (E1), and Estrone Sulfate (E1S) PK Parameters Following Multiple Doses a of Estradiol 10 mcg Uncorrected for baseline, N=29 E2 E1 E1S AUC 0-24 C ave (0-24) %CV b AUC 0-24 C ave (0-24) %CV b AUC 0-24 C ave (0-24) %CV b (h.pg/mL) (pg/mL) (h.pg/mL) (pg/mL) (h.pg/mL) (pg/mL) Day 1 242.08 10.09 33.02 485.21 20.22 44.86 5158.32 214.93

53.57Day 176.49 7.35 43.69 496.14 20.67 30.88 6323.41 263.48 50.07 14 Day 132.04 5.50 59.69 411.08 17.13 39.58 3804.65 158.53 49.76 83 a Patients received vaginal inserts as a once daily intravaginal treatment for the first 2 weeks and a twice weekly intravaginal maintenance for the following 10 weeks. b CV: Coefficient of Variance for both AUC 0-24 and C ave(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 the 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 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 portion 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 uri… [Excerpted — this section continues on DailyMed.]

12.1Mechanism 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 feedback mechanism.

Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.

12.3Pharmacokinetics Absorption Estrogen drug products are well absorbed through the skin, mucous membranes, and the gastrointestinal tract. The vaginal delivery of estrogens circumvents first-pass metabolism. In a single-center, randomized, open-label, multiple-dose study conducted in 29 patients, estradiol vaginal inserts 10 mcg demonstrated a mean estradiol (E2) C ave at Day 83 of 5.5 pg/mL after 12 weeks of treatment (see Table 2).

Table 2: Arithmetic Means of Estradiol (E2), Estrone (E1), and Estrone Sulfate (E1S) PK Parameters Following Multiple Doses a of Estradiol 10 mcg Uncorrected for baseline, N=29 E2 E1 E1S AUC 0-24 C ave (0-24) %CV b AUC 0-24 C ave (0-24) %CV b AUC 0-24 C ave (0-24) %CV b (h.pg/mL) (pg/mL) (h.pg/mL) (pg/mL) (h.pg/mL) (pg/mL) Day 1 242.08 10.09 33.02 485.21 20.22 44.86 5158.32 214.93

53.57Day 176.49 7.35 43.69 496.14 20.67 30.88 6323.41 263.48 50.07 14 Day 132.04 5.50 59.69 411.08 17.13 39.58 3804.65 158.53 49.76 83 a Patients received vaginal inserts as a once daily intravaginal treatment for the first 2 weeks and a twice weekly intravaginal maintenance for the following 10 weeks. b CV: Coefficient of Variance for both AUC 0-24 and C ave(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 the 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 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 portion 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.

12.2Pharmacodynamics Generally, a serum concentration does not predict an individual woman’s therapeutic response to estradiol vaginal inserts nor her risk for adverse outcomes. Likewise, exposure comparisons across different estrogen products to infer efficacy or safety for the individual woman may not be valid.

14 CLINICAL STUDIES

14.1Effects on Atrophic Vaginitis in Postmenopausal Women A 12-month double-blind, randomized, parallel group, placebo-controlled multicenter study was conducted in the U.S. and Canada to evaluate the efficacy and safety of estradiol 10 mcg in the treatment of atrophic vaginitis in 309 postmenopausal women between 46 and 81 years of age (mean 57.6 years of age) who at baseline identified their most bothersome symptom of atrophic vaginitis from among six symptoms (vaginal dryness, vaginal and/or vulvar irritation/itching, vaginal soreness, dysuria, dyspareunia and vaginal bleeding associated with intercourse).

Women inserted one insert intravaginally each day for 14 days, then one insert twice weekly for the remaining 50 weeks. The majority (92.9 percent) of the women were Caucasian (n=287), 3.2 percent were Black (n=10), 1.6 percent were Asian (n=5) and 2.2 percent were Other (n=7). All participants were assessed for improvement in the mean change from baseline to Week 12 for co-primary efficacy variables of: a composite of most bothersome symptoms of atrophic vaginitis; percentage of vaginal superficial cells and percentage of vaginal parabasal cells on a vaginal smear; and vaginal pH.

Relief of Vaginal Symptoms Estradiol 10 mcg was statistically superior to placebo in reducing the severity of a composite score of most bothersome symptoms associated with atrophic vaginitis at Week 12 (see Table 3). Table 3: Mean Change from Baseline to Week 12 in a Composite Score of Most Bothersome Symptoms Compared to Placebo – ITT Population a Placebo Estradiol 10 mcg ITT Population a N 93 190 Baseline mean composite score 2.29

2.35Change from baseline at Week 12 (LOCF) -0.84 -1.20 p-value versus Placebo --- 0.002 a All randomized subjects who received at least one dose of study drug and had at least one post-baseline evaluation. Also demonstrated for estradiol 10 mcg compared to placebo was a statistically significant increase in the percentage of superficial cells at Week 12 (13.2 percent compared to 3.8 percent for matching placebo, p<0.001), a statistically significant decrease in parabasal cells at Week 12 (-37.0 percent compared to -9.3 percent for matching placebo, p<0.001), and a statistically significant mean reduction between baseline and Week 12 in vaginal pH score (-1.3 compared to -0.4 for matching placebo, p<0.001).

Endometrial safety was assessed by endometrial biopsy at the screening and final study visit. Of the 172 women in the estradiol 10 mcg group who had a biopsy performed at end of study, 92 women had endometrial tissue that was atrophic or inactive and 73 women had no tissue or tissue insufficient for diagnosis. There was one case of adenocarcinoma grade 2 and one case of complex hyperplasia without atypia.

Three women exhibited polyps (two atrophic polyps and one adenomyomatus type polyp) and two others had adenomyosis and an atypical epithelial proliferation. Endometrial safety of estradiol 10 mcg was additionally evaluated in a second, 12 month, open-label, multicenter safety study. Of the 297 women who had a biopsy performed at end of study, 183 women had endometrial tissue that was atrophic or inactive and 111 women had no tissue or tissue insufficient for diagnosis.

There was one case of complex hyperplasia without atypia. Two women exhibited polyps.

14.2Women’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 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… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, 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.