Estradiol-17b – Norethindrone Acetate – Estradiol-17b
Estrogen – Progestin
Action And Clinical Pharmacology: Estracomb is designed to provide continuous estrogen and sequential progestin therapy, in a 28-day treatment cycle, for women with an intact uterus.
Estracomb contains 2 types of transdermal therapeutic systems, Estraderm 50 (10 cm and Estragest 250/50 (20 cm. Estraderm 50 contains estradiol-17b and Estragest 250/50 contains norethindrone acetate (NETA) and estradiol-17b, respectively.
Both transdermal therapeutic systems included in Estracomb are designed to deliver daily about 50 Âµg estradiol-17b, a physiologic hormone, transdermally into the systemic circulation. Due to the transdermal route of administration, the estradiol-17b does not undergo first-pass liver metabolism. Resultant estradiol-17b plasma levels, which are between 30 and 40 pg/mL above baseline (typically 10 pg/mL), are comparable to those seen in premenopausal women in the early follicular phase of the menstrual cycle. Estradiol-17b stimulates target tissues such as the uterus, breast and vagina.
NETA is administered only when the transdermal therapeutic system Estragest 250/50 is correctly used. NETA, after hydrolysis to the active form, NET (norethindrone), shares some of the biological effects of the endogenously produced progestin, progesterone. Like progesterone, NET induces protein synthesis thereby limiting excessive growth stimulation of the endometrium by estrogen. NET induces the enzyme 17b-hydroxysteroid-dehydroxygenase, which locally oxidizes estradiol to estrone. After application of an Estragest 250/50 patch, plasma NET levels range between 0.5 and 1.0 ng/mL.
The tissue effects of NET are dependent on prior estrogen stimulation. One of the major target organs for NET is the uterus, where it acts by inducing secretory transformation of the estrogen-primed endometrium. Once transformation of the endometrium is completed, the estrogen-primed endometrium is shed resulting in a regular cyclical bleeding. However, amenorrhea has also been reported to occur during treatment with Estracomb.
Estrogen replacement therapy decreases the rate of bone loss in menopausal women; evidence of estrogen receptors on bone cells suggests there is a direct effect of estrogen on bone.
Description: The first type of transdermal system to be applied on the skin to initiate a 28-day treatment cycle is Estraderm 50. Estraderm 50 is a thin, round, multilayer, transparent transdermal therapeutic system, i.e., an adhesive patch, containing estradiol-17b that is designed for application to an area of intact skin.
The Estraderm 50 patch comprises 5 layers. Proceeding from the visible surface toward the surface attached to the skin, these layers are: 1. a transparent polyester backing film ; 2. a drug reservoir of estradiol-17b and ethanol gelled with hydroxypropyl cellulose; 3. an ethylene vinyl acetate copolymer release-controlling membrane ; 4. an adhesive formulation of light mineral oil and polyisobutylene; 5. a protective liner of siliconized polyethylene terephthalate film that is attached to the adhesive surface and must be removed before the patch can be used.
The active component of the patch is estradiol-17b. The drug reservoir provides a source for continuous delivery of drug for up to 4 days.
The second type of transdermal therapeutic system to be applied on the skin during the last 14 days of a 28-day treatment cycle is Estragest 250/50. Estragest 250/50 is a thin, twin-shaped, multilayer, transparent patch, with 2 separate drug reservoir chambers and an adhesive surface for application to an area of intact skin. Estragest 250/50 is comprised of the same 5 layers as Estraderm 50. The active substances are released from the drug reservoirs, penetrate the skin and pass directly into the bloodstream (see Supplied).
Estragest 250/50 contains a fixed combination of norethindrone acetate (NETA) and estradiol-17b. Estragest 250/50 releases controlled amounts of NETA and estradiol-17b simultaneously through the skin for up to 4 days.
Indications And Clinical Uses: The relief of menopausal and postmenopausal symptoms occurring in naturally or surgically induced estrogen deficiency states.
