Serious Warnings and Precautions
The Women’s Health Initiative (WHI) trial examined thehealth benefits and risks of oral estrogen-alone therapy (n=10,739) in postmenopausal women aged 50 to 79 years.
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 should not be prescribed for primary or secondary prevention of cardiovascular diseases.
- Estrogens should be prescribed at the lowest effective dose for the approved indication.
- Estrogens should be prescribed for the shortest period possible for the approved indication.
Carcinogenesis and Mutagenesis
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 (abnormal 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 hormone therapy (HT) 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 HT should be fully considered and discussed with patients.
Instructions for regular self-examination of the breasts should be included in this counselling.
Endometrial hyperplasia & endometrial carcinoma
An increased risk of endometrial hyperplasia and endometrial carcinoma has been reported with the use of unopposed estrogen therapy in women with a uterus. The reported endometrial cancer risk among unopposed estrogen users is about 2 to 12 times greater than in nonusers, and appears dependent on duration of treatment and on estrogen dose.
DUAVIVE contains a SERM. This component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component of DUAVIVE. Endometrial hyperplasia may be a precursor to endometrial cancer. Women taking DUAVIVE should not take additional estrogens as this may increase the risk of endometrial hyperplasia.
Break-through bleeding and spotting may occur during treatment. If break-through bleeding or spotting appears after some time on therapy, or continues after treatment has been discontinued, the reason should be investigated. The investigation may include endometrial biopsy to exclude endometrial malignancy.
Some recent epidemiologic studies have found that the use of estrogen-alone therapies, in particular for five or more years, has been associated with an increased risk of ovarian cancer.
The results of the WHI trial indicate that the use of estrogen-alone is associated with an increase in the risk of stroke in postmenopausal women.
WHI trial findings
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.
Should a stroke occur or be suspected, DUAVIVE should be discontinued immediately (see CONTRAINDICATIONS).
Women using HT sometimes experience increased blood pressure. Blood pressure should be monitored with HT use. Elevation of blood pressure in previously normotensive or hypertensive patients should be investigated and HT 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.
DUAVIVE has not been studied in women with baseline triglyceride levels >300 mg/dL (>3.4 mmol/L).
Bazedoxifene may increase serum triglyceride levels; therefore, caution should be exercised in women with known hypertriglyceridemia. Bazedoxifene has not been studied in women with triglyceride levels >300 mg/dL (>3.4 mmol/L).
In women with pre-existing hypertriglyceridemia, treatment with estrogens alone may be associated with further elevations of plasma triglycerides leading to pancreatitis and other complications. Consider discontinuation of DUAVIVE if pancreatitis occurs.
Women with porphyria need special surveillance
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 remain in an acceptable range (see Drug-Laboratory Test Interactions).
DUAVIVE contains lactose. In patients with rare hereditary galactose intolerance, lactase deficiency or glucose-galactose malabsorption, the severity of the condition should be taken into careful consideration before prescribing DUAVIVE. The patients should be closely monitored.
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.
Venous thromboembolism (VTE)
Available epidemiological data indicate that use of estrogens by postmenopausal women is associated with an increased risk of developing venous thromboembolism (VTE).
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.
SERMs (including bazedoxifene, the SERM component of DUAVIVE) and estrogens individually are known to increase the risk of VTE.
Women with active or past history of VTE should not take DUAVIVE (see CONTRAINDICATIONS).
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 HT, 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, DUAVIVE should be discontinued immediately, given the risks of long-term disability or fatality.
If feasible, DUAVIVE 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. In addition, women taking DUAVIVE should be advised to move about periodically during travel involving prolonged immobilization.
A 2 to 4 fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens alone has been reported.
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. DUAVIVE may be poorly metabolized in patients with impaired liver function.
Particular caution is indicated in women with hepatic hemangiomas as estrogens may cause an exacerbation of this condition.
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.
Estrogens may induce or exacerbate symptoms of angioedema, in particular in women with hereditary angioedema.
Systemic lupus erythematosus
Particular caution is indicated in women with systemic lupus erythematosus.
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.
The Women's Health Initiative Memory Study (WHIMS), a clinical substudy of the WHI, was designed to assess whether postmenopausal HT(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.
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.
Particular caution is indicated in women with epilepsy, as estrogens with or without progestins may cause an exacerbation of this condition.
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.
The pharmacokinetics of DUAVIVE has not been adequately evaluated in women with renal impairment, therefore use in this population is not recommended (see DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions).
The safety of DUAVIVE in premenopausal women has not been established, and its use is not recommended.
DUAVIVE must not be used in women who are or may become pregnant (see CONTRAINDICATIONS and TOXICOLOGY, Reproduction and Teratology).
DUAVIVE should not be used by lactating women (see CONTRAINDICATIONS). It is not known whether this drug is excreted in human milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving conjugated estrogens. Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk.
DUAVIVE is not indicated for pediatric use.
Geriatrics (> 75 years of age)
DUAVIVE has not been studied in women over 75 years of age, therefore DUAVIVE is not recommended for women over 75 years of age (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Geriatrics and CLNICAL TRIAL, Geriatric use).
Use in Women with High Body Mass Index (BMI)
Following DUAVIVE administration, the systemic exposures of conjugated estrogens and bazedoxifene were lower in obese women, compared to non-obese women. (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions). A greater reduction in bazedoxifene exposure may be associated with an increased risk of endometrial hyperplasia. Monitor and evaluate women with postmenopausal or unexplained genital bleeding for possible endometrial hyperplasia or malignancy.
Monitoring and Laboratory Tests
Before DUAVIVE 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. 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, prior mammogram results, and/or other risk factors.
The importance of regular self-examination of the breasts should be discussed with the patient.