The use of estrogens in postmenopausal women, with or without a progestin, carries a risk for thromboembolism, and cardiovascular events such as myocardial infarction (MI) or stroke. Detailed information regarding what is known about thromboembolic and cardiovascular risk in postmenopausal women is available in the boxed warnings and precautions section of the product labeling for the products, as these risks must be considered prior to use of HRT in women, and with consideration to age and other risk factors for these events. Risks vary with the use of estrogen-alone vs. use of estrogen with progestin therapy. Similar risk data are not available for the use of estrogens with bazedoxifene. Estrogen agonist/antagonists, including bazedoxifene, are individually known to increase the risk of thromboembolism and thrombus formation. Serious cardiovascular adverse reactions to therapy may include myocardial infarction (MI), superificial or deep venous thrombosis (DVT), pulmonary embolism (PE), or stroke. Should any of these events occur or be suspected, discontinue conjugated estrogens; bazedoxifene HRT immediately.[56074]

Although not specifically reported during clinical evaluation of conjugated estrogens; bazedoxifene, conjugated estrogens can cause sodium and fluid retention and peripheral vasodilation, resulting in edema or mild weight gain. They should be prescribed cautiously to patients in whom edema formation would be detrimental. Estrogens also can slightly increase blood pressure, occasionally causing hypertension. Data indicate in most patients the change is not clinically significant. In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In the PEPI trial, postmenopausal women 45—65 years of age randomized to any hormone therapy regimen containing conjugated estrogens experienced increases in both systolic and diastolic blood pressure of 3—5% after the first year of treatment, but the increases were not statistically different from placebo.[24010]

Although the effects appear to be minimal in most patients receiving hormone therapy with estrogens, altered glucose tolerance secondary to decreased insulin sensitivity has been reported. In the PEPI trial, fasting glucose levels were lower, and mean 2-hour glucose levels were 8% higher, in combined HRT treated women versus placebo in all treatment arms. The effects appeared to be consistent across demographic, clinical, and lifestyle variables.[24010] Limited clinical studies of estrogen regimens have not noted significant alterations in glucose metabolism in healthy post-menopausal women. However, altered glucose tolerance secondary to decreased insulin sensitivity may be important for patients with hyperglycemia or diabetes mellitus. They should be observed for changes in glucose tolerance when initiating or discontinuing conjugated estrogens therapy.[56074]

Numerous epidemiologic studies have examined the effects of estrogen and estrogen-progestin hormone replacement therapy (HRT) on the development of new primary malignancy (e.g., breast cancer, endometrial cancer, ovarian cancer) in postmenopausal women. Detailed clinical study information regarding what is known about cancer risk in postmenopausal women is available in the boxed warnings and precautions section of the product labeling for the products, as these risks must be considered prior to use of HRT in women, and with consideration to age and other risk factors for these events. There is an association of unopposed estrogen therapy and endometrial hyperplasia in women with an intact uterus. The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12-times greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Adding a progestin or a selective estrogen modifier (SERM) like bazedoxifene to estrogen therapy has been shown to reduce, but not eliminate, the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. By endometrial biopsy, the incidence of endometrial hyperplasia or malignancy for conjugated estrogens; bazedoxifene was below 1% during clinical studies in postmenopausal women.[56074] Clinical surveillance of all women using conjugated estrogens; bazedoxifene is important. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal vaginal bleeding. The Women's Health Initiative (WHI) estrogen plus progestin study reported increased risks of invasive breast cancer in patients taking combined estrogen-progestin HRT vs. placebo. The potential risk of breast cancer may increase with longer duration of use. The effect of bazedoxifene, when added to an estrogen, on the risk for breast cancer vs. estrogen-progestin therapy is not known. Women who used hormonal therapy for menopausal symptoms also had an increased risk for ovarian cancer, but data are still uncertain if risk is associated with a specific duration of use. The effect of bazedoxifene, when added to an estrogen, on the risk for ovarian cancer vs. estrogen-progestin therapy is not known.[23505] [27272] [32125] [27273] [50638] [56074]

