Climara Pro
(estradiol / levonorgestrel)Dosage & Administration
Climara Pro Prescribing Information
Estrogen Plus Progestin Therapy
Cardiovascular Disorders and Probable Dementia
The Women's Health Initiative (WHI) estrogen plus progestin substudy reported an increased risk of deep vein thrombosis (DVT), pulmonary embolism (PE), stroke and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg] combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo [see Warnings and Precautions , and Clinical Studies ].
The WHI Memory Study (WHIMS) estrogen plus progestin ancillary study of WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age and older during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions , and Clinical Studies ].
Do not use estrogen plus progestogen therapy for the prevention of cardiovascular disease or dementia [see Warnings and Precautions , and Clinical Studies ].
Breast Cancer
The WHI estrogen plus progestin substudy demonstrated an increased risk of invasive breast cancer [see Warnings and Precautions , and Clinical Studies ].
Only daily oral 0.625 mg CE and MPA were studied in the estrogen plus progestin substudy of the WHI. Therefore, the relevance of the WHI findings regarding adverse cardiovascular events, dementia and breast cancer to lower CE plus other MPA doses, other routes of administration, or other estrogen plus progestogen products is not known. Without such data, it is not possible to definitively exclude these risks or determine the extent of these risks for other products. Discuss with your patient the benefits and risks of estrogen plus progestogen therapy, taking into account her individual risk profile.
Prescribe estrogens with or without progestogens at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.
Estrogen-Alone Therapy
Endometrial Cancer
There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestogen to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Perform adequate diagnostic measures, including directed or random endometrial sampling when indicated rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding [see Warnings and Precautions ].
Cardiovascular Disorders and Probable Dementia
The WHI estrogen-alone substudy reported increased risks of stroke and DVT in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral CE (0.625 mg)-alone, relative to placebo [see Warnings and Precautions , and Clinical Studies ].
The WHIMS estrogen-alone ancillary study of WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age and older during 5.2 years of treatment with daily CE (0.625 mg)-alone, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions , Use in Specific Populations , and Clinical Studies ].
Do not use estrogen-alone therapy for the prevention of cardiovascular disease or dementia [see Warnings and Precautions , and Clinical Studies ].
Only daily oral 0.625 mg CE was studied in the estrogen-alone substudy of the WHI. Therefore, the relevance of the WHI findings regarding adverse cardiovascular events and dementia to lower CE doses, other routes of administration, or other estrogen-alone products is not known. Without such data, it is not possible to definitively exclude these risks or determine the extent of these risks for other products. Discuss with your patient the benefits and risks of estrogen-alone therapy, taking into account her individual risk profile.
Prescribe estrogens with or without progestogens at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.
Climara Pro is indicated for:
Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause
Prevention of Postmenopausal Osteoporosis
Limitation of Use
When prescribing solely for the prevention of postmenopausal osteoporosis, first consider the use of non-estrogen medications. Consider estrogen therapy only for women at significant risk of osteoporosis.
Use estrogen-alone, or in combination with a progestogen, at the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual women. Reevaluate postmenopausal women periodically as clinically appropriate to determine if treatment is still necessary.
One Climara Pro transdermal system is available for use.
Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause
Start therapy with Climara Pro 0.045 mg per day/0.015 mg per day applied to the skin once weekly. Start therapy at the lowest effective dose and the shortest duration consistent with the treatment goals. Attempts to discontinue Climara Pro should be made at 3 to 6 month intervals.
Prevention of Postmenopausal Osteoporosis
Apply Climara Pro 0.045 mg per day/0.015 mg per day applied to the skin once weekly.
Application of the Climara Pro Transdermal System
Initiation of Therapy
Women not currently using continuous estrogen-alone therapy or estrogen plus progestogen therapy may start therapy with Climara Pro at any time. However, women currently using continuous estrogen-alone therapy or estrogen plus progestogen therapy should complete the current cycle of therapy before initiating Climara Pro therapy. Women often experience withdrawal bleeding at the completion of the cycle. The first day of this bleeding would be an appropriate time to begin Climara Pro therapy.
Site Selection
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- Place the adhesive side of Climara Pro on a smooth (fold free), clean, dry area of the skin on the lower abdomen or the upper quadrant of the buttock.
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- Do not apply Climara Pro to or near the breasts.
