Estrace

It was found that some herbal products (e.g. St. John's wort) which are available as over-the-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 made aware of other non-prescription products concomitantly used by the patient, including herbal and natural products obtained from the widely spread health stores.

The effect of lifestyle choices (e.g. smoking) on the use of ESTRACE has not been established.

Inhibitors of CYP 3A4 such as grapefruit juice may increase plasma concentrations of estrogens and may result in side effects.

Possible drug-drug interactions with ESTRACE specifically have not been established.

The results of certain endocrine and liver function tests may be affected by estrogen-containing products.

• increased prothrombin time and partial thromboplastin time; increased levels of fibrinogen and fibrinogen activity; increased coagulation factors VII, VIII, IX, X;

  
  

• decreased antithrombin III (although following administration of ESTRACE for 28 days no effect on antithrombin III levels was seen); increased norepinephrine-induced platelet aggregability;

  
  

• increased thyroxine-binding globulin (TBG) (although TBG was not affected in clinical trials with ESTRACE), leading to increased circulating total thyroid hormone (T₄) as measured by column or radioimmunoassay; T₃ resin uptake is decreased, reflecting the elevated TBG, free T₄ concentration is unaltered.

  
  

• other binding proteins may be elevated in serum i.e. corticosteroid binding globulin (CBG), sex-hormone binding globulin (SHBG), leading to increased circulating corticosteroids and sex steroids respectively; free or biologically active hormone concentrations are unchanged;

  
  

• reduced serum folate concentration;

  
  

• increased serum triglyceride and phospholipid concentrations;

  
  

• impaired glucose tolerance.

  
  

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 HRT when relevant specimens are submitted.

Estrogens may diminish the effectiveness of anticoagulants, antidiabetic and antihypertensive agents.

In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP 3A4). Therefore, inducers or inhibitors of CYP 3A4 may affect estrogen drug metabolism. Inducers of CYP 3A4 such as St. John’s Wort (Hypericum perforatum) preparations, phenobarbital, carbamazepine and rifampin may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in uterine bleeding profile. Inhibitors of CYP 3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may increase plasma concentrations of estrogens and may result in side effects.

Other preparations inducing liver enzymes, (e.g. barbiturates, hydantoins, meprobamate or phenylbutazone) may interfere with the activity of orally administered estrogens.

One in vitro study has shown Cytochrome 1A2 (CYP 1A2) to be partially involved in the metabolism of 17β-estradiol through hydroxylation. The clinical significance of CYP 1A2 metabolism is unknown.

Clinical pharmacokinetic studies have not demonstrated any consistent effect of antibiotics (other than rifampin) on plasma concentrations of synthetic steroids.

Treatment of menopausal symptoms is usually initiated with 1 mg ESTRACE tablet per day. Thereafter, the dosage should be adjusted to the needs of the individual. Attempts to taper or discontinue the medication should be made at 3 to 6 month intervals.

The lowest dose of estrogen required to prevent menopausal symptoms and to prevent development of osteoporosis should be used. ESTRACE should be taken at the same time each day.

ESTRACE should be taken as soon as possible after missing a dose. However the missed dose should be skipped if it is almost time to take the next dose. Patients should be advised not to double the dose.

In general, estrogen is usually administered cyclically for the first 21 to 25 days of each month. In patients with intact uteri a progestin should be sequentially administered for the last 12 to 14 days of estrogen administration in order to prevent development of endometrial hyperplasia/carcinoma as a result of estrogen stimulation.

In hysterectomized patients, estrogen alone should be given continuously.

Prophylactic therapy with ESTRACE to prevent postmenopausal bone loss should be initiated with 0.5 mg ESTRACE tablet per day as soon as possible after menopause. The dose may be titrated upward and downward based on the patient's clinical status and plasma estradiol levels. Ideally, plasma estradiol levels should be maintained around 50 pg/mL.

breakthrough bleeding; spotting; change in menstrual flow; dysmenorrhea; vaginal itching/discharge; dyspareunia; endometrial hyperplasia; increase in size of uterine leiomyomata; vaginal candidiasis; pre-menstrual-like syndrome; reactivation of endometriosis; changes in cervical erosion and amount of cervical secretion; increased cervical mucous; breast swelling, tenderness and secretion.

neuro-ocular lesions (e.g., retinal thrombosis, optic neuritis); visual disturbances; steepening of the corneal curvature; intolerance to contact lenses.

increased blood sugar levels; decreased glucose tolerance.