Hormone replacement therapy (HRT), both estrogen/progestin combination therapy and estrogen alone therapy, fails to prevent mild impaired cognition (memory loss) and is positively associated with the risk of developing dementia in women 65 years and older; do not use HRT to prevent or treat dementia or preserve cognition (memory).[56074] When data from the 2 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, p = 0.005). 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.[27451] [32126] [50638] In the WHIMS estrogen-alone ancillary study of WHI, a population of 2,947 hysterectomized women 65 to 79 years of age was randomized to conjugated estrogens (CE 0.625 mg/day)-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 vs. 25 cases per 10,000 women-years.[56074] [27451] [32126]

Uterine bleeding pattern changes and other genitourinary effects occur commonly during chronic, systemic conjugated estrogens therapy in postmenopausal women. Amenorrhea is expected with the continued use of conjugated estrogens; bazedoxifene treatment; in clinical studies, 83% to 88% of menopausal women reported cumulative amenorrhea at year 1 of therapy. Changes in uterine and vaginal bleeding patterns and breakthrough bleeding or spotting have been noted with estrogens with or without progestins and are commonly reported. Non-cyclic vaginal breakthrough bleeding is reported in 2% to 14% of patients. Changes in uterine bleeding patterns will usually taper and stabilize within 3 to 6 months. Metrorrhagia, pelvic pain, and dysmenorrhea are infrequent. Other genitourinary effects reported during estrogen/progestin therapy include vaginitis, vaginal discharge (leukorrhea), vaginitis or vaginal candidiasis and libido increase or libido decrease. Unusual vaginal bleeding or other pelvic symptoms that persist beyond 6 months should be evaluated by a healthcare professional. For example, continued and unexpected changes in bleeding patterns may indicate a change in uterine leiomyomatas (fibroids) or cervicitis if present. Women should report unusual symptoms to their healthcare professionals and follow advice for annual pelvic examinations and periodic Papanicolaou smears as indicated.[56074]

Although not specifically reported during clinical evaluation of conjugated estrogens; bazedoxifene, breast changes that may occur with conjugated estrogen therapy include mastalgia and breast tenderness, which occur in approximately 8% to 12% of women on chronic estrogen hormone replacement therapy (HRT). Breast enlargement, breast discharge, galactorrhea, and fibrocystic breast changes have been reported with estrogens and/or progestin therapy. Gynecomastia may occur in men taking estrogen therapy. Patients should report breast changes, lumps, or breast discharge to their health care professionals. 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.[56074]

The safety of conjugated estrogens; bazedoxifene was evaluated in four Phase 3 clinical trials ranging from 12 weeks to 24 months in duration and enrolling 6210 postmenopausal women age 40—75 years (mean age 55 years). A total of 1224 patients were treated with conjugated estrogens; bazedoxifene and 1069 patients received placebo; abdominal pain upper (7% vs. 5%) and nausea (8% vs. 5%) were listed among the most common adverse reactions leading to discontinuation. Other gastrointestinal adverse events reported during evaluation include diarrhea (8% vs. 5%) and dyspepsia (7% vs. 6%).[56074] In general, gastrointestinal effects from conjugated estrogens administration are typically mild and relatively limited. With chronic use, abdominal pain can indicate biliary obstruction, and result in cholestatic jaundice. Estrogens enhance hepatic lipoprotein uptake and inhibit bile acid synthesis, resulting in increased concentration of cholesterol in the bile which can lead to cholelithiasis. Gallbladder disease and cholecystitis are 2- to 4-fold as frequent in women taking hormone replacement therapy (HRT) compared with controls.[25473] [56074] Rare adverse reactions reported with estrogen therapy include hepatitis (and elevated hepatic enzymes), enlargement of hepatic hemangiomas, ischemic colitis (bowel ischemia, no incidence reported), or pancreatitis. Patients with familial hyperlipoproteinemia may be at greater risk of pancreatitis while on estrogen therapy, which may greatly increase their serum triglycerides and cause hypertriglyceridemia in these susceptible individuals. Estrogens may induce peliosis hepatis, a very rare consequence of taking estrogens and combined oral contraceptives that is characterized by the presence of blood-filled spaces.[51257] Persistent or severe abdominal symptoms should be evaluated by a medical professional. Conjugated estrogens; bazedoxifene should be discontinued in any patient developing jaundice, cholestasis, or severe abdominal pain, and the patient should be evaluated.[56074]