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- Select an area selected that is not oily (which can impair adherence of the system), damaged, or irritated.
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- Avoid the waistline; tight clothing may rub Climara Pro off or modify drug delivery.
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- Avoid application to areas where sitting would dislodge Climara Pro.
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- Rotate the sites of application, with an interval of at least 1-week allowed between applications to the same site.
Application
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- Apply Climara Pro immediately after opening the pouch and removing the protective lining.
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- Press Climara Pro firmly in place with the fingers for at least 10 seconds, making sure there is good contact, especially around the edges.
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- If the system lifts, apply pressure to maintain adhesion.
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- In the event that a system should fall off, reapply the same system to another area of the lower abdomen. If the system cannot be reapplied, a new system may be applied, in which case, the original treatment schedule should be continued.
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- Only one system should be worn at any one time during 7-day dosing interval.
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- Do not expose the applied transdermal system to the sun for prolonged periods of time.
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- Swimming, bathing, or using a sauna while using Climara Pro has not been studied, and these activities may decrease the adhesion of the system and the delivery of the estrogen and progestin.
Removal of the Climara Pro Transdermal System
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- Remove Climara Pro carefully and slowly to avoid irritation of the skin.
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- If any adhesive remain on the skin after removal of Climara Pro, allow the area to dry for 15 minutes and then gently rub the area with an oil-based cream or lotion should remove the adhesive residue.
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- Used patches still contain some active hormones. Carefully fold each patch in half so that it sticks to itself before throwing it away.
Climara Pro (estradiol/levonorgestrel transdermal system) 0.045 mg/day estradiol and 0.015 mg/day levonorgestrel – each 22 cm2 system contains 4.4 mg of estradiol and 1.39 mg of levonorgestrel.
Pregnancy
Risk Summary
Climara Pro is not indicated for use in pregnancy. There are no data with the use of Climara Pro in pregnant women; however, epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to combined hormonal contraceptives (estrogens and progestins) before conception or during early pregnancy.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Lactation
Risk Summary
Estrogens plus progestogens are present in human milk and can reduce milk production in breast-feeding women. This reduction can occur at any time but is less likely to occur once breast-feeding is well-established. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Climara Pro and any potential adverse effects on the breastfed child from Climara Pro or from the underlying maternal condition.
Pediatric Use
Climara Pro is not indicated for use in pediatric patients. Clinical studies have not been conducted in the pediatric population.
Geriatric Use
There have not been sufficient numbers of geriatric women involved in clinical studies utilizing Climara Pro to determine whether those over 65 years of age differ from younger subjects in their response to Climara Pro.
The Women’s Health Initiative Studies
In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age [see Clinical Studies ].
In the WHI estrogen-alone substudy (daily CE [0.625 mg]-alone versus placebo), there was a higher relative risk of stroke in women greater than 65 years of age [see Clinical Studies ]
The Women’s Health Initiative Memory Study
In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen plus progestin or estrogen-alone when compared to placebo [see Warnings and Precautions , and Clinical Studies ].
Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women8(see Warnings and Precautions , and Clinical Studies ].
Climara Pro is contraindicated in women with any of the following conditions:
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- Undiagnosed abnormal genital bleeding [see Warnings and Precautions ]
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- Breast cancer or history of breast cancer [see Warnings and Precautions ]
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- Estrogen-dependent neoplasia [see Warnings and Precautions ]
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- Active DVT, PE or a history of these conditions [see Warnings and Precautions ]
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- Active arterial thromboembolic disease (for example, stroke or MI), or a history of these conditions [ see Warnings and Precautions ]
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- Known anaphylactic reaction, or angioedema, or hypersensitivity to Climara Pro
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- Hepatic impairment or disease
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- Protein C, protein S, or antithrombin deficiency, or other thrombophilic disorders
Cardiovascular Disorders
Increased risks of PE, DVT, stroke and MI are reported with estrogen plus progestin therapy. Increased risks of stroke and DVT are reported with estrogen-alone therapy. Immediately discontinue estrogen with or without progestogen therapy if any of these occur or are suspected.
Manage appropriately any risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (for example, personal history or family history of VTE, obesity, and systemic lupus erythematosus).