Precipitation or aggravation of porphyria cutanea tarda in predisposed individuals.

fatigue; changes in appetite; anorexia; changes in body weight; change in libido.

palpitations; increase in blood pressure (see Warnings and Precautions); coronary thrombosis.

aggravation of migraine episodes; headaches; dizziness; neuritis.

cystitis; dysuria; sodium retention; edema.

chloasma or melasma, which may persist when drug is discontinued; pigmentation of skin; erythema multiforme; erythema nodosum; haemorrhagic eruption; itching, allergic reactions and rashes; loss of scalp hair; hirsutism and acne.

Musculoskeletal pain including leg pain not related to thromboembolic disease (usually transient, lasting 3-6 weeks) may occur.

gallbladder disorder; asymptomatic impaired liver function; cholestatic jaundice.

Isolated cases of: thrombophlebitis; thromboembolic disorders.

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:

Altered coagulation tests (see Drug Interactions, Drug-Laboratory Test Interactions).

If adverse symptoms persist, the prescription of HRT should be reconsidered.

nausea; vomiting; abdominal discomfort (cramps, pressure, pain, bloating).

mental depression; nervousness; irritability.

Numerous reports of ingestion of large doses of estrogen products and estrogen-containing oral contraceptives by young children have not revealed acute serious ill effects. Over dosage with estrogen may cause nausea, breast discomfort, fluid retention, bloating or vaginal bleeding in women.

Remove ingested drug by gastric lavage and give symptomatic treatment.

Each lavender, round, flat-faced, bevel-edged compressed tablet, with MJ logo and “755” on one side and scored on the reverse, contains: estradiol-17β (micronized) 1 mg. Nonmedicinal ingredients: acacia, dibasic calcium phosphate, cornstarch, D&C Red No. 27 aluminum lake, FD&C Blue No. 1, lactose, magnesium stearate, silicon dioxide and talc. Bottles of 100.

Each white, round, flat-faced, bevel-edged compressed tablet, with MJ logo and “021” on one side and scored on the reverse, contains: estradiol-17β (micronized) 0.5 mg. Nonmedicinal ingredients: acacia, dibasic calcium phosphate, cornstarch, lactose, magnesium stearate, silicon dioxide and talc. Bottles of 100.

Each turquoise, round, flat-faced, bevel-edged compressed tablet, with MJ logo and “756” on one side and scored on the reverse, contains: estradiol-17β (micronized) 2 mg. Nonmedicinal ingredients: acacia, dibasic calcium phosphate, cornstarch, FD&C Blue No. 1, FD&C Yellow No. 5 aluminum lake (tartrazine), lactose, magnesium stearate, silicon dioxide and talc. Bottles of 100.

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.

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.

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, 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.

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.

In a pivotal clinical study with ESTRACE (n=64) on the prevention of early post-menopausal bone loss, three (3) abnormal mammograms were reported post-treatment, however, none showed evidence of malignancy.

It is recommended that estrogens not be given to women with existing breast cancer or those with a previous history of the disease. 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 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 counseling.

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.

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.

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 and free of dementia at baseline.

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).

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.

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.

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 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.

Particular caution is indicated in women with epilepsy, as HRT may cause an exacerbation of this condition.

Symptoms and physical findings associated with a previous diagnosis of endometriosis may reappear or become aggravated with estrogen use.

The use of unopposed estrogen by women with intact uteri increases the risk of endometrial hyperplasia and endometrial carcinoma. Estrogen should be prescribed with an appropriate dosage of a progestin in women with intact uteri in order to prevent endometrial hyperplasia/carcinoma.

During the conduct of a pivotal clinical study in an open-labeled study of 369 women (mean age=49) with endogenous estrogen deficiency associated with menopausal symptoms, endometrial biopsies were conducted in a subset of 32 subjects prior to and after therapy. Prior to therapy eleven (11) samples were considered abnormal: cystic hyperplasia (4), adenomatous hyperplasia (6) and mixed-inactive hyperplasia (1). One (1) sample biopsy remained abnormal after 11 months of treatment with ESTRACE, changing from cystic hyperplasia to benign cystic hyperplasia.

