Bijuva Drug Information
Generic name: ESTRADIOL AND PROGESTERONE
Estrogen [EPC] Progesterone [EPC]
Dosage & Administration of Bijuva
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 . 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.
Side Effects of Bijuva
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 43 1 Headache 17 14 1 Nausea 15 9 1 Vaginal bleeding 10 14 0 Vaginal discharge 8 14 1 Pelvic pain 12 13 0
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.
Warnings & Cautions for Bijuva
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 . 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 . 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) combined with medroxyprogesterone acetate (MPA), 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 . 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, 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) . 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) . 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) . 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) . 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) . 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
Malignant Neoplasms Breast Cancer
BIJUVA is contraindicated in women with breast cancer, a history of breast cancer, or estrogen-dependent neoplasia. 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) . 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 . 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 various estrogen plus progestin combinations, doses, or routes of administration. 4 Regarding breast cancer mortality, the WHI estrogen plus progestin trial did not show a statistically significant difference between CE/MPA and placebo.
The trial reported a relative risk of 1.35 (95% CI, 0.94-1.95) for CE/MPA compared to placebo, with a risk difference of 1 per 10,000 WYs (5 versus 4) after a median of 19 years of cumulative follow-up . Ovarian Cancer Comparing CE/MPA to placebo, women 50-59 years of age had a relative risk for ovarian cancer of 0.30 (95% CI, 0.06-1.47) and the risk difference was -3 per 10,000 WYs (1 versus 4) . In the overall WHI study population of women aged 50-79 years (average 63.4 years), the WHI estrogen plus progestin trial reported a relative risk for ovarian cancer of 1.41 (95% CI, 0.75-2.66) for CE/MPA versus placebo after an average follow-up of 5.6 years. The risk difference was 1 per 10,000 WYs (5 versus 4) . A large meta-analysis including 17 prospective studies of postmenopausal women compared current use of estrogen plus progestin products versus never use and reported a relative risk for ovarian cancer of 1.37 (95% CI, 1.26-1.48). The duration of hormone therapy use that was associated with an increased risk of ovarian cancer is unknown. 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.
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 woman 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. 5.10 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. 5.11 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. 5.12 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. 5.13 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. 5.14 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. 5.15 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.
Drug Interactions with Bijuva
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.
Pregnancy Safety for Bijuva
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.
Pediatric Use of Bijuva
Pediatric Use BIJUVA is not indicated for use in pediatric patients. Clinical studies have not been conducted in the pediatric population.
Contraindications for Bijuva
is contraindicated in women with any of the following conditions: Abnormal genital bleeding of unknown etiology. Breast cancer or a history of breast cancer. Estrogen-dependent neoplasia.
Active deep vein thrombosis (DVT), pulmonary embolisum (PE), or history of these conditions. Active arterial thromboembolic disease (for example, stroke, myocardial infarction (MI)), or a history of these conditions. Known anaphylactic reaction, angioedema, or hypersensitivity to BIJUVA. Hepatic impairment or disease Known thrombophilic disorders, such as protein C, protein S, or antithrombin deficiency Undiagnosed abnormal genital bleeding Breast cancer or a history of breast cancer Estrogen-dependent neoplasia Active DVT, PE, or history of these conditions Active arterial thromboembolic disease (for example, stroke and MI), or a history of these conditions Known anaphylactic reaction, angioedema, or hypersensitivity to BIJUVA Hepatic impairment or disease Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders
Overdosage Information for Bijuva
Overdosage of estrogen plus progestogen may cause nausea, vomiting, breast tenderness, abdominal pain, drowsiness and fatigue, and withdrawal bleeding may occur in women. Treatment of overdose consists of discontinuation of BIJUVA therapy with institution of appropriate symptomatic care.
Clinical Studies of Bijuva
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 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 72.1
Mean (SD) change from baseline -35.1 -40.6 -26.4 Difference from placebo Least
square mean difference (SE) from placebo -8.07 -12.81 --- 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 72.2
Mean (SD) change from baseline -53.7 -55.1 -40.2 Difference from placebo -15.07
-16.58 --- 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 2.54 2.52 Mean (SD) change from baseline -0.51 -0.48 -0.34 Difference from placebo Least square mean difference (SE) from placebo -0.17 -0.13 --- 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 2.55 2.52 Mean (SD) change from baseline -0.90 -1.12 -0.56 Difference from placebo -0.39 -0.57 --- 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/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 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 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 ). Table 5: Incidence of Endometrial Hyperplasia After up to 12 Months of Treatment 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 1/281 0/92 One-sided upper 95% confidence limit 1.83 1.97 3.93 Six cases of disordered proliferative endometrium were reported for BIJUVA (estradiol and progesterone) capsules, 0.5 mg/100 mg, and four 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 Estrogen Plus Progestin Trial
The WHI estrogen plus progestin trial enrolled predominantly healthy postmenopausal women to assess the risks and benefits of daily oral CE (0.625 mg) 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, colorectal cancer, hip fracture, or death due to other causes.
