Serious WARNINGS AND PRECAUTIONS Box
Serious WARNINGS AND PRECAUTIONS
The Women's Health Initiative (WHI) trial examined the health benefits and risks of oral combined estrogen plus progestin therapy (n=16,608) and oral estrogen–alone therapy (n=10,739) in postmenopausal women aged 50 to 79 years.1,2,3
The estrogen plus progestin arm of the WHI trial (mean age 63.3 years) indicated an increased risk of myocardial infarction (MI), stroke, invasive breast cancer, pulmonary emboli and deep vein thrombosis in postmenopausal women receiving treatment with combined conjugated equine estrogens (CEE, 0.625 mg/day and medroxyprogesterone acetate(MPA, 2.5 mg/day) for 5.2 years compared to those receiving placebo.1
The estrogen-alone arm of the WHI trial ( mean age 63.6 years ) indicated an increased risk of stroke and deep vein thrombosis in hysterectomized women treated with CEE alone (0.625 mg/day) for 6.8 years compared to those receiving placebo.2
Therefore, the following should be given consideration at the time of prescribing:
- Estrogens with or without progestins should not be prescribed for primary or secondary prevention of cardiovascular diseases.
- Estrogens with or without progestins should be prescribed at the lowest effective dose for the approved indication.
- Estrogens with or without progestins should be prescribed for the shortest period possible for the approved indication.
Carcinogenesis And Mutagenesis
In the estrogen plus progestin arm of the WHI trial, among 10,000 women over a one-year period, there were:
- 8 more cases of invasive breast cancer (38 on combined HRT versus 30 on placebo).1
The WHI study also reported that the invasive breast cancers diagnosed in the estrogen plus progestin group were similar in histology but were larger (mean [SD], 1.7 cm [1.1] vs 1.5 cm [0.9], respectively; P=0.04) and were at a more advanced stage compared with those diagnosed in the placebo group. The percentage of women with abnormal mammograms (recommendations for short-interval follow-up, a suspicious abnormality, or highly suggestive of malignancy) was significantly higher in the estrogen plus progestin group versus the placebo group. This difference appeared at one year and persisted in each year thereafter.3
In the estrogen–alone arm of the WHI trial, there was no statistically significant difference in the rate of invasive breast cancer in hysterectomized women treated with conjugated equine estrogens versus women treated with placebo.2
It is recommended that estrogens with or without progestins not be given to women with existing breast cancer or those with a previous history of the disease (see CONTRAINDICATIONS).
There is a need for caution in prescribing estrogens for women with known risk factors associated with the development of breast cancer, such as strong family history breast cancer (first degree relative) or who present a breast condition with an increased risk (abnormal mammograms and/or atypical hyperplasia at breast biopsy).
It is recommended that women undergo mammography prior to the start of HRT treatment and at regular intervals during treatment, as deemed appropriate by the treating physician and according to the perceived risks for each patient.
The overall benefits and possible risks of hormone replacement therapy should be fully considered and discussed with patients. It is important that the modest increased risk of being diagnosed with breast cancer after 4 years of treatment with combined estrogen plus progestin HRT (as reported in the results of the WHI trial) be discussed with the patient and weighed against its known benefits.
Instructions for regular self-examination of the breasts should be included in this counselling.
Endometrial Hyperplasia & Endometrial Carcinoma
Estragyn Vaginal Cream, an estrogen only HRT, increases the risk of endometrial hyperplasia/carcinoma if taken by women with intact uteri. Estrogen should be prescribed with an appropriate dosage of a progestin for women with intact uteri in order to prevent endometrial hyperplasia/carcinoma.
Some recent epidemiologic studies have found that the use of hormone replacement therapy (estrogen-alone and estrogen plus progestin therapies), in particular for five or more years, has been associated with an increased risk of ovarian cancer.8,9
The results of the Heart and Estrogen /progestin Replacement Studies (HERS and HERS II) and the Women's Health Initiative (WHI) trial indicate that the use of estrogen plus progestin is associated with an increased risk of coronary heart disease (CHD) in postmenopausal women.1,4,5 The results of the WHI trial Indicate that the use of estrogenalone and estrogen plus progestin is associated with an increased risk of stroke in postmenopausal women.1,2
WHI trial findings
In the combined estrogen plus progestin arm of the WHI trial, among 10,000 women over a one–year period, there were:
- 8 more cases of stroke (29 on combined HRT versus 21 on placebo)
- 7 more cases of CHD (37 on combined HRT versus 30 on placebo).¹
In the estrogen-alone arm of the WHI trial of women with prior hysterectomy, among 10,000 women over a one year period, there were:
- 12 more cases of stroke (44 on estrogen-alone therapy versus 32 on placebo)
- No statistically significant difference in the rate of CHD.2
HERS and HERS II findings
In the Heart and Estrogen/progestin Replacement Studies (HERS) of postmenopausal women with documented heart disease ( n=2763,average age 66.7 years), a randomized placebo-controlled clinical trial of secondary prevention of coronary heart disease (CHD), treatment with 0.625 mg/day oral conjugated equine estrogen (CEE) plus 2.5 mg oral medroxyprogesterone acetate (MPA) demonstrated no cardiovascular benefit. Specifically, during an average follow-up of 4.1 years, treatment with CEE plus 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 hormone-treated group than in the placebo group in year 1, but not during the subsequent years.4 From the original HERS trial, 2321 women consented to participate in an open label extension of HERS known as HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. After 6.8 years, hormone therapy did not reduce the risk of cardiovascular events in women with CHD.5
Women using hormone replacement therapy sometimes experience increased blood pressure. Blood pressure should be monitored with HRT use. Elevation of blood pressure in previously normotensive or hypertensive patients should be investigated and HRT may have to be discontinued.
