Bijuva
(estradiol / progesterone)Dosage & Administration
One capsule orally each evening with food. ( 2.1)
Bijuva Prescribing Information
Estrogen Plus Progestin Therapy
Cardiovascular Disorders and Probable Dementia
The Women's Health Initiative (WHI) estrogen plus progestin substudy reported increased risks of pulmonary embolism (PE), deep vein thrombosis (DVT), stroke, and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 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[see Warnings and Precautions ( 5.1), and Clinical Studies ( 14.4)] .
The WHI Memory Study (WHIMS) estrogen plus progestin ancillary study of WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age and older during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women[see Warnings and Precautions ( 5.3), Use in Specific Populations ( 8.5), and Clinical Studies ( 14.5)] .
Do not use estrogen plus progestogen therapy for the prevention of cardiovascular disease or dementia [see Warnings and Precautions ( 5.1, 5.3), and Clinical Studies ( 14.4, 14.5)].
Breast Cancer
The WHI estrogen plus progestin substudy demonstrated an increased risk of invasive breast cancer[see Warnings and Precautions ( 5.2), and Clinical Studies ( 14.4)] .
Only daily oral 0.625 mg CE and 2.5 mg MPA were studied in the estrogen plus progestin substudy of the WHI. Therefore, the relevance of the WHI findings regarding adverse cardiovascular events, dementia and 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. Discuss with your patient the benefits and risks of estrogen plus progestogen therapy, taking into account her individual risk profile.
Prescribe estrogens with or without progestogens at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.
Estrogen-Alone Therapy
Endometrial Cancer
There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestogen to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Perform adequate diagnostic measures, including directed or random endometrial sampling when indicated, to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding[see Warnings and Precautions ( 5.2)].
Cardiovascular Disorders and Probable Dementia
The WHI estrogen-alone substudy reported increased risks of stroke and DVT in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral CE (0.625 mg)-alone, relative to placebo[see Warnings and Precautions ( 5.1), and Clinical Studies ( 14.4)] .
The WHIMS estrogen-alone ancillary study of WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age and older during 5.2 years of treatment with daily CE (0.625 mg)-alone, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [seeWarnings and Precautions ( 5.3), Use in Specific Populations ( 8.5), and Clinical Studies ( 14.5) ].
Do not use estrogen-alone therapy for the prevention of cardiovascular disease or dementia [see Warnings and Precautions ( 5.1, 5.3), and Clinical Studies ( 14.4, 14.5)] .
Only daily oral 0.625 mg CE was studied in the estrogen-alone substudy of the WHI. Therefore, the relevance of the WHI findings regarding adverse cardiovascular events and dementia to lower CE doses, other routes of administration, or other estrogen-alone 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. Discuss with your patient the benefits and risks of estrogen-alone therapy, taking into account her individual risk profile.
Prescribe estrogens with or without progestogens at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.
Treatment of Moderate to Severe Vasomotor Symptoms Due to Menopause
Use estrogen, alone or in combination with a progestogen, at the lowest effective dose and the shortest duration consistent with treatment goals and risks for the individual woman. Re-evaluate postmenopausal women periodically as clinically appropriate to determine whether treatment is still necessary.
Treatment of Moderate to Severe Vasomotor Symptoms Due to Menopause
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.
BIJUVA capsules, 0.5 mg/100 mg, are oval shaped, opaque, light pink on one side, dark pink on the other side, and printed with "5C1" in white ink.
BIJUVA capsules, 1 mg/100 mg, are oval shaped, opaque, light pink on one side, dark pink on the other side, and printed with "1C1" in white ink.
Pregnancy
Risk Summary
BIJUVA is not indicated for use in pregnancy. There are no data with the use of BIJUVA in pregnant women, however, epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to combined hormonal contraceptives (estrogens and progestins) before conception or during early pregnancy.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Lactation
Risk Summary
Estrogens plus progestogens are present in human milk and can reduce milk production in breast-feeding females. This reduction can occur at any time but is less likely to occur once breast-feeding is well-established. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for BIJUVA and any potential adverse effects on the breastfed child from BIJUVA or from the underlying maternal condition.
Pediatric Use
BIJUVA is not indicated for use in pediatric patients. Clinical studies have not been conducted in the pediatric population.
