Source: Health Products and Food Branch (CA) Revision Year: 2016
Estragyn Vaginal Cream should not be administrated to patients with any of the following conditions:
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 oneyear 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 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).
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 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.
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
In the combined estrogen plus progestin arm of the WHI trial, among 10,000 women over a one-year 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:
In the Heart and Estrogen/progestin Replacement Studies (HERS) of postmenopausal women with documented heart disease (n=2,763,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, 2,321 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.
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.
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 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.
Estrogens may induce or exacerbate symptoms of angioedema, in particular in women with hereditary angioedema.
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.
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=4,532), 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:
In the estrogen-alone arm of the WHIMS (n=2,947), 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 one-year period, there were:
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 (please see CONTRAINDICATIONS).
Nursing Women: Estragyn Vaginal Cream should not be used during lactation (please see CONTRAINDICATIONS).
Pediatrics (<16 years of age): Estragyn Vaginal Cream is not indicated for use in children.
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.
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 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.
Eye 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, pressure, pain, 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: Chloasma or melasma, which may persist when drug is discontinued; erythema multiforme; erythema nodosum; haemorrhagic eruption; loss of scalp hair; hirsutism and acne.
Vascular disorders: Isolated cases of: thrombophlebitis; thromboembolic disorders.
Clinical Trial Adverse Drug Reactions: Data are not available.
Less Common Clinical Trial Adverse Drug Reactions: Data are not available.
Case #1- Complaint of a burning sensation.
Case# 2- Complaint of inflammation and vaginal discharge.
Estrogens may diminish the effectiveness of anticoagulant, antidiabetic and antihypertensive agents.
Preparations inducing liver enzymes (e.g. barbiturates, hydantoins, carbamazepine, meprobamates, phenylbutazone or rifampicin) may interfere with the activity of orally administered estrogens.
Potential Drug-Drug Interactions Summary as Associated With Estrogen Therapy:
| Proper Name or Drug Classes | Reference | Effect | Clinical Comment |
|---|---|---|---|
| Oral antidiabetic drugs | The Essential Guide to Prescription Drugs 2002 Author: James J. Rybacki, Pharm. D. | May cause loss of glucose control and high blood sugars. | Caution is warranted and therapeutic concentration monitoring is recommended |
| Warfarin | May cause alterations of prothrombin activity. | ||
| Rifampin | May decrease the effects of estrogens | ||
| Anticonvulsants: Barbiturates (Phenobarbital) Phenytoin Carbamazepine Primidone | The Essential Guide to Prescription Drugs 2002 Author: James J. Rybacki, Pharm. D. | May decrease the effects of estrogens | Caution is warranted and therapeutic concentration monitoring is recommended |
| Corticosteroids | Fiche professionnelle Santexpert | May increase the effects of Corticosteroids | |
| Ascorbic acid | Health Canada Branch | May increase AUC and/or plasma concentrations of ethinyl estradiol | |
| Acetaminophen | May increase AUC and/or plasma concentrations of ethinyl estradiol | ||
| Atorvastatin (Lipitor) | The Essential Guide to Prescription Drugs 2002 Author: James J. Rybacki, Pharm. D. | May increase AUC for ethinyl estradiol by as much as 20% | |
| Cyclosporine | Health Canada Branch | Ethinyl estradiol may cause increased plasma concentrations of cyclosporine | |
| Prednisolone | Ethinyl estradiol may cause increased plasma concentrations of prednisolone. | ||
| Theophylline | Ethinyl estradiol may cause increased plasma concentrations of theophylline. | ||
| Troglitazone | Co-administrated with certain ethinyl estradiol drug (e.g. oral contraceptives) may reduce plasma concentrations of estradiol by as much as 30% | ||
| Salicylic acid | May increase clearance of salicylic acid. | ||
| Temazapam | May increase clearance of temazapam | ||
| Morphine | Health Canada Branch | May increase clearance of morphine | |
| Clofibric acid | May increase clearance of Clofibric acid |
As other inhibitors of CYP3A4, grapefruit juice may increase plasma concentrations of estrogens, possibly resulting in side effects.
It was found that some herbal products (e.g. St. John’s wort) which are available as overthe-counter (OTC) products might interfere with steroid metabolism and therefore alter the efficacy and safety of estrogen /progestin products.
Physicians and other health care providers should be aware of other non-prescription products concomitantly used by the patient, including herbal and natural products, obtained from the widely spread Health Stores.
The results of certain endocrine and liver function test may be affected by estrogencontaining products:
The results of the above laboratory tests should not be considered reliable unless therapy has been discontinued for two to four weeks.
The pathologist should be informed that the patient is receiving hormone replacement therapy (HRT) when relevant specimens are submitted.
Acute alcohol ingestion during HRT may lead to elevations in circulating estradiol levels.
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