Estracomb is also indicated for the prevention of osteoporosis in naturally occurring or surgically induced estrogen-deficiency states in addition to other important therapeutic measures such as adequate diet and regular exercise.
Estracomb is recommended for the above indications only in patients with an intact uterus since the regimen includes a progestin whose role is to prevent endometrial hyperplasia.
Contra-Indications: Estracomb should not be administered to patients with any of the following conditions: active hepatic dysfunction or disease, especially of the obstructive type; known or suspected breast cancer; known or suspected estrogen-dependent neoplasia; endometrial hyperplasia; undiagnosed abnormal vaginal bleeding; porphyria; known or suspected pregnancy; a history of cerebrovascular accident, coronary thrombosis, or in the presence of classical migraine; active thrombophlebitis, thrombosis or thromboembolic disorders; partial or complete loss of vision from ophthalmic vascular disease; known or suspected hypersensitivity to any component of the patch.
Manufacturers’ Warnings In Clinical States: There is evidence from several studies that estrogens, unopposed by progestins, increase the risk of carcinoma of the endometrium in humans. Estracomb provides plasma norethindrone (NET) levels within the therapeutic range to counteract the effects of estradiol-17b on the endometrium. However, the overall impact on health from progestin administration to postmenopausal women is not completely known.
Breast cancer is a multifactorial disease, which increases in frequency in older age. Much of the etiology of breast cancer is unknown. Several published epidemiological studies have documented an association between a modest increase in the risk of developing breast cancer and the use of hormone replacement therapy in menopause when given for periods exceeding 5 years. Information is still lacking to show whether the risks of combination estrogen-progestin therapy differ from those of estrogen used alone. It is recommended to avoid giving estrogens to women previously treated for breast cancer. There is a need for caution in prescribing estrogens for women with a strong family history of breast cancer or who present breast nodules, fibrocystic disease of the breast, or abnormal mammograms. 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 a mammography be performed before starting treatment and repeated at regular intervals in patients at high risk for breast cancer.
The overall benefits and possible risks of hormone replacement therapy should be fully considered and discussed with patients. Instructors for self-examination of the breasts should be included in this counselling.
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.
Benign hepatic adenomas have been associated with the use of combined estrogen and progestin oral contraceptives. Although benign and rare, these tumors may rupture and cause death from intra-abdominal hemorrhage. Such lesions have not yet been reported in association with other estrogen or progestin 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.
The relatively small number of epidemiological studies assessing the relation between hormone replacement therapy and risk of venous thromboembolism has led to conflicting results. While earlier studies have not shown an association, some epidemiological studies have suggested that, for healthy women, there is an increased relative risk of about 2 to 3.6 for developing deep vein thrombosis or pulmonary embolism for current users of hormone replacement therapy compared to nonusers.
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. Women with severe varicose veins, severe obesity (body mass index >30 kg/m, or those undergoing immobilization for 3 weeks or more, trauma or surgery requiring bed rest, are generally considered to be at increased risk of venous thromboembolism. These women, and those with a past history of thromboembolic disorders during pregnancy or in association with estrogen use should be kept under special observation while using hormone replacement therapy.
Precautions: Before Estracomb 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 and endometrial biopsy should be performed. Baseline tests should include measurements of blood glucose, calcium, triglycerides and cholesterol, and liver function tests.
The first follow-up examination should be done within 6 months after initiation of treatment to assess response to treatment. Thereafter, examinations should be made once a year and should include at least those procedures outlined above. It is important that patients are encouraged to practice frequent self-examination of the breasts.
Abnormal vaginal bleeding due to its prolongation, irregularity or heaviness occurring during therapy should prompt diagnostic measures like endometrial biopsy or curettage to rule out the possibility of uterine malignancy and the treatment should be re-evaluated.
Pre-existing uterine leiomyoma may increase in size during estrogen use. Growth, pain or tenderness of uterine leiomyoma requires discontinuation of medication.
