Biest

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Biest

Dosage Strength

Estriol / Estradiol (50/50) Estriol / Estradiol (70/30) Estriol / Estradiol (80/20)

General Information

Estradiol is the principal intracellular human estrogen and is substantially more active than its metabolites, estrone and estriol, at the cellular level. Estradiol can be obtained from natural sources or prepared synthetically. There is no evidence that 'natural' estrogens are more or less efficacious or safe than 'synthetic' estrogens.1 Due to almost complete first-pass metabolism, estradiol must be given in a micronized oral dosage form to ensure therapeutic effect. Estradiol is available in many dosage forms, including oral tablets, transdermal systems, topical emulsions, topical gels, topical sprays, vaginal creams, vaginal rings, and parenteral depot injections. Vaginal therapies are preferred in postmenopausal women with exclusive genitourinary symptoms, due to lower systemic absorption/exposure with most of these dosage forms. Unopposed estrogen has been associated with increased risk of endometrial cancer in menopausal women with an intact uterus; concomitant progestin therapy reduces, but does not eliminate, this risk. In men with advanced prostate cancer, estrogens exert their effect by inhibition of the hypothalamic-pituitary axis through negative feedback. This results in decreased secretion of luteinizing hormone (LH). Decreased testosterone production from the Leydig cells in the testes occurs, which may decrease tumor growth and lower prostate specific antigen (PSA) levels. Improvement in bone metastasis may also occur. In the past, high-dose estrogen therapy was also used in selected men and postmenopausal women with inoperable, progressive breast cancer. Since the development of selective estrogen receptor modifiers (SERMs), high-dose estrogen therapy for the palliative treatment of breast cancer is rarely used today. The primary source of estrogens in premenopausal women is the ovary, which normally secretes 0.07 to 0.5 mg of estradiol daily, depending on the phase of the menstrual cycle. Once estrogens enter the cells of responsive tissues (e.g., female organs, breasts, hypothalamus, pituitary), they increase the rate of synthesis of DNA, RNA, and some proteins. The secretion of gonadotropin-releasing hormone by the hypothalamus is reduced during estrogen administration, causing reduction in follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary. Exogenous estrogens elicit all of the actions of endogenous estrogens. Estrogens are responsible for the growth and development of female sex organs and the maintenance of sex characteristics including growth of axillary and pubic hair and shaping of body contours and skeleton. At the cellular level, estrogens increase cervical secretions, cause proliferation of the endometrium, and increase uterine tone. Paradoxically, prolonged administration of estrogen can shrink the endometrium. During the preovulatory or nonovulatory phase of the menstrual cycle, withdrawal of estrogen can initiate menstruation; in the ovulatory phase, the decrease in progesterone secretion is the more significant factor causing menstruation. In post-menopausal use, amenorrhea occurs in most women within several months of oral estrogen use. Estrogens have a weak anabolic effect and also can affect bone calcium deposition and accelerate epiphysial closure. Estrogens appear to prevent osteoporosis associated with the onset of menopause. Estrogens generally have a favorable effect on blood lipids, reducing LDL- and increasing HDL-cholesterol concentrations on average, by 15%. Serum triglycerides increase with estrogen administration. Estrogens increase the rate of synthesis of many proteins, including thyroid binding globulin and several clotting factors. Estrogens reduce levels of antithrombin III, and increase platelet aggregation. Estrogens also enhance sodium and fluid retention.

