Estradiol and Progesterone

INDICATIONS AND USAGE BIJUVA is a combination of an estrogen and progesterone indicated in a woman with a uterus for the treatment of moderate to severe vasomotor symptoms due to menopause. ( 1.1 ) 1.1 Treatment of Moderate to Severe Vasomotor Symptoms Due to Menopause

DOSAGE AND ADMINISTRATION The timing of BIJUVA initiation can affect the overall risk-benefit profile. Consider initiating BIJUVA in women < 60 years old or < 10 years from onset of menopause [see Warnings and Precautions (5) , Adverse Reactions (6.1) , Use in Specific Populations (8.5) and Clinical Studies (14) ] . Take a single BIJUVA capsule orally each evening with food. Generally, start therapy with BIJUVA 0.5 mg estradiol/100 mg progesterone dosage strength. Make dosage adjustment based on the clinical response. Attempt to taper or discontinue BIJUVA at 3 to 6 month intervals. One capsule orally each evening with food. (2.1)

WARNINGS AND PRECAUTIONS Cardiovascular Disorders: Increased risks of PE, DVT, stroke, and MI are reported with estrogen plus progestin therapy. Manage risk factors for arterial vascular disease and/or venous thromboembolisum. Discontinue if an arterial or venous thrombotic or thromboembolic event occurs. ( 5.1 ) Malignant Neoplasms: Assess risk and provide surveillance measures for breast cancer, such as breast examinations and mammography. ( 5.2 ) Estrogens increase the risk of gallbladder disease. ( 5.3 ) Discontinue estrogen if severe hypercalcemia, loss of vision, severe hypertriglyceridemia, or cholestatic jaundice occurs. ( 5.4 , 5.5 , 5.7 , 5.8 ) Monitor thyroid function in women on thyroid replacement hormone therapy. ( 5.9 , 5.15 ) 5.1 Cardiovascular Disorders BIJUVA is contraindicated in females with active DVT, PE, arterial thromboembolic disease (e.g., stroke, MI) disease, or a history of these conditions [see Contraindications (4) ] . Immediately discontinue BIJUVA if a PE, DVT, stroke, or MI occurs or is suspected. If feasible, discontinue BIJUVA at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization. The safety and efficacy of BIJUVA for the prevention of cardiovascular disorders has not been established [see Clinical Studies (14.4) ] . The Women's Health Initiative (WHI) estrogen plus progestin trial reported increased risks of PE, DVT, stroke, and MI in postmenopausal women (50 to 79 years of age, average age 63.4 years) during the 5.6 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg] combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo. Analyses were also conducted in women aged 50-59 years, a group of women more likely to present with new onset of moderate to severe VMS compared to women in other age groups in the trial [see Clinical Studies (14.4) ] . Only daily oral 0.625 mg CE and 2.5 mg MPA were studied in the estrogen plus progestin trial of the WHI. Therefore, the relevance of the WHI findings regarding adverse cardiovascular events to lower CE plus other MPA doses, other routes of administration, or other estrogen plus progestogen products is not known. Without such data, it is not possible to definitively exclude these risks or determine the extent of these risks for other products. Venous Thromboembolism In women aged 50-59 years, the WHI estrogen plus progestin trial reported a relative risk for PE of 2.05 (95% confidence interval [CI], 0.89-4.71) for CE/MPA compared to placebo, with a risk difference of 6 per 10,000 women-years (WYs; 11 versus 5). The relative risk for DVT was 3.01 (95% CI, 1.36-6.66) in those receiving CE/MPA compared to placebo, with a risk difference of 10 per 10,000 WYs (15 versus 5) [see Clinical Studies (14.4) ] . In the overall study population of women aged 50-79 years (average 63.4 years), the trial reported a relative risk for PE of 1.98 (95% CI, 1.36-2.87) for CE/MPA compared to placebo, with a risk difference of 9 per 10,000 WYs (18 versus 9). The relative risk for DVT was 1.87 (95% CI, 1.37-2.54) for CE/MPA compared to placebo, with a risk difference of 12 per 10,000 WYs (25 versus 14) [see Clinical Studies (14.4) ] . Stroke In women aged 50-59 years, the WHI estrogen plus progestin trial reported a relative risk for stroke of 1.51 (95% CI, 0.81-2.82) for CE/MPA compared to placebo, with a risk difference of 5 per 10,000 WYs (15 versus 10) [see Clinical Studies (14.4) ] . In the overall study population of women aged 50-79 years (average 63.4 years), the WHI estrogen plus progestin trial reported relative risk for stroke of 1.37 (95% CI, 1.07-1.76) for CE/MPA compared to placebo, with a risk difference of 9 per 10,000 WYs (33 versus 24) [see Clinical Studies (14.4) ] . Coronary Heart Disease In women 50 to 59 years of age, the WHI estrogen plus progestin trial reported a relative risk for coronary heart disease (CHD) events (defined as nonfatal MI, silent MI, or CHD death) of 1.34 (95% CI, 0.82-2.19) for CE/MPA compared placebo, with a risk difference of 5 per 10,000 WYs (23 versus 17). In the overall study population of women aged 50-79 years (average 63.4 years), the trial reported a relative risk of CHD of 1.18 (95% CI, 0.95-1.45) for CE/MPA compared to placebo, with a risk difference of 6 per 10,000 WYs (41 versus 35) [see Clinical Studies (14.4) ] . In the Heart and Estrogen/Progestin Replacement Study (HERS) and open label extension (HERS II), postmenopausal women with documented heart disease (n=2,763, average age 66.7 years) received daily CE (0.625 mg) plus MPA or placebo. In Year 1, there were more CHD events in the CE plus MPA-treated group than placebo; however, rates of CHD events were comparable among both groups for the remainder of the duration of the studies (average total follow-up of 6.8 years). 2, 3 5.2 Malignant Neoplasms Breast Cancer BIJUVA is contraindicated in women with breast cancer, a history of breast cancer, or estrogen-dependent neoplasia [see Contraindications (4) ]. Discontinue BIJUVA if a hormone-sensitive malignancy is diagnosed.The use of estrogen plus progestin therapy has been reported to result in an increase in abnormal mammograms requiring further evaluation. Only daily oral CE 0.625 mg and MPA 2.5 mg were studied in the estrogen plus progestin trial of the WHI. Therefore, the relevance of the WHI findings regarding breast cancer to lower CE plus other MPA doses, other routes of administration, or other estrogen plus progestogen products is not known. Without such data, it is not possible to definitively exclude these risks or determine the extent of these risks for other products. In women 50-59 years of age, the WHI estrogen plus progestin trial reported a relative risk for invasive breast cancer of 1.21 (95% CI, 0.81-1.80) for CE/MPA compared to placebo, with a risk difference of 6 per 10,000 WYs (33 versus 27). In this age group, among those who reported no prior use of hormone therapy, the relative risk was 1.06 (95% CI, 0.67-1.67) for CE/MPA compared to placebo, with a risk difference of 2 per 10,000 WYs (33 versus 31) [see Clinical Studies (14.4) ] . In the overall study population of women aged 50-79 years (average 63.4 years), the WHI estrogen plus progestin trial reported a relative risk for invasive breast cancer of 1.24 (95% CI, 1.01-1.53) for CE/MPA compared to placebo, with a risk difference of 9 per 10,000 WYs (43 versus 35). In the overall study population, among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.85 (95% CI, 1.18-2.90) for CE/MPA compared to placebo, with a risk difference of 21 per 10,000 WYs (46 versus 25). Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09 (95% CI, 0.86-1.39), with a risk difference of 4 per 10,000 WYs (40 versus 36). Invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at a more advanced stage in the CE/MPA group compared with the placebo group. Metastatic disease was rare, with no apparent difference between the two groups. Other prognostic factors, such as histologic subtype, grade and hormone receptor status did not differ between the groups. Extension of the WHI trial also demonstrated increased breast cancer risk associated with estrogen plus progestin therapy [see Clinical Studies (14.4) ] . 1 Consistent with the WHI trial, observational studies have also reported an increased risk of breast cancer with estrogen plus progestin therapy. A large meta-analysis including 24 prospective studies of postmenopausal women comparing current use of estrogen plus progestin products with use duration of 5 to 14 years (average of 9 years) versus never use reported a relative risk for breast cancer of 2.08 (95% CI, 2.02-2.15). These studies have not generally found the risk of breast cancer to be different among the var