Symptoms and physical findings associated with a previous diagnosis of endometriosis may reappear or become aggravated with estrogen use.
Patients who develop visual disturbances, classical migraine, transient aphasia, paralysis, or loss of consciousness should discontinue medication.
If feasible, estrogens should also be discontinued at least 4 weeks before surgery which may be associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.
Women using oral estrogen and progestin contraceptives sometimes experience increased blood pressure which, in most cases, returns to normal upon discontinuing the drug. This may occur with use of oral estrogens during menopause and blood pressure should be monitored with estrogen use. Elevation of blood pressure in previously normotensive or hypertensive patients should be evaluated and estrogen therapy may have to be discontinued.
Estrogens may cause fluid retention. Therefore, particular caution is indicated in cardiac or renal dysfunction, epilepsy or asthma. Treatment should be stopped if there is an increase in epileptic seizures. 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.
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.
A worsening of glucose tolerance has been observed in a significant percentage of patients on estrogen-containing oral contraceptives. 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.
A 2- to 4-fold increase in the risk of surgically confirmed gallbladder disease has been reported in postmenopausal women receiving oral estrogens.
Caution is advised in patients with a history of estrogen-related jaundice and pruritus. If cholestatic jaundice develops during treatment, the treatment should be discontinued and appropriate investigations carried out.
Women with familial hypertriglyceridemia need special surveillance. Lipid-lowering measures are recommended additionally, before treatment is started.
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 Laboratory Tests.
Drug Interactions: Estrogens may diminish the effectiveness of anticoagulants, antidiabetic and antihypertensive agents.
Preparations inducing liver enzymes, (e.g., barbiturates, hydantoins, carbamazepine, meprobamate, phenylbutazone or rifampin) may interfere with the activity of orally administered estrogens. The extent of interference with transdermally administered estradiol-17b and NETA is not known.
Laboratory Tests: The results of certain endocrine and liver function tests may be affected by estrogen-containing products: increased sulfobromophthalein retention; increased prothrombin time and partial thromboplastin time; increased levels of fibrinogen and fibrinogen activity; increased coagulation factors VII, VIII, IX, X; increased norepinephrine-induced platelet aggregability; decreased antithrombin III; increased thyroxine-binding globulin (TBG), leading to increased circulating total thyroid hormone (T4) as measured by column or radioimmunoassay; free 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 protein (CBG), sex-hormone binding globulin (SHBG), leading to increased circulating corticosteroids and sex steroids respectively; free or biologically active hormone concentrations are unchanged; reduced response to the metopirone test; reduced serum folate concentration; increased serum triglyceride and phospholipid concentration.
In clinical trials with Estraderm, no effect on fibrinogen, antithrombin III, TBG, CBG or SHBG was seen.
The results of the above laboratory tests should not be considered reliable unless therapy has been discontinued for 2 to 4 months. The pathologist should be informed that the patient is receiving estrogen therapy when relevant specimens are submitted.
Information to be Provided to the Patient: See Information for the Patient.
Adverse Reactions: See Warnings and Precautions regarding potential induction of malignant neoplasms and adverse effects similar to those of oral contraceptives.
The most commonly reported adverse reaction to Estracomb in clinical trials was redness and irritation at the application site. This occurred in about 7% of the women treated and caused approximately 6% to discontinue therapy.
The following adverse reactions have been reported with estrogens in general. Gastrointestinal: nausea; vomiting; abdominal discomfort (cramps, pressure, pain); bloating; gallbladder disorder; asymptomatic impaired liver function; cholestatic jaundice.
Genitourinary: The incidence of adverse reactions reported with Estracomb are indicated in brackets.
Breakthrough bleeding (>10%); spotting (>10%); change in menstrual flow (1 to 10%); dysmenorrhea (1 to 10%); vaginal itching/discharge.
