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.
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.
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.
Therefore, the following should be given serious 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.
For the treatment of postmenopausal symptoms, Hormone replacement therapy (HRT) should only be initiated for symptoms/conditions that are consistent with the indications (see INDICATIONS AND CLINICAL USE). In all cases, a careful appraisal of the risks and benefits should be undertaken at least annually and HRT should only be continued as long as the benefit outweighs the risks.
Combined Estrogen and Progestin Therapy:
There are additional and/or increased risks that may be associated with the use of combination estrogen-plus-progestin therapy compared with using estrogen-alone regimens. These include an increased risk of myocardial infarction, pulmonary embolism, invasive breast cancer and ovarian cancer.
Systematic absorption may occur with the use of Premarin® Vaginal Cream. Warnings and precautions associated with oral Premarin® treatment should be taken into account.
NOTE: Preliminary studies conducted by the Health Products and Food Branch have demonstrated that Premarin® Vaginal Cream may react with the latex rubber of certain mechanical barrier devices used for prevention of sexually transmitted diseases and pregnancy (diaphragms and condoms). In additional studies, Premarin® Vaginal Cream has been shown to weaken latex condoms. The potential for Premarin® Vaginal Cream to weaken and contribute to the failure of condoms, diaphragms, or cervical caps made of latex or rubber should be considered.
Carcinogenesis and Mutagenesis
Available epidemiological data indicate that the use of combined estrogen plus progestin by postmenopausal women is associated with an increased risk of invasive breast cancer.
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).
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 year one and persisted in each year thereafter.
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.
It is recommended that estrogens 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 of breast cancer (first degree relative) or who present a breast condition with an increased risk (abnorma1 mammograms and/or atypical hyperplasia at breast biopsy).
Other known risk factors for the development of breast cancer such as nulliparity, obesity, early menarche, late age at first full term pregnancy and at menopause should also be evaluated.
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
The use of unopposed estrogens has been associated with an increased risk of endometrial hyperplasia/carcinoma. Estrogen should be prescribed with an appropriate dosage of a progestin for women with intact uteri or hysterectomized women with a history of residual endometriosis in order to prevent endometrial hyperplasia/carcinoma (see WARNINGS AND PRECAUTIONS, Endometriosis).
The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12-fold or greater than in non-users and appears to be dependent on duration of treatment and on estrogen dose. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for five years or more, and this risk has been shown to persist for at least 8 to15 years after ERT is discontinued. Adding a progestin to postmenopausal estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer (see WARNINGS AND PRECAUTIONS, General).
Clinical surveillance of all women taking combined estrogen plus progestin HRT 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.
In some epidemiologic studies, the use of estrogen therapy, in particular for 5 or more years, has been associated with an increased risk of ovarian cancer.
ERT has been reported to increase the risk of stroke and deep venous thrombosis (DVT).
Risk factors for cardiovascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) should be managed appropriately.
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. The results of the WHI trial indicate that the use of estrogen-alone and estrogen plus progestin is associated with an increased risk of stroke in postmenopausal women.
Patients who are at risk of developing migraines with aura may be at risk of ischemic stroke and should be kept under careful observation.
Should a stroke occur or be suspected, Premarin® Vaginal Cream should be discontinued immediately.
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).
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/was:
- 12 more cases of stroke (44 on estrogen-alone therapy versus 32 on placebo)
- no statistically significant difference in the rate of CHD.
HERS and HERS II findings
In the Heart and Estrogen/progestin Replacement Study (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.
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.
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.
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.
Caution should be exercised in patients with pre-existing hypertriglyceridemia since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with estrogen therapy in this population.
Women with porphyria need special surveillance.
Estrogens should be used with caution in individuals with pre-existing severe hypocalcemia.
Calcium and phosphorus metabolism
Because the prolonged use of estrogens influences the metabolism of calcium and phosphorus, estrogens should be used with caution in patients with metabolic and malignant bone diseases associated with hypercalcemia and in patients with renal insufficiency.
Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Patients who require thyroid hormone replacement therapy and who are also taking estrogen may require increased doses of their thyroid replacement therapy. These women should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range (see Drug-Laboratory Test Interactions).