Stroke
The WHI estrogen plus progestin substudy reported a statistically significant increased risk of stroke in women 50 to 79 years of age receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women in the same age group receiving placebo (33 versus 25 strokes per 10,000 women-years, respectively) [see Clinical Studies ]. The increase in risk was demonstrated after the first year and persisted.1 Immediately discontinue estrogen plus progestogen therapy if a stroke occurs or is suspected.
The WHI estrogen-alone substudy, reported a statistically significant increased risk of stroke in women 50 to 79 years of age receiving daily CE (0.625 mg)-alone compared to women in the same age group receiving placebo (45 versus 33 strokes per 10,000 women-years, respectively). The increase in risk was demonstrated in year 1 and persisted [see Clinical Studies ]. Immediately discontinue estrogen-alone therapy if a stroke occurs or is suspected.
Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving CE (0.625 mg)-alone versus those receiving placebo (18 versus 21 per 10,000 women-years).1
Coronary Heart Disease
The WHI estrogen plus progestin substudy reported an increased risk (not statistically significant) of coronary heart disease (CHD) events (defined as nonfatal MI, silent MI, or CHD death) in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (41 versus 34 per 10,000 women-years).1 An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5 [see Clinical Studies ].
The WHI estrogen-alone substudy reported no overall effect on CHD events in women receiving estrogen-alone compared to placebo2[see Clinical Studies ]. Immediately discontinue estrogen plus progestogen therapy if a VTE occurs or is suspected.
In the WHI estrogen-alone substudy, the risk of VTE was increased for women receiving daily CE (0.625 mg)-alone compared to placebo (30 versus 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 versus 15 per 10,000 women-years). The increase in VTE risk was demonstrated during the first 2 years4[see Clinical Studies ]. Immediately discontinue estrogen-alone therapy if a VTE occurs or is suspected.
If feasible, discontinue estrogens at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.
Malignant Neoplasms
Breast Cancer
After a mean follow-up of 5.6 years, the WHI substudy of daily CE (0.625 mg) plus MPA (2.5 mg) reported an increased risk of invasive breast cancer in women who took daily CE plus MPA compared to placebo.
In this substudy, prior use of estrogen-alone or estrogen plus progestin therapy was reported by 26 percent of the women. The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years, for CE plus MPA compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 versus 25 cases per 10,000 women-years, for CE plus MPA compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 versus 36 cases per 10,000 women-years for CE plus MPA compared with placebo. In the same substudy, invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at a more advanced stage in the CE (0.625 mg) plus MPA (2.5 mg) group compared with the placebo group. Metastatic disease was rare with no apparent difference between the two groups. Other prognostic factors such as histologic subtype, grade and hormone receptor status did not differ between the groups5 [see Clinical Studies ].
The WHI substudy of daily CE (0.625 mg)-alone provided information about breast cancer in estrogen-alone users. In the WHI estrogen-alone substudy, after an average follow-up of 7.1 years, daily CE-alone was not associated with an increased risk of invasive breast cancer [relative risk (RR) 0.80] 6 [see Clinical Studies ].
Consistent with the WHI clinical trials, observational studies have also reported an increased risk of breast cancer with estrogen plus progestin therapy, and a smaller increase in the risk for breast cancer with estrogen-alone therapy, after several years of use. One large meta-analysis of prospective cohort studies reported increased risks that were dependent upon duration of use and could last up to >10 years after discontinuation of estrogen plus progestin therapy and estrogen-alone therapy. Extension of the WHI trials also demonstrated increased breast cancer risk associated with estrogen plus progestin therapy. Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen plus progestin therapy as compared to estrogen-alone therapy. These studies have not generally found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, doses, or routes of administration.
The use of estrogen-alone and estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation.
All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results.
Endometrial Cancer
An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in a woman with a uterus. The reported endometrial cancer risk among unopposed estrogen users is about 2 to 12 times greater than in nonusers, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than 1 year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for 5 to 10 years or more. This risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.
Clinical surveillance of all women using estrogen-alone or estrogen plus progestogen therapy is important. Perform adequate diagnostic measures, including directed or random endometrial sampling when indicated, to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding with unknown etiology.
There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding a progestogen to estrogen therapy in postmenopausal women has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.
