Bijuva estradiol and progesterone 1 mg; 100 mg Capsule, 30-count — NDC 68308-750-30 (Billing 68308-0750-30)

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. Endogenous progesterone is secreted by the ovary, placenta, and adrenal gland. In the presence of adequate estrogen, progesterone transforms a proliferative endometrium into a secretory endometrium.

Progesterone enhances cellular differentiation and generally opposes 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. Progesterone exerts its 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 BIJUVA 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 The oral absorption of both estradiol and progesterone is subject to first-pass metabolism. After multiple doses of BIJUVA (estradiol and progesterone) capsules administered with food, the t max (the time at which the maximum concentration is attained) for estradiol is approximately 3 to 6 hours and approximately 3 hours for progesterone (Figure 1, Figure 2, and Table 2, below). Steady state for both estradiol and progesterone components of BIJUVA, as well as estradiol's main metabolite, estrone, is achieved within seven days.

A dose-dependent increase in AUC 0-t and C max of estradiol and a slightly more than proportionality increase in AUC 0-t and C max of estrone were observed when the dose of estradiol was increased from 0.5 mg/day to 1 mg/day (Table 2). Figure 1: Mean Steady-State Serum Estradiol Concentrations Following Daily Oral Administration of 0.5 mg Estradiol/100 mg Progesterone or 1 mg Estradiol/100 mg Progesterone with Food (Baseline Adjusted, at Day 7) Figure 2: Mean Steady-State Serum Progesterone Concentrations Following Daily Oral Administration of 0.5 mg Estradiol/100 mg Progesterone or 1 mg Estradiol/100 mg Progesterone with Food (Baseline Adjusted, at Day 7) Table 2: Mean (SD) Steady-State Pharmacokinetic Parameters after Administration of Capsules Containing 0.5 mg Estradiol/100 mg Progesterone or 1 mg Estradiol/100 mg Progesterone with Food in Healthy Postmenopausal Women (Baseline Adjusted, at Day 7) Dosage Strength (estradiol/progesterone) BIJUVA 0.5 mg/100 mg Mean (SD) BIJUVA 1 mg/100… [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. Endogenous progesterone is secreted by the ovary, placenta, and adrenal gland. In the presence of adequate estrogen, progesterone transforms a proliferative endometrium into a secretory endometrium.

Progesterone enhances cellular differentiation and generally opposes 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. Progesterone exerts its 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.

12.3Pharmacokinetics Absorption The oral absorption of both estradiol and progesterone is subject to first-pass metabolism. After multiple doses of BIJUVA (estradiol and progesterone) capsules administered with food, the t max (the time at which the maximum concentration is attained) for estradiol is approximately 3 to 6 hours and approximately 3 hours for progesterone (Figure 1, Figure 2, and Table 2, below). Steady state for both estradiol and progesterone components of BIJUVA, as well as estradiol's main metabolite, estrone, is achieved within seven days.

A dose-dependent increase in AUC 0-t and C max of estradiol and a slightly more than proportionality increase in AUC 0-t and C max of estrone were observed when the dose of estradiol was increased from 0.5 mg/day to 1 mg/day (Table 2). Figure 1: Mean Steady-State Serum Estradiol Concentrations Following Daily Oral Administration of 0.5 mg Estradiol/100 mg Progesterone or 1 mg Estradiol/100 mg Progesterone with Food (Baseline Adjusted, at Day 7) Figure 2: Mean Steady-State Serum Progesterone Concentrations Following Daily Oral Administration of 0.5 mg Estradiol/100 mg Progesterone or 1 mg Estradiol/100 mg Progesterone with Food (Baseline Adjusted, at Day 7) Table 2: Mean (SD) Steady-State Pharmacokinetic Parameters after Administration of Capsules Containing 0.5 mg Estradiol/100 mg Progesterone or 1 mg Estradiol/100 mg Progesterone with Food in Healthy Postmenopausal Women (Baseline Adjusted, at Day 7) Dosage Strength (estradiol/progesterone) BIJUVA 0.5 mg/100 mg Mean (SD) BIJUVA 1 mg/100 mg Mean (SD) Abbreviations: AUC 0-τ = area under the concentration vs time curve within the dosing interval at steady-state, C avg = average concentration at steady-state, C max = maximum concentration, SD = standard deviation, t max = time to maximum concentration, t ½ = half-life Estradiol N N AUC 0-τ (pg∙h/mL) 17 386.8 (356.6) 20 772.4 (384.1) C max (pg/mL) 17 23.95 (16.86) 20 42.27 (18.60) C avg (pg/mL) 17 16.64 (14.50) 19 33.99 (14.53) t max (h) Median and range 17 6.00 (0.00 – 12.00) 19 3.00 (0.67 – 18.03) t ½ (h) Effective t½.