Dermatological/Hypersensitivity: allergic contact dermatitis; reversible post-inflammatory pigmentation; general pruritus and exanthema; loss of scalp hair; chloasma; pigmentation of the skin; erythema nodosum; erythema multiforme; hemorrhagic skin eruptions; precipitation or aggravation of porphyria cutanea tarda in predisposed individuals.
Isolated cases of anaphylactoid reactions (some of the patients had a history of previous allergy or allergic disorders).
Endocrine: breast swelling and tenderness; increased blood sugar levels; decreased glucose tolerance; sodium retention.
Cardiovascular/Hematologic: palpitations; isolated cases of: thrombophlebitis, thromboembolic disorders, exacerbations of varicose veins, increase in blood pressure (see Precautions). Coronary thrombosis; altered coagulation tests (see Precautions, Laboratory Tests).
CNS: aggravation of migraine headaches; headaches; mental depression; nervousness; dizziness; fatigue; irritability, neuro-ocular lesions (e.g., retinal thrombosis, optic neuritis).
Ophthalmic: visual disturbances; steepening of the corneal curvature; intolerance to contact lenses; neuro-ocular lesions (see CNS above).
Miscellaneous: Changes in appetite; changes in body weight; edema; neuritis; change in libido; musculoskeletal pain [including leg pain not related to thromboembolic disease (usually transient, lasting 3 to 6 weeks). If symptoms persist, the dose of estrogen should be reduced].
Symptoms And Treatment Of Overdose: Symptoms: 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. Overdosage with estrogen may cause nausea, breast discomfort, fluid retention, bloating or vaginal bleeding in women.
Progestin (norethindrone acetate) overdosage has been characterized by depressed mood, tiredness, acne and hirsutism.
Treatment: Owing to the mode of administration (transdermal), plasma levels of estradiol-17b and norethindrone acetate can be rapidly reduced by removal of the patch. Symptomatic treatment should be given.
Dosage And Administration: In women who are not currently taking oral estrogens, treatment with Estracomb can be initiated at once. In women who are currently taking oral estrogens, treatment with Estracomb can be initiated on reappearance of menopausal symptoms, following discontinuation of oral therapy.
One 28-day treatment cycle with Estracomb consists of 8 patches, 4 patches of Estraderm 50 and 4 patches of Estragest 250/50. Therapy is started with Estraderm 50. For 2 weeks, 1 Estraderm 50 patch is applied twice weekly i.e., the patch should be changed every 3 to 4 days. For the following 2 weeks, 1 Estragest 250/50 patch is applied twice weekly, i.e., the patch should be changed every 3 to 4 days. Once the 8 patches of Estracomb have been used in the recommended sequence over a 28-day period, the subsequent treatment cycle is again started with Estraderm 50 immediately after removal of the last Estragest 250/50 patch.
Estracomb provides, therefore, 14 days of progestin per cycle. The addition of sufficient NETA to induce secretory transformation of the endometrium during estrogen replacement therapy is mandatory.
As observed in the normal menstrual cycle, cyclical administration of NETA from Estragest 250/50 should induce regular cyclical bleeding with mean onset toward the end of Estragest 250/50 application phase. The normal duration of vaginal bleeding associated with Estracomb is around 6 days. This cyclical bleeding is expected to be of light intensity or spotting for 60 to 70% of this time. There are individual variations in these parameters. Once all 8 patches of Estracomb have been used as recommended, the first Estraderm 50 patch of the new cycle is applied even if some vaginal bleeding still persists. Vaginal bleeding should stop early in the new cycle.
Abnormal vaginal bleeding due to its prolongation, irregularity or heaviness, in any patient receiving hormone replacement therapy requires institution of prompt diagnostic measures like endometrial biopsy or curettage to rule out the possibility of uterine malignancy.
The short-term effects of NETA coadministration may include vaginal bleeding during or after NETA treatment, breast tenderness, and mood and weight changes. The long-term effects generally depend on the dosage and type of progestin used. The lowest effective dose of estrogen and progestin should be prescribed.