Geriatric Use
There have not been sufficient numbers of geriatric women involved in clinical studies utilizing BIJUVA to determine whether those over 65 years of age differ from younger women in their response to BIJUVA.
The Women's Health Initiative Studies
In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age [see Clinical Studies ( 14.4)] .
In the WHI estrogen-alone substudy (daily CE [0.625 mg]-alone versus placebo), there was a higher relative risk of stroke in women greater than 65 years of age [see Clinical Studies ( 14.4)] .
The Women's Health Initiative Memory Study
In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen plus progestin or estrogen-alone when compared to placebo [see Warnings and Precautions ( 5.3), and Clinical Studies ( 14.5)] .
Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women 8[see Warnings and Precautions ( 5.3), and Clinical Studies ( 14.5)] .
BIJUVA is contraindicated in women with any of the following conditions:
- Undiagnosed abnormal genital bleeding [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 DVT, PE, or history of these conditions [see Warnings and Precautions ( 5.1)] .
- Active arterial thromboembolic disease (for example, stroke, 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.
- Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders.
Cardiovascular Disorders
Increased risks of PE, DVT, stroke, and MI are reported with estrogen plus progestin therapy. Increased risks of stroke and DVT are reported with estrogen-alone therapy. Immediately discontinue estrogen with or without progestogen therapy if any of these occur or are suspected.
Manage appropriately any risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (for example, personal history or family history of VTE, obesity, and systemic lupus erythematosus).
Stroke
The WHI estrogen plus progestin substudy reported a statistically significant increased risk of stroke in women 50 to 79 years of age receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women in the same age group receiving placebo (33 versus 25 strokes per 10,000 women-years, respectively) [see Clinical Studies ( 14.4)] . The increase in risk was demonstrated after the first year and persisted. 1Immediately discontinue estrogen with or without progestogen therapy if a stroke occurs or is suspected.
The WHI estrogen-alone substudy reported a statistically significant increased risk of stroke in women 50 to 79 years of age receiving daily CE (0.625 mg)-alone compared to women in the same age group receiving placebo (45 versus 33 strokes per 10,000 women-years, respectively). The increase in risk was demonstrated in year 1 and persisted [see Clinical Studies ( 14.4)] . Immediately discontinue estrogen-alone therapy if a stroke occurs or is suspected.
Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving CE (0.625 mg)-alone versus those receiving placebo (18 versus 21 per 10,000 women-years). 1
Coronary Heart Disease
The WHI estrogen plus progestin substudy reported an increased risk (not statistically significant) of coronary heart disease (CHD) events (defined as nonfatal MI, silent MI, or CHD death) in those women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (41 versus 34 per 10,000 women-years). 1An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5 [see Clinical Studies ( 14.4)] .
The WHI estrogen-alone substudy reported no overall effect on CHD events in women receiving estrogen-alone compared to placebo 2[see Clinical Studies ( 14.4)] .
Subgroup analysis of women 50 to 59 years of age, who were less than 10 years since menopause, suggests a reduction (not statistically significant) of CHD events in those women receiving CE (0.625 mg)-alone compared to placebo (8 versus 16 per 10,000 women-years). 1
In postmenopausal women with documented heart disease (n=2,763), average 66.7 years of age, in a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study; HERS), treatment with daily CE (0.625 mg) plus MPA (2.5 mg) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE plus MPA did not reduce the overall rate of CHD events in postmenopausal women with established CHD. There were more CHD events in the CE plus MPA-treated group than in the placebo group in year 1, but not during the subsequent years. Two thousand three hundred and twenty-one (2,321) women from the original HERS trial agreed to participate in an open label extension of the original HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the CE plus MPA group and the placebo group in HERS, HERS II, and overall.
Venous Thromboembolism
The WHI estrogen plus progestin substudy reported a statistically significant 2-fold greater rate of VTE (DVT and PE) in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (35 versus 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 versus 13 per 10,000 women-years) and PE (18 versus 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted 3[see Clinical Studies ( 14.4)] . Immediately discontinue estrogen plus progestogen therapy if a VTE occurs or is suspected.