Symptoms and physical findings associated with a previous diagnosis of endometriosis may reappear or become aggravated with estrogen use. A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen-alone therapy. For women known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered.
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.
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.
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 oral 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.
In the oral 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.
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 > 30 kg/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 to 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, Premarin® Vaginal Cream should be discontinued immediately, given the risks of long-term disability or fatality.
If feasible, Premarin® Vaginal Cream 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.
Patients who have previously had liver disorders such as liver adenoma should be closely supervised as this condition may recur or be aggravated during treatment with Premarin® Vaginal Cream.
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 HRT may cause an exacerbation of this 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. Estrogens may be poorly metabolized in patients with impaired liver functions.
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 Monitoring and Laboratory Tests.
Systemic lupus erythematosus
Particular caution is indicated in women with systemic lupus erythematosus, as HRT may cause an exacerbation of this condition.
Exogenous estrogens may induce or exacerbate symptoms of angioedema, particularly in women with hereditary angioedema.
Patients who develop visual disturbances, classical migraine, transient aphasia, paralysis or loss of consciousness should discontinue medication.
Patients with a previous history of classical migraine and who develop a recurrence or worsening of migraine symptoms should be reevaluated.
Ophthalmologic: If visual abnormalities develop: Discontinue Premarin® Vaginal Cream 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, Premarin® Vaginal Cream should be withdrawn. Retinal vascular thrombosis has been reported in patients receiving estrogens with or without progestins (see WARNINGS AND PRECAUTIONS, Hematologic, Venous thromboembolism).
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.
It is unknown whether these findings apply to younger postmenopausal women (see Special Populations, Geriatrics).
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 2.5 mg 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).
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.
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).
Particular caution is indicated in women with epilepsy, as HRT may cause an exacerbation of this condition.
Estrogens should be used with caution in patients with otosclerosis.
Patients who are taking progestogens and have a history of depression should be observed. If the depression occurs to a serious degree, the drug should be discontinued.
Estrogens may cause fluid retention.
Therefore, particular caution is indicated in cardiac, 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: Premarin® Vaginal Cream is contraindicated during pregnancy (see CONTRAINDICATIONS). If pregnancy occurs during medication with PREMARIN treatment should be withdrawn immediately.
Nursing Women: Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of breast milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving the drug. Where an assessment of the risk to benefit ratio suggests the use of this product in nursing women is unfavourable, formula feeding should be substituted for breast feeding.
Pediatrics (< 16 years of age): Premarin® Vaginal Cream is not indicated for use in children. Safety and effectiveness in pediatric population have not been established. Estrogen treatment of prepubertal girls induces premature breast development and vaginal cornification, and may induce uterine bleeding.
Since large and repeated doses of estrogen over an extended time period have been shown to accelerate epiphyseal closure, hormonal therapy should not be started before epiphyseal closure has occurred in order not to compromise final growth.
Geriatrics (> 65 years of age): The estrogen-alone substudy of the Women’s Health Initiative (WHI) reported an increased risk of stroke compared with placebo in postmenopausal women 65 years of age or older (see WARNINGS AND PRECAUTIONS, Cardiovascular, and CLINICAL TRIALS).
There have not been sufficient numbers of geriatric women involved in clinical studies utilizing Premarin ® Vaginal Cream to determine whether those over 65 years of age differ from younger subjects in their response to Premarin ® Vaginal Cream.
Information for Patients
No studies on the effect of ability to drive or use machines have been performed.
Monitoring and Laboratory Tests
Before Premarin® Vaginal Cream is administered, the patient should have a complete physical examination including 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. Before starting treatment pregnancy should be excluded. Periodic check-ups and careful benefit/risk evaluations should be undertaken in women treated with ERT/HRT therapy. The first follow-up examination should be done within three to six months of initiation of treatment to assess response to treatment. Thereafter, examinations should be made at intervals of at least once a year. Appropriate investigations should be arranged at regular intervals as determined by the physician.
Mammography examinations should be scheduled based on patient age, risk factors and prior mammogram results.
The importance of regular self-examination of the breasts should be discussed with the patient.