The safety of conjugated estrogens; bazedoxifene was evaluated in four Phase 3 clinical trials ranging from 12 weeks to 24 months in duration and enrolling 6210 postmenopausal women age 40—75 years (mean age 55 years). A total of 1224 patients were treated with conjugated estrogens; bazedoxifene and 1069 patients received placebo. Adverse reactions reported in > 5% of patients relative to placebo include: muscle cramps (9% vs. 6%), musculoskeletal pain/neck pain (5% vs. 4%), and oropharyngeal pain (7% vs. 6%).[56074]

Although not specifically reported during clinical evaluation of conjugated estrogens; bazedoxifene, headache has been reported in greater than 5% of patients receiving conjugated estrogens by any route, and has been reported in patients receiving chronic HT. In some women, headache patterns are hormonally influenced. A number of changes can occur when a woman initiates HRT and include 1) migraines can appear for the first time, 2) a change in frequency, severity and duration of migraine headaches may be seen, or 3) an improvement or decrease in the occurrence of migraine headaches. When initiating therapy an individual's headache pattern should be observed and if migraines worsen consider discontinuing therapy. A severe headache may be a warning sign of a serious adverse event such as a stroke or retinal thrombosis.[56074] Retinal thrombosis has been reported in patients receiving estrogens such as conjugated estrogens. Discontinue medication pending examination if there is sudden visual impairment either partial or complete or a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema, visual loss, or retinal vascular lesions, permanently discontinue estrogens. Exogenous estrogen use can cause a conical cornea to develop from steepening or increased curvature of the cornea, caused by thinning of the stroma. Patients with contact lenses may develop intolerance to their lenses.

The safety of conjugated estrogens; bazedoxifene was evaluated in four Phase 3 clinical trials ranging from 12 weeks to 24 months in duration and enrolling 6210 postmenopausal women age 40—75 years (mean age 55 years). A total of 1224 patients were treated with conjugated estrogens; bazedoxifene and 1069 patients received placebo. Adverse reactions reported in >= 5% of patients relative to placebo included dizziness (5% vs. 3%).[56074] Although not specifically reported during clinical evaluation of conjugated estrogens; bazedoxifene, nervous system and mood disturbances occur in some women taking conjugated estrogens for hormonal therapy. These changes can include mental depression, fatigue, asthenia, nervousness, anxiety, or insomnia. Paresthesias have also been reported. Less common central nervous system events include chorea, emotional lability, irritability, exacerbation of epilepsy, and dementia. Possible growth potentiation of a benign meningioma may occur.

Although not specifically reported during clinical evaluation of conjugated estrogens; bazedoxifene, conjugated estrogens and other estrogens used for hormone therapy can cause a variety of dermatological reactions. Melasma and chloasma, in the form of tan or brown patches, may develop on the forehead, cheeks, temples and upper lip. These patches may persist after the drug is discontinued. Other infrequent reactions include urticaria, erythema nodosum, alopecia, hirsutism, or rash (unspecified). Erythematous eruptions, with or without pruritus, may also occur. In some cases estrogens may induce or aggravate an existing acne vulgaris or cause an acneiform rash.[56074]

Cases of anaphylactoid reactions with or without angioedema, requiring emergency medical treatment, have been reported during post marketing use of conjugated estrogen oral tablets. Reported symptoms include hives, pruritis, swollen lips-tongue-face, bronchospasm, abdominal pain, or vomiting. Angioedema involving the tongue, larynx, face, hands, and feet requiring medical intervention has occurred post marketing. Patients who develop these symptoms following treatment should discontinue use not be re-challenged with oral conjugated estrogen. Other potential events related to hypersensitivity can include erythema multiforme, urticaria and other rashes.[56074]

Some women taking conjugated estrogens or other estrogens notice tenderness, swelling, or minor bleeding of their gums, which may lead to gingivitis. Proper attention to oral care and regular dental visits are recommended.