In the WHI estrogen-alone substudy, the risk of VTE was increased for women receiving daily CE (0.625 mg)-alone compared to placebo (30 versus 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 versus 15 per 10,000 women-years). The increase in VTE risk was demonstrated during the first 2 years 4[see Clinical Studies ( 14.4)] . Immediately discontinue estrogen-alone therapy if a VTE occurs or is suspected.
If feasible, discontinue estrogens at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.
Malignant Neoplasms
Breast Cancer
After a mean follow-up of 5.6 years, the WHI substudy of daily CE (0.625 mg) plus MPA (2.5 mg) reported an increased risk of invasive breast cancer in women who took daily CE plus MPA compared to placebo. In this substudy, prior use of estrogen-alone or estrogen plus progestin therapy was reported by 26% of the women. The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years, for CE plus MPA compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 versus 25 cases per 10,000 women-years, for CE plus MPA compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 versus 36 cases per 10,000 women-years for CE plus MPA compared with placebo. In the same substudy, invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at a more advanced stage in the CE (0.625 mg) plus MPA (2.5 mg) 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 5[see Clinical Studies ( 14.4)] .
The WHI substudy of daily CE (0.625 mg)-alone provided information about breast cancer in estrogen-alone users. In the WHI estrogen-alone substudy, after an average follow-up of 7.1 years, daily CE-alone was not associated with an increased risk of invasive breast cancer [relative risk (RR) 0.80] compared to placebo 6[see Clinical Studies ( 14.4)] .
Consistent with the WHI clinical trials, observational studies have also reported an increased risk of breast cancer with estrogen plus progestin therapy, and a smaller increase in the risk for breast cancer with estrogen-alone therapy, after several years of use. One large meta-analysis of prospective cohort studies reported increased risks that were dependent upon duration of use and could last up to >10 years after discontinuation of estrogen plus progestin therapy and estrogen-alone therapy. Extension of the WHI trials also demonstrated increased breast cancer risk associated with estrogen plus progestin therapy.Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen plus progestin therapy as compared to estrogen-alone therapy. These studies have not generally found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, doses, or routes of administration.
The use of estrogen-alone and estrogen plus progestin therapy has been reported to result in an increase in abnormal mammograms requiring further evaluation.
In a one-year trial, among 1,684 women who received a combination of estradiol plus progesterone (1 mg estradiol plus 100 mg progesterone or 0.5 mg estradiol plus 100 mg progesterone or 0.5 mg estradiol plus 50 mg progesterone or 0.25 mg estradiol plus 50 mg progesterone) or placebo (n=151), six new cases of breast cancer were diagnosed, two of which occurred among the group of 424 women treated with BIJUVA (estradiol and progesterone) capsules, 0.5 mg/100 mg, and two of which occurred among the group of 415 women treated with BIJUVA (estradiol and progesterone) capsules, 1 mg/100 mg. No new cases of breast cancer were diagnosed in the group of 151 women treated with placebo.
All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results.
Endometrial Cancer
Endometrial hyperplasia (a possible precursor of endometrial cancer) has been reported to occur at a rate of approximately 1 percent or less with BIJUVA (estradiol and progesterone) capsules, 0.5 mg/100 mg or 1 mg/100 mg.
An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in a woman with a uterus. The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12-fold greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than 1 year. The greatest risk appears associated with prolonged use, with an increased risk of 15- to 24-fold for 5 to 10 years or more, and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.
Clinical surveillance of all women using estrogen-alone or estrogen plus progestogen therapy is important. Perform adequate diagnostic measures, including directed or random endometrial sampling when indicated, to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding with unknown etiology.
There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding a progestogen to estrogen therapy in postmenopausal women has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.
Ovarian Cancer
The CE plus MPA substudy of WHI reported that estrogen plus progestin increased the risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE plus MPA versus placebo was 1.58 (95% confidence interval [CI], 0.77 to 3.24), but it was not statistically significant. The absolute risk for CE plus MPA versus placebo was 4 versus 3 cases per 10,000 women-years. 7
A meta-analysis of 17 prospective and 35 retrospective epidemiology studies found that women who used hormonal therapy for menopausal symptoms had an increased risk for ovarian cancer. The primary analysis, using case-control comparisons, included 12,110 cancer cases from the 17 prospective studies. The relative risks associated with current use of hormonal therapy was 1.41 (95% CI, 1.32 to 1.50); there was no difference in the risk estimates by duration of the exposure (less than 5 years [median of 3 years] vs. greater than 5 years [median of 10 years] of use before the cancer diagnosis). The relative risk associated with combined current and recent use (discontinued use within 5 years before cancer diagnosis) was 1.37 (95% CI, 1.27 to 1.48), and the elevated risk was significant for both estrogen-alone and estrogen plus progestin products. The exact duration of hormone therapy use associated with an increased risk of ovarian cancer, however, is unknown.