Mechanisms of Action

Interactions

Bromocriptine is used to restore ovulation and ovarian function in amenorrheic women.43 Estrogens can cause amenorrhea and, therefore, counteract the desired effects of bromocriptine. Concurrent use is not recommended. Estrogens can increase calcium absorption. In general, the interaction between calcium salts and estrogen is beneficial and is used to therapeutic advantage in postmenopausal women who have osteoporosis. However, this interaction may not be advantageous in patients predisposed to hypercalcemia or nephrolithiasis. Cyclosporine may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness.4 Estrogens have reportedly potentiated the anti-inflammatory effects of hydrocortisone.50 Patients should be monitored for increased corticosteroid effects if estrogens, oral contraceptives, or non-oral combination contraceptives are used with hydrocortisone. Concurrent use of HRT in female patients receiving anticoagulation therapy with warfarin is generally avoided. If concurrent use of an estrogen or estrogen-progestin containing HRT cannot be avoided in a patient taking warfarin, carefully monitor for signs and symptoms of thromboembolic complications. Raloxifene58 exerts its effects by blocking estrogen receptors. Since raloxifene and estrogens are pharmacological opposites, it would be illogical to co administer them. Cimetidine has been reported to reduce the hepatic clearance of estradiol; this interaction may partially explain the association between cimetidine therapy and gynecomastia.

Contraindictions / Precautions

The primary source of estrogens in premenopausal women is the ovary, which normally secretes 0.07 to 0.5 mg of estradiol daily, depending on the phase of the menstrual cycle. Once estrogens enter the cells of responsive tissues (e.g., female organs, breasts, hypothalamus, pituitary), they increase the rate of synthesis of DNA, RNA, and some proteins. The secretion of gonadotropin-releasing hormone by the hypothalamus is reduced during estrogen administration, causing reduction in follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary. Exogenous estrogens elicit all of the actions of endogenous estrogens. Estrogens are responsible for the growth and development of female sex organs and the maintenance of sex characteristics including growth of axillary and pubic hair and shaping of body contours and skeleton. At the cellular level, estrogens increase cervical secretions, cause proliferation of the endometrium, and increase uterine tone. Paradoxically, prolonged administration of estrogen can shrink the endometrium. During the preovulatory or nonovulatory phase of the menstrual cycle, withdrawal of estrogen can initiate menstruation; in the ovulatory phase, the decrease in progesterone secretion is the more significant factor causing menstruation. In post-menopausal use, amenorrhea occurs in most women within several months of oral estrogen use. Estrogens have a weak anabolic effect and also can affect bone calcium deposition and accelerate epiphysial closure. Estrogens appear to prevent osteoporosis associated with the onset of menopause. Estrogens generally have a favorable effect on blood lipids, reducing LDL- and increasing HDL-cholesterol concentrations on average, by 15%. Serum triglycerides increase with estrogen administration. Estrogens increase the rate of synthesis of many proteins, including thyroid binding globulin and several clotting factors. Estrogens reduce levels of antithrombin III, and increase platelet aggregation. Estrogens also enhance sodium and fluid retention. Indications Estradiol is primarily used to prevent osteoporosis and relieve vasomotor and genitourinary symptoms associated with menopause (natural or surgical), for postmenopausal osteoporosis prevention, and is also used to treat female hypogonadism and other abnormalities of female gonadotropin dysfunction. Contraindications / Precautions Do not use estradiol products in patients with a known hypersensitivity to any of the specific product ingredients; estradiol is contraindicated in patients with known anaphylactic reactions or history of angioedema to the drug. Cases of both anaphylactic reactions and angioedema have