Description: Vivelle is a thin, circular, 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 Vivelle patch comprises 3 layers. Proceeding from the visible surface toward the surface attached to the skin, these layers are: 1. A flexible semi-transparent backing film of polyurethane and ethylene vinyl alcohol polymer. 2. An adhesive formulation containing estradiol-17b, acrylic polymers, polyisobutylene, oleic acid, synthetic rubber based adhesive, vinyl acetate resin base, phosphatidylcholine, propylene glycol, bentonite, butylene glycol, mineral oil and dipropylene glycol. 3. A protective liner of polyester 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 matrix provides a source for continuous delivery of drug for up to 4 days. Vivelle is available in 4 strengths; the composition per unit area in each strength is identical.
Action And Clinical Pharmacology: Vivelle is designed to deliver daily estradiol-17b, a physiologic hormone, transdermally into the systemic circulation. Due to the transdermal route of administration, the estradiol-17b does not undergo firstpass liver metabolism. Resultant estradiol-17b plasma levels 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.
Indications And Clinical Uses: For the relief of menopausal and postmenopausal symptoms occurring in naturally or surgically induced estrogen deficiency states.
In patients with an intact uterus, estradiol-17b should always be supplemented by sequential administration of a progestin whose role is to prevent endometrial hyperplasia.
Contra-Indications: Estradiol-17b 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; a history of thrombophlebitis, thrombosis or thromboembolic disorders associated with previous estrogen use; 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. The incidence of endometrial hyperplasia is reported to be lowered with sequential coadministration of a progestin (see Dosage, Coadministration of Progestins).
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. Instructions 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 estradiol-17b 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 and 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-17b is not known.
Laboraratory 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 Metopirone test; reduced serum folate concentration; increased serum triglyceride and phospholipid concentration.
With transdermally administered estradiol-17b, no effect on fibrinogen, antithrombin III, TBG, CBG or SHBG and decreases in serum triglycerides have been observed.
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.
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 Vivelle in clinical trials was redness and irritation at the application site. This caused about 0.8% of the patients 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: breakthrough bleeding; spotting and vaginal bleeding; change in menstrual flow; dysmenorrhea; vaginal itching/discharge; dyspareunia; dysuria; endometrial hyperplasia; premenstrual-like syndrome; reactivation of endometriosis; cystitis; changes in cervical erosion and amount of cervical secretion.
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.
Treatment: Owing to the mode of administration (transdermal), plasma levels of estradiol-17b 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 estradiol-17b can be initiated at once. In women who are currently taking oral estrogens, treatment with Vivelle can be initiated on reappearance of menopausal symptoms, following discontinuation of oral therapy.
Vivelle should be applied twice weekly, i.e., the patch should be changed once every 3 to 4 days.
Cyclical administration is recommended (21 to 25 days of therapy followed by 5 to 7 days without). Continuous non-cyclic therapy may be indicated in hysterectomized women or in cases where the signs and symptoms of estrogen deficiency become problematic during the treatment-free interval.
In women with an intact uterus, a progestin should be sequentially coadministered for a minimum of 10, but preferably 12 to 14 days/cycle to avoid overstimulation of the endometrium. The addition of sufficient progestin to induce secretory transformation of the endometrium during estrogen replacement therapy is mandatory.
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 progestin coadministration may include vaginal bleeding during or after progestin 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 Coadministration of Progestins).
See the Precautions section on the examination of the patient before estradiol-17b administration.
Dose Adjustment: Treatment of menopausal symptoms is usually initiated with a patch that releases 50 g estradiol-17b/day i.e., Vivelle 50. 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 may be considered.
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.
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 Vivelle 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. The patch should be placed consistently on the same area of the body with each application (i.e., either the buttocks, lower abdomen, hip, 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 Vivelle 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.
Vivelle must not be applied to the breasts to avoid potentially harmful effects on the breast tissue.
Coadministration of Progestins: Studies have reported that the addition of a progestin for 10 or more days of a cycle of estrogen administration greatly lowers the incidence of endometrial hyperplasia, and thereby irregular bleeding and endometrial carcinoma, compared to estrogen treatment alone.
Wide interpatient variation in absorption occurs with progestins. The following regimens have been shown, in general, to produce histological and biochemical changes consistent with a uniform secretory pattern in the endometrium: norethindrone 0.7 mg/day orally, administered sequentially for 12 days each cycle; medroxyprogesterone acetate (MPA) 10 mg/day orally, administered sequentially for 12 days each cycle.
There are possible additional risks that may be associated with the inclusion of a progestin in estrogen replacement regimens. The potential risks include adverse effects on carbohydrate and lipid metabolism, mood changes and edema. The choice and dose of progestin may be important in minimizing these adverse effects and may differ among women.
Availability And Storage: Vivelle 37.5: Each thin, circular, multilayer, transparent, 11 cmtransdermal therapeutic system, contains: estradiol-17b 3.28 mg for continuous delivery of estra- diol-17b 37.5 g/day. Nonmedicinal ingredients: acrylic adhesive, bentonite, butylene glycol, dipropylene glycol, ethylene vinyl acetate copolymer, lecithin, oleic acid, mineral oil, polyisobutylene, propylene glycol and styrene-butadiene rubber. Patient packs of 8 patches.
Vivelle 50: Each thin, circular, multilayer, transparent, 14.5 cmtransdermal therapeutic system, contains: estra- diol-17b 4.33 mg for continuous delivery of estradiol-17b 50 g/day. Nonmedicinal ingredients: acrylic adhesive, bentonite, butylene glycol, dipropylene glycol, ethylene vinyl acetate copolymer, lecithin, oleic acid, mineral oil, polyisobutylene, propylene glycol and styrene-butadiene rubber. Patient packs of 8 patches.
Vivelle 75: Each thin, circular, multilayer, transparent, 22 cmtransdermal therapeutic system, contains: estradiol-17b 6.56 mg for continuous delivery of estradiol-17b 75 g/day. Nonmedicinal ingredients: acrylic adhesive, bentonite, butylene glycol, dipropylene glycol, ethylene vinyl acetate copolymer, lecithin, oleic acid, mineral oil, polyisobutylene, propylene glycol and styrene-butadiene rubber. Patient packs of 8 patches.
Vivelle 100: Each thin, circular, multilayer, transparent, 29 cmtransdermal therapeutic system, contains: estra- diol-17b 8.66 mg for continuous delivery of estradiol-17b 100 g/day. Nonmedicinal ingredients: acrylic adhesive, bentonite, butylene glycol, dipropylene glycol, ethylene vinyl acetate copolymer, lecithin, oleic acid, mineral oil, polyisobutylene, propylene glycol and styrene-butadiene rubber. Patient packs of 8 patches.
Store 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 out of the reach of children and pets both before use and when disposing of used patches.
VIVELLE® Novartis Pharmaceuticals Estradiol-17b Estrogen Description: Vivelle is a thin, circular, 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 Vivelle patch comprises 3 layers. Proceeding from the visible surface toward the surface attached to the skin, these layers are: 1. A flexible semi-transparent backing film of polyurethane and ethylene vinyl alcohol polymer. 2. An adhesive formulation containing estradiol-17b, acrylic polymers, polyisobutylene, oleic acid, synthetic rubber based adhesive, vinyl acetate resin base, phosphatidylcholine, propylene glycol, bentonite, butylene glycol, mineral oil and dipropylene glycol. 3. A protective liner of polyester 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 matrix provides a source for continuous delivery of drug for up to 4 days. Vivelle is available in 4 strengths; the composition per unit area in each strength is identical.