Probable Dementia
In the WHI Memory Study (WHIMS) estrogen plus progestin ancillary study, a population of 4,532 postmenopausal women 65 to 79 years of age was randomized to daily CE (0.625 mg) plus MPA (2.5 mg) or placebo. After an average follow-up of 4 years, 40 women in the CE plus MPA group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95% CI, 1.21 to 3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years 8[see Use in Specific Populations ( 8.5), and Clinical Studies ( 14.5)] .
In the WHIMS estrogen-alone ancillary study, a population of 2,947 hysterectomized women 65 to 79 years of age was randomized to daily CE (0.625 mg)-alone or placebo. After an average follow-up of 5.2 years, 28 women in the estrogen-alone group and 19 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE-alone versus placebo was 1.49 (95% CI, 0.83 to 2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years 8[see Use in Specific Populations ( 8.5), and Clinical Studies ( 14.5)] .
When data from the two populations in the WHIMS estrogen-alone and estrogen plus progestin ancillary studies were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95% CI, 1.19 to 2.60). Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women 8[see Use in Specific Populations ( 8.5), and Clinical Studies ( 14.5)] .
Gallbladder Disease
A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.
Hypercalcemia
Estrogen administration may lead to severe hypercalcemia in women with breast cancer and bone metastases. Discontinue estrogens, including BIJUVA if hypercalcemia occurs, and take appropriate measures to reduce the serum calcium level.
Visual Abnormalities
Retinal vascular thrombosis has been reported in women receiving estrogens. Discontinue BIJUVA pending examination if there is a sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. Permanently discontinue estrogens, including BIJUVA, if examination reveals papilledema or retinal vascular lesions.
Addition of a Progestogen When a Woman Has Not Had a Hysterectomy
Studies of the addition of a progestogen for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer.
There are, however, possible risks that may be associated with the use of progestogens with estrogens compared to estrogen-alone regimens. These include an increased risk of breast cancer.
Elevated Blood Pressure
In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogens on blood pressure was not seen.
Exacerbation of Hypertriglyceridemia
In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Discontinue BIJUVA if pancreatitis occurs.
Hepatic Impairment and/or Past History of Cholestatic Jaundice
Estrogens may be poorly metabolized in women with hepatic impairment. Exercise caution in any women with a history of cholestatic jaundice associated with past estrogen use or with pregnancy. In the case of recurrence of cholestatic jaundice, discontinue BIJUVA.
Exacerbation of Hypothyroidism
Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Women with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Women dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. Monitor thyroid function in these women during treatment with BIJUVA to maintain their free thyroid hormone levels in an acceptable range.
Fluid Retention
Estrogens plus progestogens may cause some degree of fluid retention. Monitor any woman with a condition(s) that might predispose her to fluid retention, such as cardiac or renal impairment. Discontinue estrogen plus progestogen therapy, including BIJUVA, with evidence of medically concerning fluid retention.
Hypocalcemia
Estrogen-induced hypocalcemia may occur in women with hypoparathyroidism. Consider whether the benefits of estrogen therapy, including BIJUVA, outweigh the risks in such women.
Exacerbation of Endometriosis
A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen-alone therapy.
Hereditary Angioedema
Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema. Consider whether the benefits of estrogen therapy, including BIJUVA, outweigh the risks in such women.
Exacerbation of Other Conditions
Estrogen therapy, including BIJUVA, may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas. Consider whether the benefits of estrogen therapy outweigh the risks in women with such conditions.
Laboratory Tests
Serum follicle stimulating hormone (FSH) and estradiol levels have not been shown to be useful in the management of postmenopausal women with moderate to severe vasomotor symptoms.
Drug Laboratory Test Interactions
- Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of antifactor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.