Estrogens should be used with caution in patients with otosclerosis.
Endocrine And Metabolism
Glucose and lipid metabolism
A worsening of glucose tolerance and lipid metabolism has been observed in a significant percentage of peri- and post-menopausal patients. Therefore, diabetic patients or those with a predisposition to diabetes should be observed closely to detect any alterations in carbohydrate or lipid metabolism, especially in triglyceride blood levels.
Women with familial hyperlipidemias need special surveillance. Lipid-lowering measures are recommended additionally, before treatment is started.
Women with porphyria need special surveillance.
Calcium and phosphorous metabolism
Because the prolonged use of estrogens with or without progestins influences the metabolism of calcium and phosphorus, estrogens with or without progestins should be used with caution in patients with metabolic and malignant bone diseases associated with hyperglycaemia and in patients with renal insufficiency.
Patients who require thyroid hormone replacement therapy and who are taking estrogen should have their thyroid function monitored regularly to assure that thyroid hormone levels remain in an acceptable range (see Drug-Laboratory Test Interactions).
Abnormal vaginal bleeding, due to its prolongation, irregularity or heaviness, occurring during therapy should prompt appropriate diagnostic measures to rule out the possibility of uterine malignancy and the treatment should be re-evaluated.
Pre-existing uterine leiomyomata may increase in size during estrogen use. Growth, pain or tenderness of uterine leiomyomata requires discontinuation of medication and appropriate investigation.
Symptoms and physical findings associated with a previous diagnosis of endometriosis may reappear or become aggravated with estrogen use.
Available epidemiological data indicate that use of estrogen with or without progestin by postmenopausal women is associated with an increased risk of developing venous thromboembolism(VTE).
In the estrogen plus progestin arm of the WHI trial, among 10,000 women on combined HRT over a one-year period, there were 18 more cases of venous thromboembolism, including 8 more cases of pulmonary embolism.1
In the estrogen-alone arm of the WHI trial, among 10,000 women on estrogen therapy over a one-year period, there were 7 more cases of venous thromboembolism, although there was no statistically significant difference in the rate of pulmonary embolism.2
Generally recognized risk factors for VTE include a personal history, a family history (the occurrence of VTE in a direct relative at a relatively early age may indicate genetic predisposition), severe obesity (body mass index > 30kg/m²) and systemic lupus erythematosus. The risk of VTE also increases with age and smoking.
The risk of VTE may be temporarily increased with prolonged immobilization, major surgery or trauma. In women on HRT, attention should be given prophylactic measures to prevent VTE following surgery. Also, patients with varicose veins should be closely supervised. The physician should be alert to the earliest manifestations of thrombotic disorders (thrombophlebitis, retinal thrombosis, cerebral embolism and pulmonary embolism). If these occur or are suspected, hormone replacement therapy should be discontinued immediately, given the risks of long-term disability or fatality.
If feasible, estrogens with or without progestins should be discontinued at least 4 weeks before major surgery which may be associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.
A 2- to 4- fold increase in the risk of gallbladder disease requiring surgery in women receiving postmenopausal estrogens has been reported.
Particular caution is indicated in women with hepatic hemangiomas as estrogens may cause an exacerbation of the condition.
Caution is advised in patients with a history of liver and/or biliary disorders. If cholestatic jaundice develops during treatment, the treatment should be discontinued and appropriate investigations carried out.
Liver function tests
Liver function tests should be done periodically in subjects who are suspected of having hepatic disease. For information on endocrine and liver function tests, see the section under Monitoring and Laboratory Tests.
Systemic Lupus erythematosus
Particular caution is indicated in women with systemic lupus erythematosus.
