Estradiol and Norethindrone Acetate 1 mg; .5 mg Tablet, 168-count — NDC 50742-657-68 (Billing 50742-0657-68)

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. Progestin compounds enhance cellular differentiation and generally oppose the actions of estrogens by decreasing estrogen receptor levels, increasing local metabolism of estrogens to less active metabolites, or inducing gene products that blunt cellular responses to estrogen. Progestins exert their effects in target cells by binding to specific progesterone receptors that interact with progesterone response elements in target genes.

Progesterone receptors have been identified in the female reproductive tract, breast, pituitary, hypothalamus, and central nervous system.

12.2Pharmacodynamics Generally, a serum estrogen concentration does not predict an individual woman's therapeutic response to estradiol and norethindrone acetate tablets 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 Estradiol Estradiol is absorbed through the gastrointestinal tract. Following oral administration of estradiol and norethindrone acetate tablets, peak plasma estradiol concentrations are reached within 5 to 8 hours. The oral bioavailability of estradiol following administration of estradiol and norethindrone acetate tablets 1 mg/0.5 mg when compared to a combination oral solution is 53%.

Administration of estradiol and norethindrone acetate tablets 1 mg/0.5 mg with food did not modify the bioavailability of estradiol. Norethindrone Acetate After oral administration, norethindrone acetate is absorbed and transformed to norethindrone. Norethindrone reaches a peak plasma concentration within 0.5 to 1.5 hours after the administration of estradiol and norethindrone acetate tablets.

The oral bioavailability of norethindrone following administration of estradiol and norethindrone acetate tablets 1 mg/0.5 mg when compared to a combination oral solution is 100%. Administration of estradiol and norethindrone acetate tablets 1 mg/0.5 mg with food increases norethindrone AUC 0-72 by 19% and decreases C max by 36%. The pharmacokinetic parameters of estradiol (E 2 ), estrone (E 1 ), and norethindrone (NET) following oral administration of 1 estradiol and norethindrone acetate 1 mg/0.5 mg tablet or 2 estradiol and norethindrone acetate 0.5 mg/0.1 mg tablet(s) to healthy postmenopausal women are summarized in Table 3.

Following continuous dosing with once-daily administration of estradiol and norethindrone acetate tablets 1 mg/0.5 mg, serum concentrations of estradiol, estrone, and norethindrone reached steady-state within two weeks with an accumulation of 33 to 47% above concentrat… [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. Progestin compounds enhance cellular differentiation and generally oppose the actions of estrogens by decreasing estrogen receptor levels, increasing local metabolism of estrogens to less active metabolites, or inducing gene products that blunt cellular responses to estrogen. Progestins exert their effects in target cells by binding to specific progesterone receptors that interact with progesterone response elements in target genes.

Progesterone receptors have been identified in the female reproductive tract, breast, pituitary, hypothalamus, and central nervous system.

12.2Pharmacodynamics Generally, a serum estrogen concentration does not predict an individual woman's therapeutic response to estradiol and norethindrone acetate tablets 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 Vasomotor Symptoms in Postmenopausal Women In a 12-week randomized clinical trial involving 92 subjects, estradiol and norethindrone acetate tablets 1 mg/0.5 mg was compared to 1 mg of estradiol and to placebo. The mean number and intensity of hot flushes were significantly reduced from baseline to week 4 and 12 in both the estradiol and norethindrone acetate tablets 1 mg/0.5 mg and the 1 mg estradiol group compared to placebo (see Figure 2 ). In a study conducted in Europe a total of 577 postmenopausal women were randomly assigned to either estradiol and norethindrone acetate tablets 0.5 mg/0.1 mg, 0.5 mg E2/0.25 mg NETA, or placebo for 24 weeks of treatment.

The mean number and severity of hot flushes were significantly reduced at week 4 and week 12 in the estradiol and norethindrone acetate tablets 0.5 mg/0.1 mg (see Figure 3 ) and 0.5 mg E 2 /0.25 mg NETA groups compared to placebo.

14.2Effects on the Endometrium in Postmenopausal Women Estradiol and norethindrone acetate tablets 1 mg/0.5 mg reduced the incidence of estrogen-induced endometrial hyperplasia at 1 year in a randomized, controlled clinical trial. This trial enrolled 1,176 postmenopausal women who were randomized to one of 4 arms: 1 mg estradiol unopposed (n=296), 1 mg E 2 + 0.1 mg NETA (n=294), 1 mg E 2 + 0.25 mg NETA (n=291), and estradiol and norethindrone acetate tablets 1 mg/0.5 mg (n=295). At the end of the study, endometrial biopsy results were available for 988 women.

The results of the 1 mg estradiol unopposed arm compared to estradiol and norethindrone acetate tablets 1 mg/0.5 mg are shown in Table 4 . TABLE 4 INCIDENCE OF ENDOMETRIAL HYPERPLASIA WITH UNOPPOSED ESTRADIOL AND ESTRADIOL AND NORETHINDRONE ACETATE TABLETS 1 MG/0.5 MG IN A 12-MONTH STUDY Estradiol and norethindrone acetate tablets 1 mg E 2 1 mg E 2 /0.5 mg NETA 1 mg E 2 /0.25 mg NETA 1 mg E 2 /0.1 mg NETA (n=296) (n=295) (n=291 ) (n=294 ) No. of subjects with histological evaluation at the end of the study 247 241 251 249 No.

(%) of subjects with endometrial hyperplasia at the end 36 (14.6%) 1 (0.4%) 1 (0.4%) 2 (0.8%) of the study E 2 = Estradiol NETA = Norethindrone Acetate

14.3Effects on Uterine Bleeding or Spotting in Postmenopausal Women During the initial months of therapy, irregular bleeding or spotting occurred with estradiol and norethindrone acetate tablets 1 mg/0.5 mg treatment. However, bleeding tended to decrease over time, and after 12 months of treatment with estradiol and norethindrone acetate tablets 1 mg/0.5 mg, about 86 percent of women were amenorrheic (see Figure 4 ). In the clinical trial with estradiol and norethindrone acetate tablets 0.5 mg/0.1 mg, 88 percent of women were amenorrheic after 6 months of treatment (See Figure 5 ).

14.4Effects on Bone Mineral Density in Postmenopausal Women The results of two randomized, multicenter, calcium-supplemented (500 to 1,000 mg per day), placebo-controlled, 2 year clinical trials have shown that estradiol and norethindrone acetate tablets 1 mg/0.5 mg and estradiol 0.5 mg are effective in preventing bone loss in postmenopausal women. A total of 462 postmenopausal women with intact uteri and baseline BMD values for lumbar spine within 2 standard deviations of the mean in healthy young women (T-score > - 2.0) were enrolled.

In a US trial, 327 postmenopausal women (mean time from menopause 2.5 to 3.1 years) with a mean age of 53 years were randomized to 7 groups (0.25 mg, 0.5 mg, and 1 mg of estradiol alone, 1 mg estradiol with 0.25 mg norethindrone acetate, 1 mg estradiol with 0.5 mg norethindrone acetate, and 2 mg estradiol with 1 mg norethindrone acetate, and placebo.) In a European trial (EU trial), 135 postmenopausal women (mean time from menopause 8.4 to 9.3 years) with a mean age of 58 years were randomized to 1 mg estradiol with 0.25 mg norethindrone acetate, 1 mg estradiol with 0.5 mg norethindrone acetate, and placebo.

Approximately 58 percent and 67 percent of the randomized subje… [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.