- Increased thyroid-binding globulin (TBG) levels leading to increased circulating total thyroid hormone as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 levels by radioimmunoassay. T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Women on thyroid replacement therapy may require higher doses of thyroid hormone.
- Other binding proteins may be elevated in serum, for example, corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG), leading to increased total circulating corticosteroids and sex steroids, respectively. Free hormone concentrations, such as testosterone and estradiol, may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).
- Increased plasma high-density lipoprotein (HDL) and HDL2 cholesterol subfraction concentrations, reduced low-density lipoprotein (LDL) cholesterol concentrations, increased triglyceride levels.
- Impaired glucose tolerance.
The following serious adverse reactions are discussed elsewhere in the labeling:
- Cardiovascular Disorders [see Boxed Warning, Warnings and Precautions ( 5.1)].
- Malignant Neoplasms [see Boxed Warning, Warnings and Precautions ( 5.2)].
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.
| Preferred Term | BIJUVA 0.5 mg/100 mg (N=424) | BIJUVA 1 mg/100 mg (N=415) | Placebo (N=151) |
| 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 |
Postmarketing Experience
The following 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.
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.
BIJUVA (estradiol and progesterone) is an oval shaped opaque capsule in which the estradiol is solubilized and the progesterone is micronized and suspended in the mixture of medium chain mono and di-glycerides and lauroyl polyoxyl-32 glycerides.
Each 0.5 mg/100 mg capsule is light pink on one side, dark pink on the other side, and printed with "5C1" in white ink.
Each 1 mg/100 mg capsule is light pink on one side, dark pink on the other side, and printed with "1C1" in white ink.
Estradiol (estra-1,3,5 (10)-triene-3,17β-diol), an estrogen, has a molecular weight of 272.38, and chemical formula C 18H 24O 2.
Progesterone (pregn-4-ene-3, 20-dione) has a molecular weight of 314.47, and chemical formula C 21H 30O 2.
The structural formulas are as follows:
 | Estradiol |
 | Progesterone |
Each BIJUVA (estradiol and progesterone) capsule contains the following inactive ingredients: ammonium hydroxide, ethanol, ethyl acetate, FD&C Red #40, gelatin, glycerin, hydrolyzed gelatin, isopropyl alcohol, lauroyl polyoxyl-32 glycerides, lecithin, medium chain mono and di-glycerides, medium chain triglycerides, polyethylene glycol, polyvinyl acetate phthalate, propylene glycol, purified water, and titanium dioxide.
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.
Pharmacodynamics
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.
Pharmacokinetics
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-tand C maxof estradiol and a slightly more than proportionality increase in AUC 0-tand C maxof 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)
# Median and range *Effective t½. Calculated as 24•ln(2)/ ln (accumulation ratio/(accumulation ratio-1)) for subjects with accumulation ratio >1. | ||||
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 | ||||
| Dosage Strength (estradiol/progesterone) | BIJUVA 0.5 mg/100 mg Mean (SD) | BIJUVA 1 mg/100 mg Mean (SD) | ||
| 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) # | 17 | 6.00 (0.00 - 12.00) | 19 | 3.00 (0.67 - 18.03) |
| t ½(h)* | 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 maxof 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 maxand AUC of progesterone were 162% and 79% higher, respectively, relative to the fasting state and the median t maxof 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 maxby approximately 54% and delayed median t max 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 or 1 mg/100 mg, the half-life of estradiol was 28 ± 10 hours and 26 ± 15 hours, respectively, and the half-life of progesterone was 9 ± 3 hours and 10 ± 3 hours, respectively ( Table 2).
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, 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 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.
Progesterone
Progesterone is metabolized primarily by the liver largely to pregnanediols and pregnanolones. Pregnanediols and pregnanolones are conjugated in the liver to glucuronide and sulfate metabolites. Progesterone metabolites, which are excreted in the bile, may be deconjugated and may be further metabolized in the intestine via reduction, dehydroxylation, and epimerization.
Excretion
Estradiol
Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates.
Progesterone
The glucuronide and sulfate conjugates of pregnanediol and pregnanolone are excreted in the bile and urine. Progesterone metabolites are eliminated mainly by the kidneys. Progesterone metabolites which are excreted in the bile may undergo enterohepatic recycling or may be excreted in the feces.
