"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
Estrogen (estropipate) and estrogen (estropipate) /progestin therapy 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 or VTE). Should any of these occur or be suspected, estrogen (estropipate) s 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.
Coronary heart disease and stroke
In the Women's Health Initiative (WHI) study, an increase in the number of myocardial infarctions and strokes has been observed in women receiving CE compared to placebo. These observations are preliminary, and the study is continuing. (See CLINICAL PHARMACOLOGY, Clinical Studies.)
In the CE/MPA substudy of WHI, an increased risk of coronary heart disease (CHD) events (defined as nonfatal myocardial infarction and CHD death) was observed in women receiving CE/MPA compared to women receiving placebo (37 vs. 30 per 10,000 womenyears). The increase in risk was observed in year one and persisted.
In the same substudy of WHI, an increased risk of stroke was observed in women receiving CE/MPA compared to women receiving placebo (29 vs. 21 per 10,000 women-years). The increase in risk was observed after the first year and persisted.
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 (estropipate) /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. Two thousand three hundred and twenty one women from the original HERS trial agreed to participate in an open label extension of 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/MPA group and the placebo group in HERS, HERS II, and overall.
Large doses of estrogen (estropipate) (5 mg conjugated estrogen (estropipate) s 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.
Venous thromboembolism (VTE)
In the Women's Health study (WHI) an increase in VTE has been observed in women receiving CE compared to placebo. These observations are preliminary, and the study is continuing.
In the CE/MPA treatment substudy of WHI, a 2-fold greater rate of VTE, including deep venous thrombosis and pulmonary embolism, was observed in women receiving treatment with CE/MPA compared to women receiving placebo. The rate of VTE was 34 per 10,000 woman-years in the CE/MPA group compared to 16 per 10,000 woman-years in the placebo group. The increase in VTE risk was observed during the first year and persisted.
If feasible, estrogen (estropipate) s 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.
The use of unopposed estrogen (estropipate) s in women with intact uteri has been associated with an increased risk of endometrial cancer. The reported endometrial cancer risk among unopposed estrogen (estropipate) users is about 2–to-12 fold greater than in nonusers, and appears dependent on duration of treatment and on estrogen (estropipate) dose. Most studies show no significant increased risk associated with use of estrogen (estropipate) s for less than one year. The greatest risk appears associated with prolonged use, with increased risks of 15–to-24 fold for five to ten years or more and this risk has been shown to persist for at least 8 to 15 years after estrogen (estropipate) therapy is discontinued. Clinical surveillance of all women taking estrogen (estropipate) /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 estrogen (estropipate) s results in a different endometrial risk profile than synthetic estrogen (estropipate) s of equivalent estrogen (estropipate) dose. Adding a progestin to estrogen (estropipate) therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.
The use of estrogen (estropipate) s 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) substudy of CE/ MPA (see CLINICAL PHARMACOLOGY, Clinical Studies). The results from observational studies are generally consistent with those of the WHI clinical trial and report no significant variation in the risk of breast cancer among different estrogen (estropipate) s or progestins, doses, or routes of administration.
The CE/MPA substudy of WHI reported an increased risk of breast cancer in women who took CE/MPA for a mean follow-up of 5.6 years. Observational studies have also reported an increased risk for estrogen (estropipate) /progestin combination therapy, and a smaller increased risk for estrogen (estropipate) alone therapy, after several years of use. In the WHI trial and from observational studies, the excess risk increased with duration of use. From observational studies, the risk appeared to return to baseline in about five years after stopping treatment. In addition, observational studies suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen (estropipate) /progestin combination therapy as compared to estrogen (estropipate) alone therapy.
In the CE/MPA substudy, 26% of the women reported prior use of estrogen (estropipate) alone and/or estrogen (estropipate) /progestin combination hormone therapy. After a mean follow-up of 5.6 years during the clinical trial, the overall relative risk of invasive breast cancer was 1.24 (95% confidence interval 1.01–1.54), and the overall absolute risk was 41 vs. 33 cases per 10,000 women-years, for CE/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 vs. 25 cases per 10,000 women-years, for CE/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 vs. 36 cases per 10,000 women-years for CE/MPA compared with placebo. In the same substudy, invasive breast cancers were larger and 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 groups.