In a second pivotal clinical study on the prevention of early post-menopausal bone loss, exit endometrial biopsy specimens were obtained for 21 subjects. Abnormalities consistent with estrogen stimulation of the endometrium were found in 27% of these subjects. Two (2) subjects had progression to the point of adenomatous hyperplasia and one (1) subject had atypical nuclear changes. No subjects, however, developed adenocarcinoma of the endometrium.

The use of combined estrogen plus progestin in women aged 65 and over may increase the risk of developing probable dementia (see Warnings and Precautions, Neurologic).

Recent epidemiologic studies have found 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.

Before ESTRACE 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.

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 need special surveillance. Lipid-lowering measures are recommended additionally, before treatment is started.

Women with porphyria need special surveillance.

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.

Estrogens 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.

A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in women receiving postmenopausal estrogens has been reported.

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.

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.

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).

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.

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.

Estrogens circulate in both unconjugated and conjugated forms in the blood, with the unconjugated estrogens, either free or bound to proteins, mainly albumin, or to the specific sex-hormone binding globulin (SHBG) which shows a great affinity for estradiol.

A number of steroids with 3 oxygen functions have been identified such as 16-epiestriol, 16-ketoestradiol, 16-hydroxyestrone and 2-methoxyestrone with estradiol being a precursor to these compounds.

Micronized 17 β-estradiol is efficiently absorbed by the gastrointestinal tract. The drug passes through the gastrointestinal mucosa and directly into the liver via the portal circulation before its access by the systemic circulation.

Estradiol is the most potent physiologic estrogen and, in fact, is the major estrogenic hormone secreted in humans. Estradiol controls the development and maintenance of the female sex organs, the secondary sex characteristics and the mammary glands as well as certain functions of the human uterus and accessory organs, particularly the proliferation of the endometrium, the development of the decidua, and the cyclic changes in the cervix and vagina. The production of estradiol by the ovaries is under the control of pituitary gonadotropins, follicle stimulating hormone (FSH) and luteinizing hormone (LH). In menopausal women, the depletion of ovarian follicles leads to lower plasma estradiol and elevated plasma FSH and LH.

The active ingredient in ESTRACE tablets is derived from soy beans and it contains only one estrogen, 17β-estradiol, which is structurally identical to the estradiol produced by the human ovary. Estrogens are secreted mainly by the gonads and in a very small amount by the adrenals. In addition, they are formed, to an important degree, from peripheral conversion of adrenal and gonadal androgens to estrogens.

Estradiol is the most potent of the known naturally occurring estrogens in stimulating the growth of the reproductive tissues. Estradiol promotes uterine growth in the rat without undergoing chemical transformation and responsive tissues, such as the uterus and vagina, show a characteristic affinity for estradiol.

Estrogen deficiency is manifested by hot flushes, sweating, insomnia, paresthesia, irritability, and urogenital atrophy. As replacement therapy in estrogen deficiency states (such as menopause), low doses of estradiol in cyclic regimens have been found to relieve such deficiency.

Estrogen deficiency is the main cause of postmenopausal bone loss and contributes to age-associated losses leading to osteoporosis. Numerous clinical studies have demonstrated that estrogen therapy prevents bone loss and reduces the incidence of vertebral, hip, and Colles' fractures.

Although the mechanism of action of estrogen on bone metabolism is still not completely elucidated, estrogens have been shown to have several effects: increase in renal tubular absorption of calcium, thus reducing urinary calcium; decrease in the sensitivity of bone to the parathyroid hormone (PTH); increase in the intestinal absorption of calcium and increase in circulating levels of active 1-25-dihydroxyvitamin D. Recent research has shown that osteoblasts also possess receptors for estrogens.

When administered to humans, about 65% of the dose is excreted in the urine, almost entirely in the water-soluble form as β-glucuronides or sulfate esters. Estrone, estradiol and estriol account for about 1/2 of the excreted products.

Estrogens are metabolized mainly in the liver, with the metabolites being conjugated with glucuronic acid or sulfuric acid and even double conjugates such as estriol-3-sulfate-16α-glucuronide are formed. About 1/3 to 1/2 of the circulating estrogens are secreted in the bile and of this fraction 20% is reabsorbed after hydrolysis in the intestinal tract. The exact site of the hydrolysis is not known, but it probably takes place in the intestinal lumen and is catalyzed by enzymes secreted into the intestinal tract or present in the microflora.