CONTRAINDICATIONS BIJUVA is contraindicated in women with any of the following conditions: Abnormal genital bleeding of unknown etiology [see Warnings and Precautions (5.2) ]. Breast cancer or a history of breast cancer [see Warnings and Precautions (5.2) ]. Estrogen-dependent neoplasia [see Warnings and Precautions (5.2) ]. Active deep vein thrombosis (DVT), pulmonary embolisum (PE), or history of these conditions [see Warnings and Precautions (5.1) ]. Active arterial thromboembolic disease (for example, stroke, myocardial infarction (MI)), or a history of these conditions [see Warnings and Precautions (5.1) ]. Known anaphylactic reaction, angioedema, or hypersensitivity to BIJUVA. Hepatic impairment or disease [see Warnings and Precautions (5.8) ] Known thrombophilic disorders, such as protein C, protein S, or antithrombin deficiency Undiagnosed abnormal genital bleeding ( 4 , 5.2 ) Breast cancer or a history of breast cancer ( 4 , 5.2 ) Estrogen-dependent neoplasia ( 4 , 5.2 ) Active DVT, PE, or history of these conditions ( 4 , 5.1 ) Active arterial thromboembolic disease (for example, stroke and MI), or a history of these conditions ( 4 , 5.1 ) Known anaphylactic reaction, angioedema, or hypersensitivity to BIJUVA ( 4 , 5.15 ) Hepatic impairment or disease ( 4 , 5.8 ) Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders ( 4 )

DRUG INTERACTIONS In-vitro and in-vivo studies have shown that estrogens and progestins are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen and progestin drug metabolism. Inducers of CYP3A4 such as St. John's wort (Hypericum perforatum) preparations, phenobarbital, carbamazepine, and rifampin may reduce plasma concentrations of estrogens and progestins, 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 the estrogen or the progestin or both and may result in adverse reactions. Inducers and inhibitors of CYP3A4 may affect estrogen drug metabolism and decrease or increase the estrogen plasma concentration. ( 7 )

ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: Cardiovascular Disorders [see Warnings and Precautions (5.1) ]. Malignant Neoplasms [see Warnings and Precautions (5.2) ]. The most common adverse reactions with BIJUVA (incidence ≥ 3% of women and greater than placebo) are: breast tenderness, headache, nausea, vaginal bleeding, vaginal discharge and pelvic pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mayne Pharmaat 1-844-825-8500 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of estradiol and progesterone capsules was assessed in a 1-year trial that included 1,835 postmenopausal women (1,684 were treated with estradiol and progesterone capsules once daily and 151 women received placebo). Most women (~70%) in the active treatment groups were treated for ≥ 326 days. Treatment related adverse reactions with an incidence of ≥ 3% in either BIJUVA (estradiol and progesterone) capsules group and numerically greater than those reported in the placebo group are listed in Table 1. Table 1: Treatment-Emergent Adverse Reactions Reported at a Frequency of ≥ 3% and Numerically More Common in Women Receiving BIJUVA (estradiol and progesterone) 0.5 mg/100 mg and 1 mg/100 mg Preferred Term BIJUVA 0.5 mg/100 mg BIJUVA 1 mg/100 mg Placebo (N=151) (N=424) (N=415) Breast tenderness 17 (4.0) 43 (10.4) 1 (0.7) Headache 17 (4.0) 14 (3.4) 1 (0.7) Nausea 15 (3.5) 9 (2.2) 1 (0.7) Vaginal bleeding 10 (2.4) 14 (3.4) 0 Vaginal discharge 8 (1.9) 14 (3.4) 1 (0.7) Pelvic pain 12 (2.8) 13 (3.1) 0 6.2 Postmarketing Experience The following additional adverse reactions have been identified during post-approval use of BIJUVA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal disorders Abdominal pain and discomfort, abdominal distention, diarrhea, nausea, vomiting. General disorders and administration site conditions Fatigue, feeling abnormal, malaise. Investigations Weight increased. Metabolism and nutrition disorders Fluid retention. Musculoskeletal and connective tissue disorders Muscle spasms, pain in extremity. Nervous system disorders Dizziness, headache, somnolence. Psychiatric disorders Insomnia, sleep disorder. Reproductive system and breast disorders Breast pain, breast tenderness, uterine bleeding. Skin and subcutaneous tissue disorders Night sweats, pruritus. Vascular disorders Hot flush.

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 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.