This trial did not evaluate the effects of CE plus MPA on menopausal symptoms. The WHI estrogen plus progestin trial was stopped early. After an average follow-up of 5.6 years of treatment, the increased risk of invasive breast cancer crossed the predefined stopping threshold.
The global index was supportive of a finding of overall harm. The absolute excess risk of events included in the global index was 19 per 10,000 women-years. Results of the trial, which enrolled 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. 6,7 Table 6: Relative Risk and Risk Difference Observed in the WHI Estrogen Plus Progestin Trial at an Average of
Years Adapted from 2013
WHI substudy (CE/MPA n=8,506, placebo n=8,102). WHI publications can be viewed at www.nhlbi.nih.gov/whi., Results are based on centrally adjudicated data Event Relative Ratio (95% CI) In the WHI studies, hazard ratios were estimated using Cox proportional hazards models comparing treatment to placebo; however, they are described here as relative risks. Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. Risk Difference (CEMPA vs placebo/10,000 WYs) CHD events 1.18 (0.95-1.45) 6 (41 vs 35) Non-fatal MI 1.24 (0.98-1.56) 6 (35 vs 29) CHD death 1.05 (0.76-1.45) 1 (16 vs 15) All Strokes 1.37 (1.07-1.76) 9 (33 vs 24) Deep vein thrombosis Not included in "global index." 1.87 (1.37-2.54) 12 (25 vs 14) Pulmonary embolism 1.98 (1.36-2.87) 9 (18 vs 9) Invasive breast cancer Includes metastatic and non-metastatic breast cancer with the exception of in situ cancer. 1.24 (1.01-1.53) 9 (43 vs 35) Colorectal cancer 0.62 (0.43-0.89) -6 (10 vs 17) Endometrial cancer 0.83 (0.49-1.40) -1 (6 vs 7) Hip fracture 0.67 (0.47-0.95) -6 (11 vs 17) Vertebral fracture 0.68 (0.48-0.96) -6 (12 vs 17) Total factures 0.76 (0.69-0.83) -51 (161 vs 212) Overall mortality, All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. 0.97 (0.81-1.16) -1 (52 vs 53) Global Index A 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. 1.12 (1.02-1.24) 20 (189 vs 168) Timing of the initiation of estrogen plus progestin therapy relative to the start of menopause may affect the overall risk benefit profile.
The results of the WHI estrogen plus progestin trial in women 50-59 years of age (N=2,837 for CE/MPA; N=2,683 for placebo) are shown in Table 7. Table 7: Relative Risk and Risk Difference Observed Among Women 50-59 Years of Age in the WHI Estrogen Plus Progestin Trial at an Average of
Years Adapted from 2013
WHI trial (CE/MPA n=2,837; placebo=2,683). WHI publications can be viewed at www.nhlbi.nih.gov/whi., Results are based on centrally adjudicated data. Event Relative Ratio (95% CI) In the WHI studies, hazard ratios were estimated using Cox proportional hazards models comparing treatment to placebo; however, they are described here as relative risks. Nominal confidence intervals unadjusted for multiple looks and multiple comparisons.
Risk Difference (CEMPA vs placebo/10,000 WYs) CHD events 1.34 (0.82-2.19) 5 (23 vs 17) Non-fatal MI 1.32 (0.77-2.25)) 4 (19 vs 15) CHD death 0.77 (0.33-1.79) -2 (6 vs 8) All Strokes 1.51 (0.81-2.82) 5 (15 vs 10) Deep vein thrombosis Not included in "global index." 3.01 (1.36-6.66) 10 (15 vs 5) Pulmonary embolism 2.05 (0.89-4.71) 6 (11 vs 5) Invasive breast cancer Includes metastatic and non-metastatic breast cancer with the exception of in situ cancer. 1.21 (0.81-1.80) 6 (33 vs 27) Colorectal cancer 0.79 (0.29-2.18) -1 (4 vs 5) Endometrial cancer 1.07 (0.33-3.53) 0 (4 vs 3) Hip fracture 0.17 (0.22-1.45) -3 (1 vs 3) Vertebral fracture 0.38 (0.15-0.97) -6 (4 vs 10) Total factures 0.82 (0.68-1.00) -25 (120 vs 145) Overall mortality, All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. 0.67 (0.43-1.04) -10 (21 vs 31) Global Index A 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. 1.12 (0.89-1.40) 12 (103 vs 91)
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 effects of daily CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia (primary outcome) compared to placebo. 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. After an average follow-up of 4 years, the relative risk of probable dementia for CE/MPA versus placebo was 2.01 (95% CI, 1.19 to -3.42), with a risk difference of 23 per 10,000 WYs (46 versus 23). 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 . 8
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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