In women with a history of cardiovascular disease, the use of estrogen and progestin combination therapy increases the risk of developing urinary incontinence. Patients in the HERS study who did not have urinary incontinence prior to the studies initiation were observed to determine if hormone replacement therapy was helpful in preventing urinary incontinence. The study found that women who received estrogen/progestin therapy were almost twice as likely as patients receiving placebo to develop urge incontinence and 3 times as likely to develop stress incontinence after 1 year of treatment. At 4 years, the effect of hormone replacement therapy became even more pronounced, increasing the risk to 3.23 for urge incontinence and to 4.81 for stress incontinence. The applicability of these findings to women who use conjugated estrogen; bazedoxifene is unclear.[27457]

Conjugated estrogens are known to cause teratogenesis during pregnancy and are in FDA category X. Increased risk of a wide variety of fetal abnormalities, including modified development of sexual organs, cardiovascular anomalies and limb defects, have been reported following the use of estrogens in pregnant women.[56074] The use of diethylstilbestrol, DES is well known for creating disturbances in the reproductive systems of both male and female offspring; similar disturbances are reported to occur in female offspring of rats exposed to other estrogens during gestation. In any patient in whom pregnancy is suspected, pregnancy should be ruled out before continuing the use of conjugated estrogens.

Do not use conjugated estrogens; bazedoxifene in patients with a known hypersensitivity to the hormones or any of the specific product ingredients; conjugated estrogens are contraindicated in patients with known anaphylactic reactions or history of angioedema to the drug. Cases of both anaphylactic reactions and angioedema have been reported in patients taking estrogens, including conjugated estrogens. Events have developed in minutes and have required emergency medical treatment. Exogenous estrogens may also induce or exacerbate symptoms of angioedema, particularly in women with hereditary angioedema, which can be hormonally sensitive.[56074]

Conjugated estrogens; bazedoxifene products are contraindicated in patients with a known or suspected estrogen-dependent neoplasm, including breast cancer. The effect of treatment with conjugated estrogens; bazedoxifene on the risk of breast cancer is unknown. The data available are derived for studies of estrogen-alone or estrogen plus progestin hormonal replacement therapy (HRT). Since the 1970's, numerous epidemiological studies have examined the association of exogenous estrogen and breast cancer (new primary malignancy). The most important randomized clinical study providing information about breast cancer in estrogen-alone users is the Women's Health Initative (WHI) substudy of daily conjugated estrogens (0.625 mg)-alone. In the WHI estrogen-alone substudy, after an average follow-up of 7.1 years, conjugated estrogen (0.625 mg/day)-alone was not associated with an increased risk of invasive breast cancer (relative risk [RR] 0.80). The use of estrogen-alone has been reported to result in an increase in abnormal mammograms requiring further evaluation. 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.[23505] [27272] [27530] [27531] [32125] [56074] Estrogen administration may lead to severe hypercalcemia in patients with breast cancer and bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken to reduce the serum calcium level.[56074]

Conjugated estrogens; bazedoxifene is contraindicated in women with estrogen-responsive tumors, including ovarian cancer. The effect of conjugated estrogens; bazedoxifene therapy on the risk of ovarian cancer is unknown. What is known about the risk of ovarian cancer due to hormonal therapy is derived from data available for estrogen-alone and estrogen plus progestin products; studies are not available for estrogen plus selective estrogen receptor modifier combinations. The Women's Health Initiative (WHI) estrogen plus progestin substudy reported a statistically non-significant increased risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for estrogen plus progestin versus placebo was 1.58 (95% CI 0.77 to 3.24). The absolute risk for estrogen plus progestin versus placebo was 4 versus 3 cases per 10,000 women-years.[17829] 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 risk associated with current use of hormonal therapy was 1.41 (95% confidence interval [CI] 1.32 to 1.5); 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.[56074]

Conjugated estrogens; bazedoxifene therapy is contraindicated in patients with known estrogen-dependent malignancies. There is an association of unopposed estrogen therapy and endometrial cancer in women with an intact uterus. Adding a progestin to estrogen therapy has been shown to reduce, but not eliminate, the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Bazedoxifene, an estrogen agonist/antagonist, reduces the risk of endometrial hyperplasia that can occur with estrogen therapy in a manner similar to progestins. Clinical surveillance of all women using conjugated estrogens; bazedoxifene is important. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal vaginal bleeding.[56074] The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12-times 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 increased risks 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. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. With concurrent progestin use (cyclically or continuously), the incidence of endometrial hyperplasia due to conjugated estrogens is estimated to be 1% or less.[23505] [27272] [56074] Women taking conjugated estrogens; bazedoxifene should not take additional estrogens as this may increase the risk of endometrial hyperplasia. Use caution when prescribing conjugated estrogens; bazedoxifene in the overweight patient. Obesity (BMI greater than 27 kg/m²) may be associated with a reduction in bazedoxifene exposure; reduced drug exposure may be associated with an increased risk of endometrial hyperplasia.[56074]