The use of estrogen (estropipate) 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 health care 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 Women's Health Initiative Memory Study (WHIMS), 4,532 generally healthy postmenopausal women 65 years of age and older were studied, of whom 35% were 70 to 74 years of age and 18% were 75 or older. After an average follow-up of 4 years, 40 women being treated with CE/MPA (1.8%, n= 2,229) and 21 women in the placebo group (0.9%, n= 2,303) received diagnoses of probable dementia. The relative risk for CE/MPA versus placebo was 2.05 (95% confidence interval 1.21 – 3.48), and was similar for women with and without histories of menopausal hormone use before WHIMS. The absolute risk of probable dementia for CE/MPA versus placebo was 45 versus 22 cases per 10,000 women-years. It is unknown whether these findings apply to younger postmenopausal women. (See CLINICAL PHARMACOLOGY, Clinical Studies and PRECAUTIONS, Geriatric Use.)
A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogen (estropipate) s has been reported.
Estrogen (estropipate) 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.
Retinal vascular thrombosis has been reported in patients receiving estrogen (estropipate) s. 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, estrogen (estropipate) s should be permanently discontinued.
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 (estropipate) administration, or daily with estrogen (estropipate) in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen (estropipate) 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 estrogen (estropipate) s compared to estrogen (estropipate) -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.
Elevated blood pressure
In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogen (estropipate) s. In a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogen (estropipate) s on blood pressure was not seen. Blood pressure should be monitored at regular intervals with estrogen (estropipate) use.
Impaired liver function and past history of cholestatic jaundice
Estrogen (estropipate) s may be poorly metabolized in patients with impaired liver function. For patients with a history of cholestatic jaundice associated with past estrogen (estropipate) use or with pregnancy, caution should be exercised and in the case of recurrence, medication should be discontinued.
Estrogen (estropipate) 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 estrogen (estropipate) s 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.
Because estrogen (estropipate) s may cause some degree of fluid retention, patients with conditions that might be influenced by this factor, such as a cardiac or renal dysfunction, warrant careful observation when estrogen (estropipate) s are prescribed.
Estrogen (estropipate) s should be used with caution in individuals with severe hypocalcemia.
The CE/MPA substudy of WHI reported that estrogen (estropipate) plus progestin increased the risk of ovarian cancer. After an average followup of 5.6 years, the relative risk for ovarian cancer for CE/MPA versus placebo was 1.58 (95% confidence interval 0.77 – 3.24) but was not statistically significant. The absolute risk for CE/MPA versus placebo was 4.2 versus 2.7 cases per 10,000 women-years. In some epidemiologic studies, the use of estrogen (estropipate) alone, in particular for ten or more years, has been associated with an increased risk of ovarian cancer. Other epidemiologic studies have not found these associations.
Exacerbation of endometriosis
Endometriosis may be exacerbated with administration of estrogen (estropipate) s. A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen (estropipate) alone therapy. For patients known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered.
Exacerbation of other conditions
Estrogen (estropipate) s may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine or porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions.
Physicians are advised to discuss the PATIENT INFORMATION leaflet with patients for whom they prescribe OGEN (estropipate) .
Estrogen (estropipate) 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).
Carcinogen (estropipate) esis, Mutagenesis, Impairment Of Fertility
Long-term continuous administration of estrogen (estropipate) , with and without progestin, in women with and without a uterus, has shown an increased risk of endometrial cancer, breast cancer, and ovarian cancer. (See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.)
Long-term continuous administration of natural and synthetic estrogen (estropipate) s in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.
OGEN (estropipate) should not be used during pregnancy. (See CONTRAINDICATIONS.)
Estrogen (estropipate) administration to nursing mothers has been shown to decrease the quantity and quality of the milk. Detectable amounts of estrogen (estropipate) s have been identified in the milk of mothers receiving this drug. Caution should be exercised when OGEN (estropipate) is administered to a nursing woman.
In the Women's Health Initiative Memory Study, including 4,532 women 65 years of age and older, followed for an average of 4 years, 82% (n= 3,729) were 65 to 74 while 18% (n= 803) were 75 and over. Most women (80%) had no prior hormone therapy use. Women treated with conjugated estrogen (estropipate) s plus medroxyprogesterone acetate were reported to have a two-fold increase in the risk of developing probable dementia. Alzheimer's disease was the most common classification of probable dementia in both the conjugated estrogen (estropipate) s plus medroxyprogesterone acetate group and the placebo group. Ninety percent of the cases of probable dementia occurred in the 54% of women that were older than 70. (See WARNINGS, Dementia.)
Last reviewed on RxList: 4/30/2009
This monograph has been modified to include the generic and brand name in many instances.
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