Climara (Estradiol-17b)

CLIMARA®

Berlex Canada

Estradiol-17b

Estrogen

Action And Clinical Pharmacology: Climara is composed of a translucent polyethylene film with an acrylate adhesive matrix containing estradiol-17b. Upon application to intact skin, Climara provides continuous systemic delivery of estrogen by releasing estradiol-17b, the major estrogenic hormone secreted by the human ovary.

Estradiol-17b is the predominant estrogen produced by the ovaries in premenopausal women. Administration of transdermal estradiol to postmenopausal women elevates plasma estradiol concentrations into the range observed in premenopausal women at the early to mid-follicular stage. As a result of the increased plasma estradiol concentrations, plasma concentrations of follicle-stimulating hormone and luteinizing hormone are decreased and vaginal cytology is converted to a pattern resembling that found in premenopausal women, with improvement of the maturation and karyopyknotic indices. Estrogens are effective in reducing the number and intensity of hot flushes associated with menopause.

Pharmacokinetics: When given orally, estrogens and their esters are extensively metabolized by the liver (first pass effect) and circulate primarily as estrone sulfate, with smaller amounts of other conjugated and unconjugated weaker estrogens. This results in limited oral potency.

In contrast, because the skin metabolizes estradiol only to a small extent, the transdermal administration of estradiol produces therapeutic serum levels of estradiol with lower circulating levels of estrone and estrone conjugates. Climara maintains the favorable estradiol/estrone ratio associated with transdermal application, which is comparable to that observed in premenopausal women during the early follicular phase.

Transdermal administration of estradiol offers several advantages over oral administration. It avoids the hepatic “first pass” effect thereby minimizing interpatient and intrapatient variations due to variable hepatic metabolism. Transdermal administration avoids gastrointestinal intolerance associated with oral administration of estrogens.

The Climara 50 and Climara 100 systems provide controlled delivery of approximately 0.05 mg and 0.1 mg of estradiol/day, respectively, into the systemic circulation. The expected 2:1 dose proportionality between the two strengths has been demonstrated. Consistent serum estradiol serum concentrations, within the desired therapeutic range, are maintained with both Climara systems over a 1 week application interval. On average, Climara 100 maintained mean steady-state serum estradiol levels of approximately 70 pg/mL, and Climara 50 maintained mean steady-state serum estradiol levels of approximately 35 pg/mL.

Climara does not produce an accumulation of estrogens following multiple 1-week applications. Because estradiol has a short half-life, transdermal administration of estradiol allows a rapid decline in blood levels after the Climara system is removed.

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, Climara should always be supplemented by sequential administration of a progestin to prevent endometrial hyperplasia.

Contra-Indications: Should not be used in individuals with any of the following conditions: known or suspected estrogen-dependent neoplasia such as breast or endometrial cancer; endometrial hyperplasia; undiagnosed vaginal bleeding; known or suspected pregnancy; active liver dysfunction or disease, especially of the obstructive type; active thrombophlebitis, thrombosis or thrombotic disorders; a history of cerebrovascular accident, coronary thrombosis, or in the presence of classical migraine; 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. tag_WarningWarnings

Manufacturers’ Warnings In Clinical States: Before Climara is administered, the patient should have a complete physical examination. The breasts should be examined together with mammography where indicated. Pelvic organs should be examined, a Papanicolaou smear and an endometrial biopsy should be taken. Baseline tests should include measurement of blood glucose, calcium, triglycerides and cholesterol, and liver function tests.

The first followup examination should be done within 6 months after initiation of treatment to assess medical 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.

If any surgical procedures are performed, the pathologist should be advised of the patient’s therapy when specimens are sent for examination.

If unexpected or abnormal vaginal bleeding occurs during therapy, diagnostic aspiration biopsy or curettage should be performed to rule out the possibility of uterine malignancy.

Patients with acute hepatic disease, especially of the obstructive type, should not be given estrogens.

Patients who develop visual disturbances, classical migraine, transient aphasia, paralysis, or loss of consciousness should discontinue medication.

Although the estrogen content of oral contraceptive therapy has been associated with an increased risk of various thromboembolic, thrombotic and vascular disease, to date no such risk has been reported in epidemiological studies looking at currently prescribed doses of estrogen products used in menopause. Nevertheless, the physician should be alert to the earliest manifestations of thrombotic disorders (phlebitis, thrombophlebitis, retinal thrombosis, cerebral embolism and pulmonary embolism). If these occur or are suspected, estrogen therapy should be discontinued immediately. Women with a positive family history and women with a history of thromboembolic disorders during pregnancy or in association with estrogen use should be kept under special observation.

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.

Estrogen use, unopposed by progestins, has been reported to increase the risk of endometrial carcinoma in postmenopausal women. The incidence of endometrial hyperplasia is reported to be lowered with sequential coadministration of a progestin. Close clinical surveillance of all women taking estrogens is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding.

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. 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 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.

Precautions: Pre-existing uterine leiomyoma may increase in size during estrogen use. Growth, pain or tenderness of uterine leiomyoma requires discontinuation of medication.

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

Estrogens may cause fluid retention. Therefore, particular caution is indicated in cardiac or renal dysfunction, epilepsy or asthma.

Because the prolonged use of estrogens influences the metabolism of calcium or 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 patients with a history of jaundice during pregnancy, there is an increased risk that jaundice will recur with the use of estrogen-containing oral contraceptives. If jaundice develops with the use of estrogens, the drug should be discontinued while the cause is investigated.

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 the use of oral estrogens during menopause and blood pressure should be monitored during estrogen use. Elevation of blood pressure in previously normotensive or hypertensive patients should be evaluated and estrogen therapy may have to be discontinued.

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.

When liver or endocrine tests are indicated, the laboratory should be advised of the patient’s therapy before specimens are forwarded.

Studies have reported a 2-to 4-fold increase in the risk of gallbladder disease requiring surgery in women receiving postmenopausal estrogens.

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 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 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 response to the 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 the potential for induction of neoplasia and other effects of estrogens.

The most commonly reported adverse reaction to Climara in clinical trials was skin irritation at the application site. In 2 controlled clinical studies, the overall rate of discontinuation due to skin irritation at the application site was 6.8% (7.9% for the Climara 50 system and 5.3% for the Climara 100 system) compared with 11.5% for the placebo system.

The following additional adverse reactions have been reported with Climara and estrogens in general:

Genitourinary: changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow, breakthrough bleeding, spotting, increase in size of uterine leiomyomata, vaginal candidiasis, change in amount of cervical secretion, endometrial hyperplasia, premenstrual-like syndrome, reactivation of endometriosis, changes in cervical erosion, dysuria, cystitis.

Breasts: pain, tenderness, enlargement.

Gastrointestinal: nausea, vomiting, abdominal cramps, bloating, cholestatic jaundice, increased incidence of gallbladder disease.

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).

Eyes: steepening of corneal curvature, intolerance to contact lenses.

CNS: headache, migraine, dizziness, mental depression, chorea, neuro-ocular lesions (e.g., retinal thrombosis, optic neuritis).

Cardiovascular/Hematologic: palpitation, isolated cases of thrombophlebitis, pulmonary embolism and cerebral thrombosis, exacerbations of varicose veins, increase in blood pressure, coronary thrombosis, altered coagulation tests.

Miscellaneous: increase or decrease in weight, reduced carbohydrate tolerance, sodium retention, aggravation of porphyria, edema, changes in libido, musculoskeletal pain.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Overdosage with transdermal application of estradiol is unlikely. Serious ill effects have not been reported following acute ingestion of large doses of estrogen-containing products by young children. Overdosage of estrogen may cause nausea and vomiting, and withdrawal bleeding may occur in females. Symptomatic treatment should be given.

Dosage And Administration: In women who are not currently taking oral estrogens, treatment with estradiol-17b transdermal system can be initiated at once. In women who are currently taking oral estrogens, treatment with estradiol-17b transdermal system can be initiated on reappearance of menopausal symptoms, following discontinuation of oral therapy.

Therapy with estradiol-17b transdermal system is usually administered in a cyclic schedule (e.g., 3 weeks of therapy followed by 1 week without). In women with an intact uterus, a progestin should be sequentially coadministered for 12 to 14 days every month at a dose sufficient to prevent overstimulation of endometrial tissue. Unexpected or abnormal vaginal bleeding in such patients is an indication for prompt diagnostic measures. The lowest clinically effective (relief of symptoms) dose of each hormone should be used.

Continuous treatment at the lowest effective dose may be given to postmenopausal hysterectomized women.

Initiation of Therapy: Two Climara systems are available: Climara 50 (0.05 mg/day) and Climara 100 (0.1 mg/day). Treatment is usually initiated with Climara 50 applied to the skin once-weekly. The dose should be adjusted as necessary to control symptoms. Clinical response at the lowest effective dose should be the guide for establishing administration of Climara. 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 Climara 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 wrinking 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 (e.g., 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 the patch 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.

Climara must not be applied to the breasts to avoid potentially harmful effects on the breast tissue.

Coadministration of Progestins: Studies of the addition of a progestin for 7 days or more days of estrogen administration have reported a lowered incidence of endometrial hyperplasia. Histological and biochemical studies of the endometrium suggest that at least 10 but most probably 12 to 14 days of progestin are needed to provide maximal maturation of the endometrium and to eliminate any hyperplastic changes. Whether this will provide protection from endometrial carcinoma has not been clearly established.

Wide interpatient variation in absorption occurs with progestins. The adequacy of the dose of progestin can be assessed by the bleeding patterns. Bleeding before day 11 of progestin administration indicates inadequate secretory transformation and the need for a higher dose of progestin.

The following regimens have been shown, in general, to produce histological and biochemical changes with 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: The Climara system is composed of 2 layers: a translucent polyethylene film with an acrylate adhesive matrix containing estradiol hemihydrate (Ph. Eur.) A protective liner is attached to the adhesive surface and must be removed before the system can be used. Other system components: low density polyethylene backing polyester film (release liner).

Climara 50: Each translucent 12.5 cmsystem contains: estradiol hemihydrate 3.9 mg (Ph. Eur.) and provides controlled delivery of estradiol-17b 0.05 mg/day to the patient. Nonmedicinal ingredients: ethyl oleate, glyceryl monolaurate, isopropyl myristate, acrylate copolymer: acrylamide, isooctyl acrylate, vinyl acetate copolymer. Packages of 4.

Climara 100: Each translucent 25 cmsystem contains: estradiol hemihydrate 7.8 mg (Ph. Eur.) and provides controlled delivery of estradiol-17b 0.1 mg/day to the patient. Nonmedicinal ingredients: ethyl oleate, glyceryl monolaurate, isopropyl myristate, acrylate copolymer: acrylamide, isooctyl acrylate, vinyl acetate copolymer. Packages of 4.

Store between 15 and 30°C. Store in sealed pouch. Apply immediately upon removal from the protective pouch. Keep out of the reach of children and pets before and after use.

CLIMARA® Berlex Canada Estradiol-17b Estrogen

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