Carcinogenesis, 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.
Effects 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 3and Table 4, respectively.
*Least square mean difference (SE) from placebo | |||
**P-value of least square mean difference from placebo using mixed model repeated measures analyses | |||
Definitions: SD – standard deviation; SE – standard error | |||
| BIJUVA 0.5 mg/100 mg (N=149) | BIJUVA 1 mg/100 mg (N=141) | Placebo (N=135) | |
| 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* | -8.07 (3.25) | -12.81 (3.30) | --- |
| P-value** | 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 | --- |
| BIJUVA 0.5 mg/100 mg (N=149) | BIJUVA 1 mg/100 mg (N=141) | Placebo (N=135) | |
*Least square mean difference (SE) from placebo | |||
**P-value of least square mean difference from placebo using mixed model repeated measures analyses | |||
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* | -0.17 (0.060) | -0.13 (0.061) | --- |
| P-value** | 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 notdemonstrate statistically significant reductions in bothfrequency and severity of moderate to severe vasomotor symptoms by Week 12 in women who self-identified as Black/African Americans (data not shown).
Effects on Endometrium in Postmenopausal Women
Effects of BIJUVA (estradiol and progesterone) capsules, 0.5 mg/100 mg and 1 mg/100 mg, on endometrial hyperplasia and endometrial malignancy were assessed in the 52-week safety trial. The Endometrial Safety population included women who had taken at least one dose of BIJUVA (estradiol and progesterone) capsules, 0.5 mg/100 mg or 1 mg/100 mg, and had baseline and post-baseline endometrial biopsies. During the trial, endometrial biopsy assessments revealed one (1) case of endometrial hyperplasia and no cases of endometrial cancer in women who received BIJUVA (estradiol and progesterone) 0.5 mg/100 mg capsules, one (1) case of endometrial hyperplasia and no cases of endometrial cancer in women who received BIJUVA (estradiol and progesterone) 1 mg/100 mg capsules, and no cases of endometrial hyperplasia or endometrial cancer in women who received placebo (see Table 5).
| BIJUVA 0.5 mg/100 mg (N=303) | BIJUVA 1 mg/100 mg (N=281) | Placebo (N=92) | |
| Hyperplasia incidence rate % (n/N) | 1/303 (0.33) | 1/281 (0.36) | 0/92 (0.00) |
| One-sided upper 95% confidence limit | 1.83 | 1.97 | 3.93 |
Six (6) cases of disordered proliferative endometrium were reported for BIJUVA (estradiol and progesterone) capsules, 0.5 mg/100 mg, and four (4) cases of disordered proliferative endometrium were also reported for BIJUVA (estradiol and progesterone) capsules, 1 mg/100 mg, in the 52-week safety trial.
Effects on Uterine Bleeding or Spotting in Postmenopausal Women
Uterine bleeding or spotting was evaluated in the 52-week safety study by daily diary. At 52 weeks, cumulative amenorrhea was reported by 67.6% of women who received BIJUVA (estradiol and progesterone) capsules, 0.5 mg/100 mg, 56.1% of women who received BIJUVA (estradiol and progesterone) capsules, 1 mg/100 mg, and 78.9% who received placebo.
Women'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 death due to other causes. These substudies did not evaluate the effects of CE plus MPA or CE-alone on menopausal symptoms.
WHI Estrogen Plus Progestin Substudy
The WHI estrogen plus progestin substudy was stopped early. According to the predefined stopping rule, after an average follow-up of 5.6 years of treatment, the increased risk of invasive breast cancer and cardiovascular events exceeded the specified benefits included in the "global index." The absolute excess risk of events included in the "global index" was 19 per 10,000 women-years.
For those outcomes included in the WHI "global index" that reached statistical significance after 5.6 years of follow-up, the absolute excess risks per 10,000 women-years in the group treated with CE plus MPA were 7 more CHD events, 8 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures.