Available epidemiological data indicate that the use of combined estrogen plus progestin in women age 65 and over may increase the risk of developing probable dementia.
The Women's Health Initiative Memory Study (WHIMS), a clinical substudy of the WHI, was designed to assess whether postmenopausal hormone replacement therapy (oral estrogen plus progestin or oral estrogen-alone) reduces the risk of dementia in women aged 65 and over (age range 65-79 years) and free of dementia at baseline.6,7
In the estrogen plus progestin arm of the WHIMS (n=4532), women with intact uteri were treated with daily 0.625 mg conjugated equine estrogens (CEE) plus 2.5mg medroxyprogesterone acetate (MPA) or placebo for an average of 4.05 years. The results, when extrapolated to 10,000 women treated over a one-year period showed:
- 23 more cases of probable dementia (45 on combined HRT versus 22 on placebo).6
In the estrogen-alone arm of the WHIMS (n=2947), women with prior hysterectomy were treated with daily 0.625 mg CEE or placebo for an average of 5.21 years. The results, when extrapolated to 10,000 women treated over a one-year period showed:
- 12 more cases of probable dementia (37 on estrogen-alone versus 25 on placebo), although this difference did not reach statistical significance.7
When data from the estrogen plus progestin arm of the WHIMS and the estrogen-alone arm of the WHIMS were combined, as per the original WHIMS protocol, in 10,000 women over a one-year period, there were:
- 18 more cases of probable dementia (41 on estrogen plus progestin or estrogen-alone versus 23 on placebo).7
Particular caution is indicated in women with epilepsy, as estrogens with or without progestins may cause an exacerbation of this condition.
Estrogens with or without progestins may cause fluid retention.
Therefore particular caution is indicated in cardiac or renal dysfunction, or asthma. If, in any of the above-mentioned conditions, a worsening of the underlying disease is diagnosed or suspected during treatment, the benefits and risks of treatment should be reassessed based on the individual case.
Pregnant Women: Estragyn Vaginal Cream should not be used during pregnancy.
Nursing Women: Estragyn Vaginal Cream should not be used during lactation.
Pediatrics ( < 16 years of age): Estragyn Vaginal Cream is not indicated for use in children.
Monitoring and laboratory Tests
Before Estragyn Vaginal Cream is administered, the patient should have a complete physical examination including a blood pressure determination. Breasts and pelvic organs should be appropriately examined and a Papanicolaou smear should be performed. Endometrial biopsy should be done only when indicated. Baseline tests should include mammography, measurements of blood glucose, calcium, triglycerides and cholesterol, and liver function tests. The first follow-up examination should be done within 3-6 months after initiation of treatment to assess response to treatment. Thereafter, examinations should be made at intervals at least once a year. Appropriate investigations should be arranged at regular intervals as determined by the physician.
The importance of regular self-examination of the breasts should be discussed with the patient.
1. Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. Principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002; 288(3):321-333
2. The Women's Health Initiative steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy. The Women's Health Initiative randomized controlled trial. JAMA. 2004; 291(14):1701 – 1712.
3. Chlebowski RT, Hendrix SL, Langer RD, Stefanick ML, Grass M, Lane D, et al. The Women's Health Initiative randomized trial. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women. JAMA. 2003;289(24):3243-3253
4. Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, et al for the Heart and Estrogen/progestin Replacement Study (HERS) Research group. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA.1998;280(7):605-613
5. Grady D, Herrington D, Bittner V, Blumenthal R, Davidson M, Hlatky M, et al for the HERS Research Group. Cardiovascular disease outcomes during 6.8 years of hormone therapy. Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA.2002; 288(1):49-57.
6. Shumaker SA, Legault C, Rapp SR, Thal L, Wallace RB, Ockene JK, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women. The Women's Health Initiative Memory Study: A randomized controlled trial. JAMA.2003; 289(20):2651-2662.
7. Shumaker SA, Legault C, Kuller L, Rapp SR, Thal L, Lane DS, et al. Conjugated Equine Estrogens and Incidence of Probable Dementia and Mild Cognitive Impairment in Postmenopausal Women. Women's Health Initiative Memory Study. JAMA.2004; 291(24):2947-2958.
8. Beral V, Million Women Study Collaborators, Bull D, Green J, Reeves G, Ovarian cancer and hormone replacement therapy in the Million Women Study. Lancet 2007; 369(9574):1703-10
9. Lacey JV, Brinton LA, Leitzmann MF, Mouw t, Hollenbeck A, Schatzkin A, et al. Menopausal hormone therapy and ovarian cancer risk in the National Institutes of Health-AARP Diet and Health Study Cohort, J Natl Cancer Inst. 2006; 98(19): 1397-405.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 3/31/2014
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