Conjugated estrogens; bazedoxifene is contraindicated in the presence of vaginal cancer, cervical cancer, uterine cancer, or other estrogen-responsive tumors. Clinical surveillance of all women using estrogen plus bazedoxifene therapy is important; all women receiving estrogen treatment should have an annual pelvic examination and other diagnostic or screening tests, such as cervical cytology, as clinically indicated or as generally recommended based on age, risk factors, and other individual needs. Because estrogens influence the growth of endometrial tissues, use conjugated estrogens cautiously in women with endometriosis or uterine leiomyomata (uterine fibroids).[56074] Bazedoxifene, an estrogen agonist/antagonist, reduces the risk of endometrial tissue growth that can occur with estrogen therapy, in a manner similar to use of progestins. Women taking conjugated estrogens; bazedoxifene should not take progestins, additional estrogens, or additional estrogen agonist/antagonists.[56074]

Conjugated estrogens; bazedoxifene products are contraindicated in patients with an active or past history of stroke, thrombophlebitis, thromboembolism, thromboembolic disease, or myocardial infarction (MI). An increased risk of cerebrovascular disease (stroke) and deep venous thrombosis (DVT) has been reported with unopposed estrogen therapy; selective estrogen receptor modifiers (SERMS), like bazedoxifene, are also known to increase the risk for DVT. An increased risk of thromboembolism, including pulmonary embolism (PE), DVT, stroke and myocardial infarction (MI) has been reported with estrogen-containing hormone replacement therapy (HRT). Should any of these events occur or be suspected, discontinue conjugated estrogens; bazedoxifene immediately.[56074] Estrogens are also contraindicated for patients with known protein C deficiency, protein S deficiency, or antithrombin deficiency or other known thrombophilic disorders associated with increased risk of venous thrombosis. Other risk factors for arterial vascular disease (e.g., hypertension, diabetes, tobacco smoking, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) [e.g., personal history or family history of VTE, obesity, or systemic lupus (SLE)] should be monitored and managed appropriately.[56074] A positive relationship between estrogen use and an increased risk for thromboembolism has been demonstrated. In the WHI estrogen-alone substudy, the risk of VTE (DVT and PE) was increased for women receiving daily unopposed estrogen compared to placebo (30 vs. 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 vs. 15 per 10,000 women years). The increase in VTE risk was demonstrated during the first 2 years.[17825] [27272] Estrogens with or without a SERM or progestin should not be used for the prevention of cardiac disease or cardiovascular disease (e.g., coronary artery disease). In the Women's Health Initiative (WHI) estrogen-alone substudy, no overall effect on coronary heart disease (CHD) events (defined as non-fatal MI, silent MI, or CHD death) was reported in women receiving conjugated estrogen-alone compared to placebo. Subgroup analyses of women 50 to 59 years of age suggest a statistically non-significant reduction in CHD events (CE-alone vs. placebo) in women with less than 10 years since menopause (8 vs. 16 per 10,000 women-years).[27272] [17808] Studies have also shown no cardiovascular benefit to the use of estrogens for secondary prevention in women with documented cardiac disease or CHD.[25473] [27270] Estrogens also increase the risk for stroke. In the WHI estrogen-alone substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving estrogen-alone compared to women in the same age group receiving placebo (45 vs. 33 per 10,000 women-years). The increase in risk was demonstrated in the first year and persisted. Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving estrogen-alone versus those receiving placebo (18 vs. 21 per 10,000 women-years). Only a daily oral conjugated estrogens dose of 0.625 mg was studied in the WHI estrogen-alone substudy; therefore, the relevance of the findings regarding adverse cardiovascular events to lower doses, routes of administration, or other estrogen products is not known.[38488] [27272] Patients with hypertension should be monitored closely for increases in blood pressure if estrogens are administered. In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogen therapy. In a large, randomized, placebo controlled clinical trial, a generalized effect of estrogens on blood pressure was not seen. Estrogens may cause some degree of fluid retention. Women with conditions that might be influenced by this factor, such as a cardiac disease, warrant careful observation when estrogens are prescribed.[56074]

