"The U.S. Food and Drug Administration today approved Osphena (ospemifene) to treat women experiencing moderate to severe dyspareunia (pain during sexual intercourse), a symptom of vulvar and vaginal atrophy due to menopause.
See BOXED WARNINGS.
1. Cardiovascular disorders
Estrogen and estrogen/progestin therapies have been associated with an increased risk of cardiovascular events such as myocardial infarction and stroke, as well as venous thrombosis and pulmonary embolism (venous thromboembolism (VTE)). Should any of these occur or be suspected, estrogens should be discontinued immediately.
Risk factors for arterial vascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (e.g., personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately.
In the estrogen-alone substudy of the Women's Health Initiative (WHI) study, statistically significant increased risk of stroke was reported in women receiving CE 0.625 mg daily compared to women receiving placebo (44 versus 32 per 10,000 women-years). The increase in risk was demonstrated in year 1 and persisted. (See CLINICAL STUDIES).
In the estrogen-plus-progestin substudy of WHI study, a statistically significant increased risk of stroke was reported in women receiving CE/MPA 0.625 mg/2.5 mg daily compared to women receiving placebo (31 vs. 24 per 10, 000 women-years). The increase in risk was demonstrated after the first year and persisted. (See CLINICAL PHARMACOLOGY, CLINICAL STUDIES)
b. Coronary heart disease
In the estrogen-alone substudy of WHI, no overall effect on coronary heart disease (CHD) events (defined as non-fatal MI, silent MI or death due to CHD) was reported in women receiving estrogen alone compared to placebo. (See CLINICAL STUDIES)
In the estrogen-plus-progestin substudy of the WHI study, no statistically significant increase of CHD events was reported in women receiving CE/MPA compared to women receiving placebo (39 versus 33 per 10,000 women-years). An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5. In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years), a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study (HERS)) treatment with CE/MPA (0.625 mg/2.5 mg per day) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE/MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the CE/MPA-treated group than in the placebo group in year 1, but not during the subsequent years. Participation in an open label extension of the original HERS trial (HERS II) was agreed to by 2,321 women. 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/MPA group and the placebo group in HERS, HERS II, and overall.
Large doses of estrogen (5 mg conjugated estrogens per day), comparable to those used to treat cancer of the prostate and breast, have been shown in a large prospective clinical trial in men to increase the risks of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis.
c. Venous thromboembolism
In the estrogen-alone substudy of WHI the risk of VTE (DVT and pulmonary embolism [PE]), was reported to be increased for women taking conjugated equine estrogens (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 year. (See CLINICAL STUDIES)
In the estrogen-plus-progestin substudy of WHI, a statistically significant 2-fold greater rate of VTE was reported in women receiving CE/MPA compared to women receiving placebo (35 vs. 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 vs. 13 per 10,000 women-years) and PE (18 vs. 8 per 10,000 women years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted. If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.
2. Malignant neoplasms
a. Endometrial cancer
The use of unopposed estrogens in women with intact uteri has been associated with an increased risk of endometrial cancer. 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. This risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.
Clinical surveillance of all women taking estrogen/progestin combinations is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. 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 progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.
b. Breast cancer
In some studies, the use of estrogens and progestins by postmenopausal women has been reported to increase the risk of breast cancer. The most important randomized clinical trial providing information about this issue is the Women's Health Initiative (WHI) (see CLINICAL STUDIES). The results from observational studies are generally consistent with those of the WHI clinical trial. Observational studies have also reported an increased risk of breast cancer for estrogen-plus-progestin combination therapy, and a smaller increased risk for estrogen-alone therapy, after several years of use. For both findings, the excess risk increased with duration of use, and appeared to return to baseline over about five years after stopping treatment (only the observational studies have substantial data on risk after stopping). In these studies, the risk of breast cancer was greater, and became apparent earlier, with estrogen-plus-progestin combination therapy as compared to estrogen-alone therapy. However, these studies have not found significant variation in the risk of breast cancer among different estrogens or among different estrogen-plus-progestin combinations, doses, or routes of administration.
In the estrogen-alone substudy of WHI, after an average of 7.1 years of follow-up, CE (0.625 mg daily) was not associated with an increased risk of invasive breast cancer (RR 0.80, 95% nCI 0.62-1.04).
In the estrogen-plus-progestin substudy, after a mean follow-up of 5.6 years, the WHI substudy reported an increased risk of breast cancer. In this substudy, prior use of estrogen alone or estrogen-plus-progestin combination hormone therapy was reported by 26% of the women. The relative risk of invasive breast cancer was 1.24 (95% nCI 1.01-1.54), and the absolute risk was 41 vs. 33 cases per 10,000 women-years, for estrogen plus progestin compared with placebo, respectively. 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 vs. 25 cases per 10,000 women-years, for estrogen plus progestin 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 vs. 36 cases per 10,000 women-years for estrogen plus progestin compared with placebo. In the WHI trial, invasive breast cancers were larger and diagnosed at a more advanced stage in the estrogen-plus-progestin 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. The use of estrogen alone and estrogen plus progestin 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.
In the estrogen-alone Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, a population of 2,947 hysterectomized women aged 65 to 79 years was randomized to CE (0.625 mg daily) or placebo. In the estrogen-plus-progestin WHIMS substudy, a population of 4,532 postmenopausal women aged 65 to 79 years was randomized to CE/MPA (0.625 mg/2.5 mg daily) or placebo.
In the estrogen-alone substudy, 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 vs. placebo was 1.49 (95% CI 0.83-2.66). The absolute risk of probable dementia for CE alone vs. placebo was 37 vs. 25 cases per 10,000 women-years.
