Climara

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.

Acute alcohol ingestion during use of HRT may lead to elevations in circulating estradiol levels.

Grapefruit juice is an inhibitor of cytochrome P450 (CYP 3A4) and could therefore increase plasma concentrations of estrogens, which might result in side effects.

Estrogens are metabolized partially by cytochrome P450 (CYP 3A4). Therefore, inducers or inhibitors of CYP 3A4 may affect estrogen drug metabolism. Inducers of CYP 3A4 such as phenobarbital, carbamezepine and rifampicin may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effect and/or changes in the 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.

The results of certain endocrine, adrenal, renal 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; 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; 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;

  
  

• impaired glucose tolerance;

  
  

• increased serum triglycerides and phospholipids concentration;

  
  

With transdermally administered estradiol-17β, no effect on fibrinogen, antithrombin III, TBG, CBG or SHBG nor 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 two to four weeks.

The pathologist should be informed that the patient is receiving hormone replacement therapy when relevant specimens are submitted.

Estrogens may diminish the effectiveness of anticoagulant, 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-17β is not known.

Climara (estradiol hemihydrate transdermal system) should be prescribed with an appropriate dosage of a progestin for women with intact uteri in order to prevent endometrial hyperplasia/carcinoma. Progestin therapy is not required as part of hormone replacement therapy in women who have had a previous hysterectomy.

Use of estrogen, alone or in combination with a progestin, should be limited to the shortest duration consistent with treatment goals and risks for the individual woman. Patients should be re-evaluated periodically as clinically appropriate (e.g., 3- to 6-month intervals) to determine if treatment is still necessary. For women who have intact uteri, 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.

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 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 (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 Climara 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, a new one should be applied and 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 in order to avoid potentially harmful effects on the breast tissue.

Four Climara systems are available: Climara 25 (0.025 mg/day), Climara 50 (0.05 mg/day), Climara 75 (0.075 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. The necessity for hormone replacement therapy for menopausal symptoms should be re-assessed periodically. Attempts to taper or discontinue the medication should be made at 3- to 6-month intervals.

For the prevention of osteoporosis, Climara 50 (0.05 mg/day) is the minimum dose approved. The choice of which dose to use should be made on the basis of individual considerations such as the age of the patient, other risk factors for osteoporosis and response to therapy as assessed by biochemical markers.

Climara should be applied once a week and worn on a continuous basis for 7 days. It should be removed and a new one applied after 7 days. Only one patch should be worn at any one time during the 7-day dosing interval.

If the patient forgets to apply the patch, then she should be counseled to apply a new patch and continue with her regular treatment schedule.

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

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.

Adverse events occurring post-market with Climara are consistent with those reported during clinical trials.

If adverse symptoms persist, the prescription of HRT should be re-considered.

The most commonly reported adverse event reported in Climara (estradiol hemihydrate transdermal system) clinical trials R-838T-010 and R-838T-011 were abdominal pain (10.9% for Climara 50, 16.0% for Climara 100, 14.7% for Premarin, 8.3% for placebo), viral infection (10.0% for Climara 50, 8.8% for Climara 100, 10.3% for Premarin, 9.7% for placebo), edema (12.9% for Climara 50, 10.3% for Climara 100, 5.1% for Premarin, 5.6% for placebo), headache (17.9% for Climara 50, 13.4% for Climara 100, 22.8% for Premarin, 9.7% for placebo), breast pain (8.0% for Climara 50, 28.9% for Climara 100, 13.2% for Premarin, 4.2% for placebo) and upper respiratory tract infection (16.9% for Climara 50, 17.0% for Climara 100, 26.5% for Premarin, 8.3% for placebo). 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 to 11.5% for the placebo system.

In a further randomized, controlled, two year clinical trial (Study 308-3B) comparing Climara with placebo, the overall rate of application site reactions with Climara was 28.7%, compared to 17.4% for the placebo system; the dropout rate due to application site reactions during the period was 4.7% (6 out of 129 subjects), compared to 0% for the placebo system.

Overall, the most commonly reported adverse reaction to Climara in clinical trials was breast pain and skin irritation at the application site.

fatigue; changes in appetite; 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; erythema multiforme; erythema nodosum; haemorrhagic eruption; 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 the potential for 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).

Exogenous estrogens may induce or exacerbate symptoms of angioedema, in particular in women with hereditary angioedema.

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

mental depression; nervousness; irritability.

Overdosage with transdermal application of estradiol is unlikely. 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.

Symptomatic treatment should be given and the Climara patch(es) should be removed.

Each translucent 25 cm² system contains: estradiol hemihydrate 7.8 mg Ph. Eur. (equivalent to 7.6 mg estradiol-17β), and provides controlled delivery of estradiol-17β 0.1 mg/day to the patient. Nonmedicinal ingredients: acrylate copolymer (acrylamide, isooctyl acrylate, vinyl acetate copolymer), ethyl oleate, glyceryl monolaurate and isopropyl myristate. Packages of 4.