been reported in patients taking estrogens, including estradiol. The use of estrogen-alone and estrogen plus progestin has been reported to result in an increase in abnormal mammograms, requiring further evaluation. All women taking estrogen with or without a progestin should receive an annual clinical breast examination, perform monthly self-examinations, and have regular mammograms as recommended by their health care professional based on patient age, risk factors, and prior mammogram results. Estradiol products are contraindicated in women with estrogen-dependent neoplasms, including ovarian cancer. Estrogen therapy is contraindicated in patients with known estrogen-dependent malignancies. There is an association of unopposed estrogen therapy and endometrial cancer in women with an intact uterus. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Estrogens are contraindicated in the presence of vaginal cancer, cervical cancer, uterine cancer, or other estrogen-responsive tumors. Clinical surveillance of all women using estrogen-alone or estrogen plus progestin therapy is important; all women receiving estrogen treatment should have an annual pelvic examination and other diagnostic or screening tests, such as cervical cytology, as clinically indicated or as generally recommended based on age, risk factors, and other individual needs. Because estrogens influence the growth of endometrial tissues, use estradiol products cautiously in women with endometriosis or uterine leiomyomata (uterine fibroids). Estrogens are contraindicated in patients with an active or past history of thrombophlebitis, thromboembolism, thromboembolic disease, stroke, or myocardial infarction (MI). An increased risk of cerebrovascular disease (stroke) and deep venous thrombosis (DVT) has been reported with unopposed estrogen therapy. An increased risk of thromboembolism, including pulmonary embolism (PE), DVT, stroke and myocardial infarction (MI) has been reported with estrogen plus progestin hormone replacement therapy (HRT). Estrogens are also contraindicated for patients with known protein C deficiency, protein S deficiency, or antithrombin deficiency or other known thrombophilic disorders associated with increased risk of venous thrombosis. Other risk factors for arterial vascular disease (e.g., hypertension, diabetes, tobacco smoking, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) [e.g., personal history or family history of VTE, obesity, or systemic lupus (SLE)] should be monitored and managed appropriately. Estrogens may cause some degree of fluid retention. Women with conditions that might be influenced by this factor, such as a cardiac disease, warrant careful observation when estrogens are prescribed. In men treated with estrogens for palliation of prostate or breast cancer, estrogens have increased the risk of nonfatal MI, PE, and thrombophlebitis. Estrogens may be poorly metabolized in women with impaired liver function. Estrogens are contraindicated in the presence of hepatocellular cancer, hepatic adenoma, or in severe hepatic disease of any type. Patients with systemic lupus erythematosus (SLE) may have increased risk for thromboembolism and should be managed appropriately when estrogen therapy is considered. In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Consider discontinuation of estradiol treatment if pancreatitis occurs. Patients with diabetes mellitus should be observed for changes in glucose tolerance when initiating or discontinuing estrogen therapy, since estrogen therapy may exacerbate diabetes. Altered glucose tolerance secondary to decreased insulin sensitivity has been reported. Use estradiol with caution in patients with thyroid disease, particularly hypothyroidism. Estrogens can increase thyroid-binding globulin (TBG) levels. Patients with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Patients dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These patients should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range. Mood disorders, like depression, may be aggravated in women taking exogenous estrogens. Women with a history of depression may need special monitoring. If significant depression occurs, estradiol should be discontinued.