Calculated as 24∙ln(2)/ ln (accumulation ratio/(accumulation ratio-1)) for subjects with accumulation ratio >1. 11 28.01 (9.99) 19 26.47 (14.61) Estrone AUC 0-τ (pg∙h/mL) 17 1981 (976.0) 20 4594 (2138) C max (pg/mL) 17 108.0 (48.58) 20 238.5 (100.4) C avg (pg/mL) 17 82.81 (40.80) 20 192.1 (89.43) t max (h) 17 11.98 (2.00 – 18.00) 20 5.00 (1.50 – 12.00) t ½ (h) 17 20.46 (5.61) 19 22.37 (7.64) Progesterone AUC 0-τ (ng∙h/mL) 17 12.19 (11.01) 20 18.05 (15.58) C max (ng/mL) 17 4.40 (5.72) 20 11.31 (23.10) C avg (ng/mL) 17 0.55 (0.45) 20 0.76 (0.65) t max (h) 17 2.00 (0.67 – 8.00) 20 2.51 (0.67 – 6.00) t ½ (h) 13 8.77 (2.78) 18 9.98 (2.57) Food Effect Concomitant food ingestion increased the AUC and C max of the progesterone component of BIJUVA relative to a fasting state when administered at a dose of 100 mg.

In a study where BIJUVA was administered to postmenopausal women at a dose of 1 mg estradiol/100 mg progesterone within 30 minutes of starting a high-fat meal, the C max and AUC of progesterone were 162% and 79% higher, respectively, relative to the fasting state and the median tmax of progesterone was delayed from 2 hours to 3 hours. Concomitant food ingestion had no effect on the AUC of the estradiol component of BIJUVA but decreased C max by approximately 54% and delayed median tmax from 1 hour to 12 hours. Distribution Estradiol 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 circulating in the blood largely are bound to SHBG and albumin. Progesterone Progesterone is approximately 96% to 99% bound to serum proteins, primarily to serum albumin (50% to 54%) and transcortin (43% to 48%).

Elimination Following repeat dosing with BIJUVA (estradiol and progesterone) capsules, 0.5 mg/100 mg… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Generally, a serum estrogen concentration does not predict an individual woman's therapeutic response to BIJUVA 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 The effectiveness and safety of BIJUVA (estradiol and progesterone) capsules, 0.5 mg/100 mg and 1 mg/100 mg, on moderate to severe vasomotor symptoms (hot flushes) due to menopause were examined in a 12-week randomized, double-blind, placebo-controlled substudy of a single 52-week safety study. A total of 726 postmenopausal women were randomized to multiple dose combinations of estradiol and progesterone, and placebo; these women were 40 to 65 years of age (mean 54.6 years) and had at least 50 moderate to severe vasomotor symptoms per week at baseline.

The mean number of years since last menstrual period was 5.9 years, with all women undergoing natural menopause. The primary efficacy population consisted of women who self- identified their race as: White (67%), Black/African American (31%), and "Other" (2.1%). In the substudy evaluating effects on moderate to severe vasomotor symptoms, a total of 149 women received BIJUVA (estradiol and progesterone) capsules, 0.5 mg/100 mg, 141 women received BIJUVA (estradiol and progesterone) capsules, 1 mg/100 mg, and 135 women received placebo.