Each translucent 12.5 cm² system contains: estradiol hemihydrate 3.9 mg Ph. Eur. (equivalent to 3.8 mg estradiol-17β), and provides controlled delivery of estradiol-17β 0.05 mg/day to the patient. Nonmedicinal ingredients: acrylate copolymer (acrylamide, isooctyl acrylate, vinyl acetate copolymer), ethyl oleate, glyceryl monolaurate and isopropyl myristate. Packages of 4.

Each translucent 6.5 cm² system contains: estradiol hemihydrate 2.04 mg Ph. Eur. (equivalent to 2 mg estradiol-17β), and provides controlled delivery of estradiol-17β 0.025 mg/day to the patient. Nonmedicinal ingredients: acrylate copolymer (acrylamide, isooctyl acrylate, vinyl acetate copolymer), ethyl oleate, glyceryl monolaurate and isopropyl myristate. Packages of 4.

Each translucent 18.75 cm² system contains: estradiol hemihydrate 5.85 mg Ph. Eur. (equivalent to 5.7 mg estradiol-17β), and provides controlled delivery of estradiol-17β 0.075 mg/day to the patient. Nonmedicinal ingredients: acrylate copolymer (acrylamide, isooctyl acrylate, vinyl acetate copolymer), ethyl oleate, glyceryl monolaurate and isopropyl myristate. Packages of 4.

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.

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.

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.

Exogenous estrogens may induce or exacerbate symptoms of angioedema, in particular in women with hereditary angioedema.

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

If pregnancy occurs during medication with Climara, treatment should be withdrawn immediately.

The effects of Climara on the ability to drive and use machines have not been studied.

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

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.

Benign hepatic adenomas have been associated with the use of combined estrogen and progestin oral contraceptives. Although benign and rare, these tumours 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.

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.

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.

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

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. HRT increases the density of mammographic images which may adversely affect the radiological detection of breast cancer in some cases.

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 the 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 counselling.

Caution is advised in patients with a history of liver and/or biliary disorders. If cholestatic jaundice develops, or if there is a recurrence of cholestatic pruritis which first occurred during pregnancy or during previous use of sex steroids, 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 (age range 65-79 years) 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).

Estrogen-only HRT increases the risk of endometrial hyperplasia if taken by women with intact uteri.

Estrogen should be prescribed with an appropriate dosage of progestin for women with intact uteri in order to prevent endometrial hyperplasia/carcinoma.

Clinical surveillance of all women taking estrogen/progestin combinations 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.

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

Estrogens should be used with caution in patients with otosclerosis.

Estrogens should be used with caution in patients with chorea minor.

Before Climara 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, measurement of blood glucose, calcium, triglycerides and cholesterol, and liver function tests.

The first follow-up examination should be done within three to six months after initiation of treatment to assess response to treatment. Thereafter, examinations should be made at intervals of 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.

Liver function tests should be done periodically in subjects who are suspected of having hepatic disease.

Persistent erythema or pruritis at the application site may occur.

Estrogens should be used with caution in patients with chloasma, or a history or chloasma gravidarum.

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.

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

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 Interactions, Drug-Laboratory Test Interactions).

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.

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.

Climara provides controlled delivery of approximately 0.025, 0.05, 0.075 or 0.1 mg of estradiol per day into the systemic circulation, depending on the strength of the system.

Climara (estradiol hemihydrate transdermal system) is composed of a translucent polyethylene film with an acrylate adhesive matrix containing estradiol-17β. Upon application to intact skin, Climara provides continuous systemic delivery of estrogen by releasing estradiol-17β, the major estrogenic hormone secreted by the human ovary.

Independent of the route of administration, estrogen exerts a dose-dependent stimulating effect on mitosis and proliferation of the endometrium. Unopposed estrogen increases the frequency of endometrial hyperplasia and thus the risk of endometrial carcinoma. In order to avoid endometrial hyperplasia the sequential administration of an appropriate dosage of progestin is recommended during long-term therapy in women with intact uteri.

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 favourable 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 some 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.

Consistent serum estradiol concentrations are maintained with Climara over a one-week application interval. Linear pharmacokinetics have been demonstrated for Climara. On average, Climara 100 maintained mean steady state serum estradiol levels of 70 pg/mL and Climara 50 maintained mean steady-state serum estradiol levels of approximately 35 pg/mL.

Climara does not produce an estrogen accumulation following multiple one-week applications.

Estradiol-17β 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 and in the prevention of osteoporosis.

Because estradiol has a short half-life (0.3 to 2 hours after parenteral administration), transdermal administration allows a rapid decline in blood levels after Climara is removed.