Results of the CE plus MPA substudy, which included 16,608 women (average 63 years of age, range 50 to 79; 83.9% White, 6.8% Black, 5.4% Hispanic, 3.9% Other) are presented in Table 6. These results reflect centrally adjudicated data after an average follow-up of 5.6 years.
| Event | Relative Risk CE/MPA vs Placebo (95% nCI c) | CE/MPA n=8,506 | Placebo n=8,102 |
|---|---|---|---|
| Absolute Risk per 10,000 Women-Years | |||
aAdapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. | |||
bResults are based on centrally adjudicated data. | |||
cNominal confidence intervals unadjusted for multiple looks and multiple comparisons. | |||
dNot included in "global index." | |||
eIncludes metastatic and non-metastatic breast cancer with the exception of in situ cancer. | |||
fAll deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. | |||
gA subset of the events was combined in a "global index," defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, PE, colorectal cancer, hip fracture, or death due to other causes. | |||
| CHD events Non-fatal MI CHD death | 1.23 (0.99-1.53) 1.28 (1.00-1.63) 1.10 (0.70-1.75) | 41 31 8 | 34 25 8 |
| All Strokes Ischemic stroke | 1.31 (1.03-1.68) 1.44 (1.09-1.90) | 33 26 | 25 18 |
| Deep vein thrombosis d | 1.95 (1.43-2.67) | 26 | 13 |
| Pulmonary embolism | 2.13 (1.45-3.11) | 18 | 8 |
| Invasive breast cancer e | 1.24 (1.01-1.54) | 41 | 33 |
| Colorectal cancer | 0.61 (0.42-0.87) | 10 | 16 |
| Endometrial cancer d | 0.81 (0.48-1.36) | 6 | 7 |
| Cervical cancer d | 1.44 (0.47-4.42) | 2 | 1 |
| Hip fracture | 0.67 (0.47-0.96) | 11 | 16 |
| Vertebral fractures d | 0.65 (0.46-0.92) | 11 | 17 |
| Lower arm/wrist fractures d | 0.71 (0.59-0.85) | 44 | 62 |
| Total fractures d | 0.76 (0.69-0.83) | 152 | 199 |
| Overall Mortality c,f | 1.00 (0.83-1.19) | 52 | 52 |
| Global Index g | 1.13 (1.02-1.25) | 184 | 165 |
Timing of the initiation of estrogen plus progestin therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen plus progestin substudy stratified by age showed in women 50-59 years of age, a non-significant trend toward reduced risk for overall mortality [hazard ratio (HR) 0.69 (95 percent CI, 0.44 to 1.07)].
WHI Estrogen-Alone Substudy
The WHI estrogen-alone substudy was stopped early because an increased risk of stroke was observed, and it was deemed that no further information would be obtained regarding the risks and benefits of estrogen-alone in predetermined primary endpoints.
Results of the estrogen-alone substudy, which included 10,739 women (average 63 years of age, range 50 to 79; 75.3% White, 15.1% Black, 6.1% Hispanic, 3.6% percent Other) after an average follow-up of 7.1 years, are presented in Table 7.
| Event | Relative Risk CE vs Placebo (95% nCI b) | CE n=5,310 | Placebo n=5,429 |
|---|---|---|---|
| Absolute Risk per 10,000 Women-Years | |||
aAdapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. | |||
bNominal confidence intervals unadjusted for multiple looks and multiple comparisons. | |||
cResults are based on centrally adjudicated data for an average follow-up of 7.1 years. | |||
dNot included in "global index." | |||
eResults are based on an average follow-up of 6.8 years. | |||
fAll deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. | |||
gA subset of the events was combined in a "global index," defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, or death due to other causes. | |||
| CHD events c Non-fatal MIc CHD deathc | 0.95 (0.78-1.16) 0.91 (0.73-1.14) 1.01 (0.71-1.43) | 54 40 16 | 57 43 16 |
| All Strokes c Ischemic strokec | 1.33 (1.05-1.68) 1.55 (1.19-2.01) | 45 38 | 33 25 |
| Deep vein thrombosis c,d | 1.47 (1.06-2.06) | 23 | 15 |
| Pulmonary embolism c | 1.37 (0.90-2.07) | 14 | 10 |
| Invasive breast cancer c | 0.80 (0.62-1.04) | 28 | 34 |
| Colorectal cancer c | 1.08 (0.75-1.55) | 17 | 16 |
| Hip fracture c | 0.65 (0.45-0.94) | 12 | 19 |
| Vertebral fractures c,d | 0.64 (0.44-0.93) | 11 | 18 |
| Lower arm/wrist fractures c,d | 0.58 (0.47-0.72) | 35 | 59 |
| Total fractures c,d | 0.71 (0.64-0.80) | 144 | 197 |
| Death due to other causes e,f | 1.08 (0.88-1.32) | 53 | 50 |
| Overall mortality c,d | 1.04 (0.88-1.22) | 79 | 75 |
| Global Index g | 1.02 (0.92-1.13) | 206 | 201 |
For those outcomes included in the WHI "global index" that reached statistical significance, the absolute excess risk per 10,000 women-years in the group treated with CE-alone was 12 more strokes while the absolute risk reduction per 10,000 women-years was 7 fewer hip fractures. 9The absolute excess risk of events included in the "global index" was a non-significant 5 events per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality.