If feasible, conjugated estrogens; bazedoxifene therapy should be discontinued at least 4 to 6 weeks before any surgery associated with an increased risk of thromboembolism, or during any periods of prolonged immobilization. The decision on when to resume estrogens after such procedures or conditions would be based on the perceived additional thromboembolic risk from estrogen use and the need for estrogen therapy; resume only after the patient is fully ambulatory. In addition, women taking conjugated estrogens; bazedoxifene should be advised to move about periodically during travel involving prolonged immobilization.[56074]

Conjugated estrogens; bazedoxifene is contraindicated for use during pregnancy.[56074] There appears to be little or no increased risk of birth defects in children born to women who have used estrogens as an oral contraceptive inadvertently during early pregnancy.[40617] However, an increased risk of a wide variety of fetal abnormalities, including modified development of sexual organs, cardiovascular anomalies and limb defects, have been reported following the chronic use of estrogens alone in pregnant women. Data are not available for bazedoxifene use in human pregnancy and conjugated estrogens; bazedoxifene products have no FDA-approved indication for use during pregnancy.[56074] Administration of bazedoxifene to rats at maternally toxic dosages of 1 mg/kg/day or more (0.3 times or more of the human area under the curve (AUC) at the 20 mg dose) resulted in reduced numbers of live fetuses and/or reductions in fetal body weights; no fetal developmental anomalies were observed. In studies conducted with pregnant rabbits treated with bazedoxifene, abortion and an increased incidence of heart (ventricular septal defect) and skeletal system (ossification delays, misshapen or misaligned bones, primarily of the spine and skull) anomalies in the fetuses were present at maternally toxic dosages of 0.5 mg/kg/day or more (2 times the human AUC at the 20 mg dose). In any patient in whom pregnancy is suspected, pregnancy should be ruled out before continuing estrogen use.[56074]

Conjugated estrogens; bazedoxifene should not be used during breast-feeding.[56074] It is not known if bazedoxifene is excreted in breat milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving conjugated estrogens. Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk.[56074]

Conjugated estrogens; bazedoxifene products are contraindicated in the presence of hepatocellular cancer, hepatic adenoma, or in severe hepatic disease of any type. Estrogens and bazedoxifene may be poorly metabolized in women with impaired liver function. For women with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised, and in the case of recurrence, estrogens should be discontinued. Estrogens should also be used cautiously in patients with acute intermittent, or variegate hepatic porphyria, which can be exacerbated. Estrogens have been reported during trials to increase the risk of gallbladder disease (e.g., cholestasis, cholelithiasis and cholecystitis) by roughly 2- to 4-fold in postmenopausal women; use with caution in patients with a history of gallbladder disease.[56074]

Patients with systemic lupus erythematosus (SLE) may have increased risk for thromboembolism and should be managed appropriately when estrogen therapy is considered.[56074] Approximately 85% of patients diagnosed with systemic lupus erythematosus (SLE) are females, giving support to the notion that hormonal influences, especially estrogen, contribute to the pathophysiology of SLE. Accordingly, hormone replacement therapy (HRT) has been reported to induce, unmask, and exacerbate lupus; case reports, anecdotal data, and the prospective Nurses Health Study indicate that a temporal relationship between HRT and lupus exist. However, several retrospective studies dispute a relationship between estrogens and lupus, and the SELENA trial, a large prospective, randomized clinical trial evaluating the safety of estrogen therapy (both as oral contraceptives and HRT in postmenopausal women) in patients with SLE has been completed and is being analyzed. Determining the risk of estrogen therapy in SLE patients is important as postmenopausal women with lupus can benefit from HRT; not only does it offer relief from postmenopausal symptoms (vasomotor symptoms, genital symptoms, and emotional lability), but it has the additional benefit of protecting patients from bone fracture and postmenopausal or drug-induced (i.e., chronic corticosteroid or cyclophosphamide therapy) osteoporosis. Women with hypercoagulable states are at increased risk of venous thromboembolism when taking HRT; given the increased prevalence of hypercoagulable states in patients with SLE (in particular antiphospholipid antibodies), the use of HRT in this population may be even more risky as the incidence of strokes, heart attacks, and blood clots is increased in general in women taking HRT. Unfortunately, definitive recommendations regarding the use of HRT in patients with SLE are not available. The results of the SELENA trial should provide evidence regarding the use of HRT in this population.[31435] [31436]

