### A. Absorption

Estradiol is well absorbed through the gastrointestinal tract. Following oral administration of Estradiol/Norethindrone Acetate tablets, peak plasma estradiol concentrations are reached slowly within 5-8 hours. When given orally, estradiol is extensively metabolized (first-pass effect) to estrone sulfate, with smaller amounts of other conjugated and unconjugated estrogens. After oral administration, norethindrone acetate is rapidly absorbed and transformed to norethindrone. It undergoes first-pass metabolism in the liver and other enteric organs, and reaches a peak plasma concentration within 0.5 - 1.5 hours after the administration of Estradiol/Norethindrone Acetate tablets. The oral bioavailability of estradiol and norethindrone following administration of Estradiol/Norethindrone Acetate Tablets 1.0 mg/0.5 mg when compared to a combination oral solution is 53% and 100%, respectively. Administration of Estradiol/Norethindrone Acetate Tablets 1.0 mg/0.5 mg with food did not modify the bioavailability of estradiol, although increases in AUC0-72 of 19% and decreases in Cmax of 36% for norethindrone were seen. The pharmacokinetic parameters of estradiol (E2), estrone (E1), and norethindrone (NET) following oral administration of 1 Estradiol/Norethindrone Acetate Tablets 1.0 mg/0.5 mg or 2 Estradiol/Norethindrone Acetate 0.5 mg/0.1 mg tablet(s) to healthy postmenopausal women are summarized in Table 1.

Following continuous dosing with once-daily administration of Estradiol/Norethindrone Acetate Tablets 1.0 mg/0.5 mg, serum levels of estradiol, estrone, and norethindrone reached steady-state within two weeks with an accumulation of 33-47% above levels following single dose administration. Unadjusted circulating levels of E2, E1, and NET during Estradiol/Norethindrone Acetate Tablets 1.0 mg/0.5 mg treatment at steady state (dosing at time 0) are provided in Figures 1a and 1b.

### 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. Estradiol circulates in the blood bound to sex-hormone-binding globulin (SHBG) (37%) and to albumin (61%), while only approximately 1-2% is unbound. Norethindrone also binds to a similar extent to SHBG (36%) and to albumin (61%).

### C. Metabolism

#### Estradiol

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.

#### Norethindrone Acetate

The most important metabolites of norethindrone are isomers of 5α-dihydro-norethindrone and tetrahydro-norethindrone, which are excreted mainly in the urine as sulfate or glucuronide conjugates.

### D. Excretion

Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. The half-life of estradiol following single dose administration of Estradiol/Norethindrone Acetate Tablets 1.0 mg/0.5 mg is 12-14 hours. The terminal half-life of norethindrone is about 8-11 hours.

### E. Special Populations

No pharmacokinetic studies were conducted in special populations, including patients with renal or hepatic impairment.

### F. Drug Interactions

Coadministration of estradiol with norethindrone acetate did not elicit any apparent influence on the pharmacokinetics of norethindrone. Similarly, no relevant interaction of norethindrone on the pharmacokinetics of estradiol was found within the NETA dose range investigated in a single dose study.

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.