See the Precautions section on the examination of the patient before Estracomb administration.
Dose Adjustment: Menopausal Symptoms: Treatment of menopausal symptoms is usually initiated with a patch that releases 50 Âµg estradiol-17b/day. Therefore, therapy can be initiated with Estracomb in women with an intact uterus. Thereafter the dosage should be adapted to the needs of the individual.
Breast discomfort, breakthrough or heavy vaginal bleeding, water retention, bloating or nausea (if persisting for more than 6 weeks), are generally signs that the estrogen dose is too high and needs to be lowered. If on the other hand, the selected dose fails to eliminate the signs and symptoms of estrogen deficiency, a higher dose of estrogen may be considered. Women with an intact uterus whose menopausal symptoms require Estraderm 25 or Estraderm 100 should receive appropriate treatment with oral progestins in order to prevent endometrial hyperplasia (details provided in the Estraderm Product Monograph).
For maintenance therapy one should always use the lowest dose that still proves effective. The requirement for hormone replacement therapy for menopausal symptoms should be reassessed periodically. Attempts to taper or discontinue the medication should be made at 3- to 6-month intervals.
Prevention of Osteoporosis: For optimal prevention of postmenopausal bone loss in women for whom the drug is indicated, therapy should be initiated as soon as possible after diagnosis of menopause. The dosage of estradiol-17b may require adjustment according to the patient’s clinical status, the plasma estradiol-17b levels and the results of bone mineral density studies.
Women with an intact uterus whose conditions require Estraderm 25 or Estraderm 100 should receive appropriate treatment with oral progestins in order to prevent endometrial hyperplasia (details provided in the Estraderm Product Monograph).
Discontinuation of hormone replacement therapy may re-establish the natural rate of bone loss.
Patch Application: The physician should discuss the most appropriate placement of the patch with the patient. Immediately after removal of a patch from the pouch and removal of the protective liner, the adhesive side of the Estraderm 50 or Estragest 250/50 patch should be placed on a clean, dry area of intact skin. The area selected should not be oily, damaged or irritated, and not exposed to the sun. The site selected should also be one at which little wrinkling of the skin occurs during movement of the body, preferably the buttocks, lower abdomen or hip. The patch may also be placed on the side or lower back. Experience to date has shown that less irritation of the skin occurs on the buttocks than on other sites of application. Therefore it is advisable to apply Estraderm 50 or Estragest 250/50 to the buttocks. The waistline should be avoided, since tight clothing may dislodge the patch. The patch should be pressed firmly in place with the palm of the hand, making sure there is good contact, especially around the edges. In the event that a patch should fall off, it can be reapplied. If it fails to adhere then a new patch may be applied. In either case, the original treatment schedule should be continued. Patches should not be applied to the same skin site twice in succession.
Estraderm 50 and Estragest 250/50 must not be applied to the breasts to avoid potentially harmful effects on the breast tissue.
Availability And Storage: A package consists of the following systems: Nonmedicinal ingredients: polyester backing film, hydroxypropyl cellulose and ethanol (drug reservoir), ethylene vinyl acetate copolymer (release-controlling membrane), light mineral oil and polyisobutylene (adhesive) and siliconized polyethylene terephthalate [protective liner (removed before patch is used)].
Each Estracomb package contains 4 Estraderm 50 patches (2 patches/week) and 4 Estragest 250/50 patches (2 patches/week) for a 28-day treatment cycle.
Store patches below 25°C. Do not freeze. Each patch is individually sealed in a separate pouch. Do not store out of the pouch. Apply immediately upon removal from the protective pouch.
Keep Estraderm 50 and Estragest 250/50 out of the reach of children and pets both before use and when disposing of used patches.
ESTRACOMB® Novartis Pharmaceuticals Estradiol-17b – Norethindrone Acetate – Estradiol-17b Estrogen – Progestin