The evaluated co-primary efficacy endpoints included: 1) mean weekly reduction in frequency of moderate to severe vasomotor symptoms with BIJUVA compared to placebo at Weeks 4 and 12 and 2) mean weekly reduction in severity of moderate to severe vasomotor symptoms with BIJUVA compared to placebo at Weeks 4 and 12. Overall, BIJUVA (estradiol and progesterone) capsules, 0.5 mg/100 mg and 1 mg/100 mg, statistically significantly reduced both the frequency and severity of moderate to severe vasomotor symptoms from baseline compared with placebo at Weeks 4 and 12.

The change from baseline in the frequency and severity of vasomotor symptoms observed and the difference from placebo are shown in Table 3 and Table 4, respectively. Table 3: Mean Weekly Change from Baseline and Difference from Placebo in the Frequency of Moderate to Severe Vasomotor Symptoms BIJUVA 0.5 mg/100 mg (N=149) BIJUVA 1 mg/100 mg (N=141) Placebo (N=135) Definitions: SD – standard deviation; SE – standard error Week 4 n=144 n=134 n=126 Baseline 72.3 (28.06) 72.1 (27.80) 72.3 (23.44) Mean (SD) change from baseline -35.1 (29.14) -40.6 (30.59) -26.4 (27.05) Difference from placebo Least square mean difference (SE) from placebo -8.07 (3.25) -12.81 (3.30) --- P-value P-value of least square mean difference from placebo using mixed model repeated measures analyses 0.013 < 0.001 --- Week 12 n=129 n=124 n=115 Baseline 72.8 (28.96) 72.2 (25.04) 72.2 (22.66) Mean (SD) change from baseline -53.7 (31.93) -55.1 (31.36) -40.2 (29.79) Difference from placebo -15.07 (3.39) -16.58 (3.44) --- P-value <0.001 <0.001 --- Table 4: Mean Weekly Change from Baseline and Difference from Placebo in the Severity of Moderate to Severe Vasomotor Symptoms BIJUVA 0.5 mg/100 mg (N=149) BIJUVA 1 mg/100 mg (N=141) Placebo (N=135) Definitions: SD – standard deviation; SE – standard error Week 4 n=144 n=134 n=126 Baseline 2.51 (0.248) 2.54 (0.325) 2.52 (0.249) Mean (SD) change from baseline -0.51 (0.563) -0.48 (0.547) -0.34 (0.386) Difference from placebo Least square mean difference (SE) from placebo -0.17 (0.060) -0.13 (0.061) --- P-value P-value of least square mean difference from placebo using mixed model repeated measures analyses 0.005 0.031 --- Week 12 n=129 n=124 n=115 Baseline 2.51 (0.248) 2.55 (0.235) 2.52 (0.245) Mean (SD) change from baseline -0.90 (0.783) -1.12 (0.963) -0.56 (0.603) Difference from placebo -0.39 (0.099) -0.57 (0.100) --- P-value <0.001 <0.001 --- Adjusting for potential confounders such as BMI, smoking, alcohol use, and baseline estradiol level, treatment with BIJUVA (estradiol and progesterone) capsules, 0.5 mg/100 mg or 1 mg/100 mg, did not demonstrate statistically significant reductions in both frequency and severity of moderate to severe vasomotor symptoms by Week 12 in women who self-identified as Black/Afr… [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. Progesterone has not been tested for carcinogenicity in animals by the oral route of administration. When implanted into female mice, progesterone produced mammary carcinomas, ovarian granulosa cell tumors, and endometrial stromal sarcomas.

In dogs, long-term intramuscular injections produced nodular hyperplasia and benign and malignant mammary tumors. Subcutaneous or intramuscular injections of progesterone decreased the latency period and increased the incidence of mammary tumors in rats previously treated with a chemical carcinogen. Progesterone did not show evidence of genotoxicity in in vitro studies for point mutations or for chromosomal damage.

In vivo studies for chromosome damage have yielded positive results in mice at oral doses of 1000 mg/kg and 2000 mg/kg. Exogenously administered progesterone has been shown to inhibit ovulation in a number of species and it is expected that high doses given for an extended duration would impair fertility until the cessation of treatment.