Pregnancy / Breast Feeding

Estrogens are contraindicated during pregnancy. There is no known approved indication for the use of estrogens during pregnancy. There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins from oral contraceptives inadvertently during early pregnancy.Estradiol and other estrogens freely cross the placenta to the fetus. Increased risk of a wide variety of fetal abnormalities, including modified development of sexual organs, cardiovascular anomalies and limb defects, have been reported following the continued use of estrogens in pregnant women. In any patient in whom pregnancy is suspected, pregnancy should be ruled out before continuing estrogen use.6 In select instances estradiol has been used off-label as an adjuvant to clomiphene treatment of infertility, or in donor oocyte program procedures in assisted reproduction technology (ART) under the direction of ART specialists; however, treatment is discontinued when pregnancy ensues

Caution should be used if a breast-feeding mother is receiving estradiol for hormone replacement. Estrogen administration to nursing women is generally avoided during lactation as estrogens have been shown to decrease the quantity and quality of the breast milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving estradiol and other estrogens.Estrogens are not approved by the FDA for the treatment of postpartum breast engorgement.

Adverse Reactions / Side Effects

Changes in sexuality include libido increase or libido decrease. Positive changes in libido may occur as a result of improvements in vulvar and vaginal atrophy in postmenopausal women. Vaginal changes such as discharge or irritation, vaginitis, cervicitis, or changes in cervical erosion (e.g., cervical ectropion) may appear. Vulvovaginal or vaginal candidiasis or other mycotic infections may occur infrequently with systemic or vaginal estrogen therapy. Estrogens may also cause enlargement of uterine leiomyomatas (fibroids), if present. Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow, breakthrough bleeding, spotting, and dysmenorrhea have been noted with estrogens and/or progestins and are commonly reported. When estrogens are used for the treatment of hypogonadism in premenopausal females, continued amenorrhea may signal a lack of response to estrogen therapy. Unusual vaginal bleeding, menorrhagia, or spotting that persists beyond 6 months in any woman on estrogen therapy should be evaluated by a healthcare professional. For women who have a uterus, adequate diagnostic measures such as endometrial sampling, when indicated, should be undertaken to rule out malignancy in cases of undiagnosed persistent or recurring abnormal vaginal bleeding. Women who take estrogens should follow current recommendations for periodic pelvic examinations, including Papanicolaou smears when indicated to detect cervical dysplasia. Mastalgia (breast pain) is a common adverse effect of estrogens such as estradiol. Breast tenderness, breast enlargement, breast discharge, galactorrhea, and fibrocystic breast changes have been reported with estrogens and/or progestin therapy. Gynecomastia may occur in men on estrogen therapy. Patients should report breast changes, lumps, or breast discharge to their health care professionals. All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results. Stomach/abdominal pain or cramps, bloating, nausea, and vomiting are common side effects of estrogens such as estradiol; these effects may attenuate with continued treatment. Diarrhea is infrequent with estradiol use. A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery (e.g., cholecystitis) in postmenopausal women receiving estrogens has been reported. Estrogens may be poorly metabolized in patients with impaired liver function. For patients with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, use estradiol cautiously. If cholestatic jaundice recurs, discontinue the estrogen. Deep and superficial venous thrombosis, pulmonary embolism, thrombophlebitis, myocardial infarction, and stroke have been reported with estrogens and/or progestin therapy. The use of estrogens in postmenopausal women, with or without a progestin, carries a risk for thromboembolism, and cardiovascular events such as myocardial infarction (MI) or stroke. Estrogens such as estradiol can cause sodium and fluid retention, resulting in peripheral edema or mild weight gain. They should be prescribed cautiously to patients in whom the presence of edema would be detrimental. Headache, with no other symptoms, has been noted with use of estrogens such as estradiol, including with vaginal therapy. Mental depression, nervousness or anxiety, mood disturbances such as emotional lability and irritability have been reported with estrogens such as estradiol and/or progestin therapy. Complaints of insomnia or fatigue may be associated with the underlying menopausal complaints or may be associated with treatment. Women with a history of depression may need special monitoring. If significant depression occurs, estradiol should be discontinued. Estrogens and progestins are both susceptible to drug interactions with hepatic enzyme inducing drugs such as the carbamazepine family;barbiturates;rifampin, rifabutin, or rifapentine. Concurrent administration of said drugs with estrogens, oral contraceptives, non-oral combination contraceptives, or progestins may increase the hormone's elimination. Erythromycin, amiodarone, systemic azole antifungals (fluconazole, itraconazole, ketoconazole, miconazole, posaconazole, and voriconazole), clarithromycin, conivaptan, danazol, dalfopristin,dasatinib, delavirdinine, diltiazem, duloxetine, fluvoxamine, imatinib, mifepristone, RU-486, propoxyphene, telithromycin, troleandomycin, verapamil, zafirlukast, zileuton: these compounds may increase plasma concentrations of estrogens and cause estrogen-related side effects. Interactions between anti-retroviral protease inhibitors and estrogens or progestins are complex. It may be prudent to use caution and careful monitoring during coadministration of fosamprenavir or other retrovirals with estrogens or progestins.

Storage

Store this medication at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain.