Estrogel (Estradiol Topical) - Warnings and Precautions

WARNINGS

See BOXED WARNINGS.

1. Cardiovascular Disorders

   
   

   Estrogen-alone therapy has been associated with an increased risk of stroke and deep vein thrombosis (DVT).

   Estrogen-plus-progestin therapy has been associated with an increased risk of myocardial infarction as well as stroke, venous thrombosis and pulmonary embolism. Should any of these events occur or be suspected, estrogens should be discontinued immediately.

   
   

   Risk factors for arterial vascular disease (eg, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (eg, personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately.

   
   

   Stroke : In the WHI estrogen-alone substudy of the Women's Health Initiative (WHI) study, a statistically significant increased risk of stroke was reported in women receiving CE 0.625 mg daily compared to women receiving placebo (44 vs 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, 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.

   
   

   1. 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 CHD death) was reported in women receiving estrogen-alone compared to women receiving placebo. (See CLINICAL STUDIES.)

      
      

      In the estrogen-plus-progestin substudy of WHI, no statistically significant increase of CHD events was reported in women receiving CE/MPA compared to women receiving placebo (39 vs 33 per 10,000 women-years). An increase in relative risk was demonstrated in year one, and a trend toward decreasing relative risk was reported in years 2 through 5.

      In the estrogen-plus-progestin substudy of WHI, 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.

      
      

      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. Two thousand three hundred 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 (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.

      
      

   2. Venous thromboembolism (VTE) : In the estrogen-alone substudy of WHI, the risk of VTE (DVT and pulmonary embolism [PE]), was reported for women receiving CE 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. (See CLINICAL STUDIES.)

      
      

      In the CE/MPA 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 observed during the first year and persisted. (See CLINICAL STUDIES.)

      
      

      If feasible, estrogens should be discontinued at least 4 to 6 weeks before any surgery associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.

      
      

2. Malignant Neoplasms

   
   

   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-fold greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than 1 year. The greatest risk appears to be 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.

   
   

   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.

   
   

   1. 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 5 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 of 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 2 groups. Other prognostic factors, such as histologic subtype, grade and hormone receptor status did not differ between the groups.

      
      

      The use of 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.

      
      

3. Dementia

   
   

   In the estrogen-alone Women's Health Initiatives Memory Study (WHIMS), a substudy of WHI, a population of 2947 hysterectomized women aged 65 to 79 years was randomized to CE (0.625 mg daily) or placebo. In the estrogen plus progestin WHIMS, a population of 4532 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 estrogen alone vs placebo was 1.49 (95% CI, 0.83-2.66). The absolute risk of probable dementia for estrogen alone vs placebo was 37 vs 25 cases per 10,000 women-years. It is unknown whether these findings apply to younger postmenopausal women. (See CLINICAL STUDIES and PRECAUTIONS, Geriatric Use.)

   
   

   In the estrogen-plus-progestin substudy, after an average follow-up of 4 years, 40 women in the CE/MPA group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE/MPA 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 2 populations were pooled as planned in the WHIMS protocol, the reported overall 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, Geriatric Use.)

   
   

4. Gallbladder Disease

   
   

   A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.

   
   

5. Hypercalcemia

   
   

   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.

   
   

7. Alcohol-based gels are flammable. Avoid fire, flame, or smoking until the gel has dried.

PRECAUTIONS

A. General

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 (eg, 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.
3. Hypertriglyceridemia
   In patients with preexisting hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis and other complications.
4. Impaired liver function and past history of cholestatic jaundice
   Although topically administered estrogen therapy avoids first-pass hepatic metabolism, 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.
5. Hypothyroidism
   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 in order to maintain an acceptable range.
6. Fluid retention
   Because estrogens 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 estrogens are prescribed.
7. Hypocalcemia
   Estrogens should be used with caution in individuals with severe hypocalcemia.
8. Ovarian cancer
   The CE/MPA substudy of the WHI study reported that after an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE/MPA vs placebo was 1.58 (95% nCI, 0.77-3.24) but was not statistically significant. The absolute risk for CE/MPA vs placebo was 4.2 vs 2.7 cases per 10,000 women-years. In some epidemiologic studies, the use of estrogen alone, 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 endometriosis
   Endometriosis may be exacerbated with administration of estrogen therapy. A few cases of malignant transformation of residual endometrial implants have 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.
11. Photosensitivity/Photoallergy
    Increased sensitivity to direct exposure to the sun on areas of EstroGel application has not been evaluated.
12. Effect of sunscreen application
    The effects of concomitant application of EstroGel and a sunscreen lotion have not been evaluated.