Source: Health Products and Food Branch (CA) Revision Year: 2017
Estrogen and estrogen/progestin combinations are contraindicated in patients with any of the following conditions/disorders:
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:
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.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.30
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 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.
Estrogen-only HRT increases the risk of endometrial hyperplasia (if taken by women with intact uteri).
The incidence of endometrial hyperplasia is lowered with sequential co-administration of a progestin (see administration of progestins under DOSAGE AND ADMINISTRATION). One case of endometrial hyperplasia (0.45%) among 222 patients in the OESCLIM 50-treated group was reported in an uncontrolled clinical trial conducted to evaluate the tolerability of OESCLIM over a twelve-month period. Time of onset was between 271-360 days into the treatment phase in a patient treated continuously with OESCLIM 50. The patient was withdrawn 343 days after the inclusion visit (Vi), after 329 days of exposure to the transdermal systems.
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.
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.6,9,31 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.30,31
In the combined estrogen plus progestin arm of the WHI trial, among 10,000 women over a oneyear period, there were:
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:
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 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 hormonetreated group than in the placebo group in year 1, but not during the subsequent years.9
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.6
Women using hormonal replacement therapy (HRT) 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 therapy may have to be discontinued.
A worsening of glucose tolerance and lipid metabolism have 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 or porphyria need special surveillance. Lipid-lowering measures are recommended additionally, before treatment is started.
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.
Patients who require thyroid hormone replacement therapy and who are also 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.31
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.30
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) and 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, hormone therapy should be discontinued immediately, given the risks of long-term disability or fatality.
If feasible, estrogens 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 gallbladder disease requiring surgery in women receiving postmenopausal estrogens 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.
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.
Benign hepatic adenomas have been associated with the use of combined estrogen and progestagen oral contraceptives. Although benign and rare, these tumours may rupture and cause death from intra-abdominal hemorrhage. Such lesions have not yet been reported in association with other estrogen or progestagen preparations, but they should be considered if abdominal pain and tenderness, abdominal mass, or hypovolemic shock occurs in patients receiving estrogen.
Hepatocellular carcinoma has also been reported in women taking estrogen-containing oral contraceptives. The causal relationship of this malignancy to these drugs is not known.
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.
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 (estrogen plus progestin or estrogen-alone) reduces the risk of dementia in women aged 65 and over and free of dementia at baseline.26,27
In the estrogen plus progestin arm of the WHIMS (n=4532), women with an intact uterus 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:
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:
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 oneyear period, there were:
Estrogens with or without progestins may cause fluid retention. Therefore, particular caution is indicated in cardiac or renal dysfunction, epilepsy 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.
Contact sensitization is known to occur with topical applications. Although it is extremely rare, patients who develop contact sensitization to any component of the patch should be warned that a severe hypersensitivity reaction may occur with continuing exposure to the causative agent.
Before OESCLIM 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. An endometrial biopsy should be done 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. It is important that patients are encouraged to practice frequent self-examination of the breasts.
See Warnings and Precautions regarding potential induction of malignant neoplasms and adverse effects similar to those of oral contraceptives.
The following adverse reactions have been reported with the use of estrogen/progestin combination in general.
Blood and lymphatic system disorders: Altered coagulation tests (see Warnings and Precautions, Drug-Laboratory Tests Interactions).
Cardiac disorders: Palpitations; increase in blood pressure (see Warnings and Precautions); coronary thrombosis.
Endocrine disorders: Increased blood sugar levels; decreased glucose tolerance.
Eyes disorders: Neuro-ocular lesions (e.g. retinal thrombosis, optic neuritis); visual disturbances; steepening of the corneal curvature; intolerance to contact lenses.
Gastrointestinal disorders: Nausea; vomiting; abdominal discomfort (cramps, pain, pressure); bloating.
General disorders and administration site conditions: Fatigue; changes in appetite; changes in body weight; change in libido.
Hepatobiliary disorders: Gallbladder disorder, asymptomatic impaired liver function; cholestatic jaundice.
Musculoskeletal and connective tissue disorders: Musculoskeletal pain including leg pain not related to thromboembolic disease (usually transient, lasting 3-6 weeks) may occur.
Nervous System disorders: Aggravation of migraine episodes; headaches; dizziness; neuritis.
Psychiatric disorders: Mental depression; nervousness; irritability.
Renal and urinary disorders: Cystitis; dysuria; sodium retention; edema.
Reproductive system and breast disorders: Breakthrough bleeding, spotting; change in menstrual flow, dysmenorrhea; vaginal itching/discharge, dyspareunia, endometrial hyperplasia, pre-menstrual-like syndrome; reactivation of endometriosis; changes in cervical erosion and amount of cervical secretion, breast swelling and tenderness.
Skin and subcutaneous tissue disorders: Cloasma or melasma, which may persist when drug is discontinued; erythema multiforme; hemorrhagic eruption; loss of scalp hair; hirsutism and acne.
Vascular disorders: Isolated cases of: thrombophlebitis, thromboembolic disorders.
If adverse symptoms persist, the prescription of HRT should be reconsidered.
Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
The most commonly reported adverse reaction to OESCLIM in clinical trials was application site reaction. 9 patients (28.1%) in Study # 1, 85 patients (38.3%) in Study #2 and 37 patients (25.9%) in Study #3 presented at least one local skin reaction. In all three clinical trials, 4.2% of all applications caused local skin reactions, which included redness, itching, spots, burning and swelling. Of the 22,239 applications in the three clinical trials, 1,017 (4.6%) patches became detached. The second most frequent adverse reactions were symptoms of specific estrogen therapy intolerance reported by a total of 193 patients (48.6%) treated with OESCLIM in the 3 clinical trials: 119 (30%) presented signs of hyperestrogenism including mastodynia (38.8 % to 53.8 % of the cases of hyperestrogenism), 116 (38.5%) non-hysterectomised patients presented metrorrhagia and spotting.
Estrogens may diminish the effectiveness of anticoagulant, antidiabetic and antihypertensive agents.
Preparations inducing liver enzymes, (e.g., barbiturates, hydantoins, carbamazepine, meprobamate, phenylbutazone or rifampicin) may interfere with the activity of orally administered estrogens.
The extent of interference with transdermally administered estradiol-17β is not known. Given that the first-pass effect in the liver is avoided by transdermal administration, transdermally applied estrogens may be less affected by enzyme inducers than oral estrogen preparations.
Clinical pharmacokinetic studies have not demonstrated any consistent effect of antibiotics (other than rifampin) on plasma concentrations of synthetic steroids.
It was found that some herbal products (e.g. St. John’s wort), which are available as over-thecounter (OTC) products, may affect metabolism, and therefore, efficacy and safety of estrogen/progestin products.
Physicians and other healthcare providers should be aware of other non-prescription products concomitantly used by the patient, including herbal and natural products, widely available in health food stores.
The results of certain endocrine and liver function tests may be affected by estrogen-containing products:
In clinical trials with transdermal estradiol-17β, no effect on fibrinogen, antithrombin III, TBG, CBG or SHBG and decreases in serum triglycerides were seen.2
The results of the above laboratory tests should not be considered reliable unless therapy has been discontinued for 2 to 4 weeks. The pathologist should be informed that the patient is receiving estrogen therapy when relevant specimens are submitted.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