No overall difference for primary CHD events (nonfatal MI, silent MI, and CHD death) and invasive breast cancer incidence in women receiving CE-alone compared with placebo was reported in final centrally adjudicated results from the estrogen-alone substudy, after an average follow-up of 7.1 years.
Centrally adjudicated results for stroke events from the estrogen-alone substudy, after an average follow-up of 7.1 years, reported no significant difference in distribution of stroke subtype or severity, including fatal strokes, in women receiving CE-alone compared to placebo. Estrogen-alone increased the risk for ischemic stroke, and this excess risk was present in all subgroups of women examined. 10
Timing of the initiation of estrogen-alone therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen-alone substudy, stratified by age, showed in women 50-59 years of age a non-significant trend toward reduced risk for CHD [HR 0.63 (95% CI, 0.36 to 1.09)]and overall mortality [HR 0.71 (95% CI, 0.46 to 1.11)].
Women's Health Initiative Memory Study
The WHIMS estrogen plus progestin ancillary study of WHI enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47% were 65 to 69 years of age; 35% were 70 to 74 years; 18% were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia (primary outcome) compared to placebo.
After an average follow-up of 4 years, the relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95% CI, 1.21 to 3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 per 10,000 women-years. Probable dementia as defined in this study included Alzheimer's disease (AD), vascular dementia (VaD), and mixed types (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women [see Warnings and Precautions ( 5.3), and Use in Specific Populations ( 8.5)].
The WHIMS estrogen-alone ancillary study of WHI enrolled 2,947 predominately healthy hysterectomized postmenopausal women 65 to 79 years of age and older (45% were 65 to 69 years of age; 36% were 70 to 74 years of age; 19% were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg)-alone on the incidence of probable dementia (primary outcome) compared to placebo.
After an average follow-up of 5.2 years, the relative risk of probable dementia for CE-alone versus placebo was 1.49 (95% CI, 0.83 to 2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years. Probable dementia as defined in this study included AD, VaD, and mixed types (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women [see Warnings and Precautions ( 5.3), and Use in Specific Populations ( 8.5) ].
When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95% CI, 1.19 to 2.60). Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women [see Warnings and Precautions ( 5.3), and Use in Specific Populations ( 8.5)].
How Supplied
BIJUVA (estradiol and progesterone) capsules, 0.5 mg/100 mg, are oval-shaped opaque capsules, which are light pink on one side and dark pink on the other side. Each capsule is imprinted in white ink indicating the dosage strength (5C1). BIJUVA (estradiol and progesterone) capsules, 0.5 mg/100 mg, are provided in a blister package of 30 capsules.
BIJUVA (estradiol and progesterone) capsules, 1 mg/100 mg, are oval-shaped opaque capsules, which are light pink on one side and dark pink on the other side. Each capsule is imprinted in white ink indicating the dosage strength (1C1). BIJUVA (estradiol and progesterone) capsules, 1 mg/100 mg, are provided in a blister package of 30 capsules.
| BIJUVA (estradiol and progesterone) capsules, 0.5 mg/100 mg | NDC 50261-251-30 |
| BIJUVA (estradiol and progesterone) capsules, 1 mg/100 mg | NDC 50261-211-30 |
Keep out of reach of children. Packages are not child-resistant.
Storage and Handling
Store at 20°C to 25ºC (68°F to 77ºF), excursions permitted to 15ºC to 30ºC (59ºF to 86ºF). [See USP Controlled Room Temperature]
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.