In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Consider discontinuation of conjugated estrogens; bazedoxifene treatment if pancreatitis occurs.[56074]

Retinal vascular thrombosis has been reported in women receiving estrogens. Any visual disturbance occurring during conjugated estrogens; bazedoxifene therapy should be examined by an ophthalmologist. Discontinue the product pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine with visual changes. If examination reveals papilledema or retinal vascular lesions, conjugated estrogens; bazedoxifene therapy should be permanently discontinued.[56074] Estrogen therapy may cause an exacerbation of migraine or a change in headache patterns and should be used with caution in women with migraine. Patients who complain of migraine with focal neurologic visual changes should be evaluated, and in some patients, such changes may indicate cerebrovascular events. Estrogens can increase the curvature of the cornea and may lead to intolerance of contact lenses.

Patients with risk factors for arterial vascular disease (e.g., diabetes mellitus), which may increase the risk for thromboembolism, should be monitored and managed appropriately during conjugated estrogens; bazedoxifene therapy. Patients with diabetes mellitus should be observed for changes in glucose tolerance when initiating or discontinuing estrogen therapy, since estrogen therapy may exacerbate diabetes. Altered glucose tolerance secondary to decreased insulin sensitivity has been reported.[56074]

Use conjugated estrogens; bazedoxifene therapy with caution in patients with thyroid disease, particularly hypothyroidism. Estrogens can increase thyroid-binding globulin (TBG) levels. Patients 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. Patients dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These patients should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range.[56074]

Conjugated estrogens; bazedoxifene therapy is not recommended for use in patients with renal impairment since data on the safety and efficacy in these patients is not available. Because estrogens may cause fluid retention, conditions that might be affected by fluid retention, such as heart disease or renal disease, require careful observation. Estrogen therapy may also cause an exacerbation of asthma, seizure disorder, and hepatic hemangiomas in some patients and should be used with caution in women with these conditions.[56074]

Mood disorders, like depression, may be aggravated in women taking exogenous estrogens. Women with a history of depression may need special monitoring. If significant depression occurs, the hormone therapy should be discontinued.

Estrogen therapy should be used with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur.[56074]

Conjugated estrogens; bazedoxifene is not recommended for use in geriatric adults greater than 75 years of age.[56074] Administration of HRT should generally be avoided in women 65 years of age and older, and HRT should not be used to prevent or treat dementia or preserve cognition (memory). Overall risk vs. benefit should be considered along with the goals of use of HRT for the individual patient when considering whether to continue HRT in those over 65 years of age.[27451] [32126] [50638] HRT with estrogen therapy fails to prevent or treat mild cognitive impairment (memory loss) and also increases the risk of dementia in geriatric women 65 years and older.[56074] According to the Beers Criteria, oral, topical patch, or other systemic estrogens (with or without progestins) are potentially inappropriate medications (PIMs) for use in geriatric adults and should be avoided due to evidence of carcinogenic potential and lack of protective cardiovascular or cognitive effects. Oral or transdermal estrogen is not effective for management of postmenopausal urinary incontinence. Use of vaginal estrogen is acceptable for the management of dyspareunia, recurrent lower urinary tract infections, and other vaginal/vulvar symptoms.[63923]

Conjugated estrogens; bazedoxifene is not indicated for use in pediatric patients; the products have no known use in infants, children, or premenopausal females.[56074] Large and repeated doses of estrogen over an extended time period have been shown to accelerate epiphyseal closure, which could result in short stature if treatment is initiated before the completion of physiologic puberty in normally developing children.[40617]