In the estrogen-plus-progestin substudy, after an average follow-up of four years, 40 women in the estrogen-plus-progestin group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for estrogen plus progestin vs. placebo was 2.05 (95% CI 1.21-3.48). The absolute risk of probable dementia for CE/MPA vs. placebo was 45 vs. 22 cases per 10,000 women-years.
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 1.19-2.60). Since both substudies were conducted in women aged 65 to 79 years, it is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNINGS and PRECAUTIONS, and Geriatric Use.)
4. Gallbladder disease
A two- to four-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.
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.
6. Visual abnormalities
Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, estrogens should be permanently discontinued.
1. Addition of a progestin when a woman has not had a hysterectomy
Studies of the addition of a progestin 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 progestins with estrogens compared to estrogen-alone regimens. These include: a possible increased risk of breast cancer, adverse effects on lipoprotein metabolism (e.g., lowering HDL, raising LDL) and impairment of glucose tolerance.
2. 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. Blood pressure should be monitored at regular intervals with estrogen use.
4. Impaired liver function and past history of cholestatic jaundice
Estrogens may be poorly metabolized in patients with impaired liver function. For patients with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised and in the case of recurrence, medication should be discontinued.
Estrogen administration leads to increased 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 to maintain their free thyroid hormone levels in an acceptable range.
6. Fluid retention
Estrogens may cause some degree of fluid retention. Because of this, patients who have conditions that might be influenced by this factor, such as a cardiac or renal dysfunction, warrant careful observation when estrogens are prescribed.
Estrogens should be used with caution in individuals with severe hypocalcemia.
8. Ovarian cancer
The estrogen-plus-progestin substudy of WHI reported that after an average follow-up of 5.6 years, the relative risk for ovarian cancer for estrogen plus progestin vs. placebo was 1.58 (95% nCI 0.77 - 3.24), but was not statistically significant. The absolute risk for estrogen plus progestin vs. placebo was 4.2 vs. 2.7 cases per 10,000 women-years. In some epidemiologic studies, the use of estrogen only products, in particular for 10 or more years, has been associated with an increased risk of ovarian cancer. Other epidemiologic studies have not found these associations.
9. Exacerbation of other endometriosis
Endometriosis may be exacerbated with administration of estrogens. Malignant transformation of residual endometrial implants has been reported in women treated post-hysterectomy with estrogen-alone therapy. For patients known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered.
10. Exacerbation of other conditions
Estrogens may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions.
B. Information for Patients
Physicians are advised to discuss the PATIENT INFORMATION leaflet with patients for whom they prescribe ENJUVIA (synthetic conjugated estrogens, b) tablets.
C. Laboratory Tests
Estrogen administration should be initiated at the lowest dose approved for the indication and then guided by clinical response rather than by serum hormone levels (e.g., estradiol, FSH).
D. Carcinogenesis, Mutagenesis, Impairment of Fertility
See BOXED WARNINGS, WARNINGS and PRECAUTIONS.
ENJUVIA tablets should not be used during pregnancy. (See CONTRAINDICATIONS.)
F. Nursing Mothers
Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving this drug. Caution should be exercised when ENJUVIA (synthetic conjugated estrogens, b) is administered to a nursing woman.
G. Pediatric Use
The safety and efficacy of ENJUVIA (synthetic conjugated estrogens, b) tablets in pediatric patients has not been established.
H. Geriatric Use
Clinical studies of ENJUVIA (synthetic conjugated estrogens, b) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
Of the total number of subjects in the estrogen-alone substudy of the WHI study, 46 percent (n = 4,943) were 65 years and older, while 7.1 percent (n = 767) were 75 years and older. There was a higher relative risk (CE versus placebo) of stroke in women less than 75 years of age compared to women 75 years and over.
In the estrogen-alone substudy of WHIMS, a substudy of WHI, a population of 2,947 hysterectomized women, aged 65 to 79 years, was randomized to CE (0.625 per day) or placebo. After an average follow-up of 5.2 years, the relative risk (CE vs. placebo) of probable dementia was 1.49 (95% CI 0.83-2.66). The absolute risk of developing probable dementia with estrogen alone was 37 vs. 25 cases per 10,000 women-years with placebo.
Of the total number of subjects in the estrogen-plus-progestin substudy of the WHI study, 44 percent (n = 7,320) were 65-74 years of age, while 6.6 percent (n = 1,095) were 75 years and older. There was a higher relative risk (CE/MPA versus placebo) of non-fatal stroke and invasive breast cancer in women 75 and older compared to women less than 75 years of age. In women greater than 75, the increased risk of non-fatal stroke and invasive breast cancer observed in the estrogen-plus-progestin combination group compared to the placebo group was 75 vs. 24 per 10,000 women-years and 52 vs. 12 per 10,000 women years, respectively.
In the estrogen-plus-progestin substudy of WHIMS, a population of 4,532 postmenopausal women, aged 65 to 79 years, was randomized to CE/MPA (CE 0.625 mg/2.5 mg). In the estrogen-plus-progestin group, after an average follow-up of 4 years, the relative risk (CE/MPA versus placebo) of probable dementia was 2.05 (95% CI 1.21-3.48). The absolute risk of developing probable dementia with CE/MPA was 45 vs. 22 cases per 10,000 women-years with placebo.
Seventy-nine percent of the cases of probable dementia occurred in women that were older than 70 for the CE group, and 82 percent of the cases of probable dementia occurred in women who were older than 70 in the CE/MPA group. The most common classification of probable dementia in both the treatment groups and placebo groups was Alzheimer's disease.
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 1.19-2.60). Since both substudies were conducted in women aged 65 to 79 years, it is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNINGS and WARNINGS, Dementia.)
Last reviewed on RxList: 8/7/2007
This monograph has been modified to include the generic and brand name in many instances.
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