Ovarian Cancer
The CE plus MPA substudy of WHI reported that estrogen plus progestin increased the risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE plus MPA versus placebo was 1.58 (95 percent CI, 0.77-3.24), but it was not statistically significant. The absolute risk for CE plus MPA versus placebo was 4 versus 3 cases per 10,000 women-years.7
A meta-analysis of 17 prospective and 35 retrospective epidemiology studies found that women who used hormonal therapy for menopausal symptoms had an increased risk for ovarian cancer. The primary analysis, using case-control comparisons, included 12,110 cancer cases from the 17 prospective studies. The relative risks associated with current use of hormonal therapy was 1.41 (95% confidence interval [CI] 1.32 to 1.50); there was no difference in the risk estimates by duration of the exposure (less than 5 years [median of 3 years] vs. greater than 5 years [median of 10 years] of use before the cancer diagnosis). The relative risk associated with combined current and recent use (discontinued use within 5 years before cancer diagnosis) was 1.37 (95% CI 1.27 to 1.48), and the elevated risk was significant for both estrogen-alone and estrogen plus progestin products. The exact duration of hormone therapy use associated with an increased risk of ovarian cancer, however, is unknown.
Probable Dementia
In the WHI Memory Study (WHIMS) estrogen plus progestin ancillary study of WHI, a population of 4,532 postmenopausal women 65 to 79 years of age was randomized to daily CE (0.625 mg) plus MPA (2.5 mg) or placebo.
After an average follow-up of 4 years, 40 women in the CE plus MPA group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21-3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years8[see Use in Specific Populations , and Clinical Studies ].
In the WHIMS estrogen-alone ancillary study of WHI, a population of 2,947 hysterectomized women 65 to 79 years of age was randomized to daily CE (0.625 mg)-alone or placebo.
After an average follow-up of 5.2 years, 28 women in the estrogen-alone group and 19 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83-2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years8[see Use in Specific Populations , and Clinical Studies ].
When data from the two populations in the WHIMS estrogen-alone and estrogen plus progestin ancillary studies were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 percent CI, 1.19-2.60). Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women8[see Use in Specific Populations , and Clinical Studies ].
Gallbladder Disease
A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.
Hypercalcemia
Estrogen administration may lead to severe hypercalcemia in women with breast cancer and bone metastases. Discontinue estrogens, including Climara Pro if hypercalcemia occurs, and take appropriate measures to reduce the serum calcium level.
Visual Abnormalities
Retinal vascular thrombosis has been reported in women receiving estrogens. Discontinue Climara Pro pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. Permanently discontinue estrogens, including Climara Pro, if examination reveals papilledema or retinal vascular lesions.
Addition of a Progestogen When a Woman Has Not Had a Hysterectomy
Studies of the addition of a progestogen for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer.
There are, however, possible risks that may be associated with the use of progestogens with estrogens compared to estrogen-alone regimens. These include an increased risk of breast cancer.
Elevated Blood Pressure
In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogens on blood pressure was not seen.
Exacerbation of Hypertriglyceridemia
In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Discontinue Climara Pro if pancreatitis occurs.
Hepatic Impairment and/or Past History of Cholestatic Jaundice
Estrogens may be poorly metabolized in women with hepatic impairment. Exercise caution in any woman with a history of cholestatic jaundice associated with past estrogen use or with pregnancy. In the case of recurrence of cholestatic jaundice, discontinue Climara Pro.
Exacerbation of Hypothyroidism
Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Women with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Women dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. Monitor thyroid function in these women during treatment with Climara Pro to maintain their free thyroid hormone levels in an acceptable range.
Fluid Retention
Estrogens plus progestogens may cause some degree of fluid retention. Monitor any woman with a condition(s) that might predispose her to fluid retention, such as a cardiac or renal impairment. Discontinue estrogens plus progestogens therapy, including Climara Pro, with evidence of medically concerning fluid retention.
Hypocalcemia
Estrogen-induced hypocalcemia may occur in women with hypoparathyroidism. Consider whether the benefits of estrogen therapy, including Climara Pro, outweigh the risks in such women.
Exacerbation of Endometriosis
A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen-alone therapy.
Hereditary Angioedema
Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema. Consider whether the benefits of estrogen therapy, including Climara Pro, outweigh the risks in such women.
Exacerbation of Other Conditions
Estrogen therapy, including Climara Pro, may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas. Consider whether the benefits of estrogen therapy outweigh the risks in women with these conditions.
Laboratory Tests
Serum follicle stimulating hormone (FSH) and estradiol levels have not been shown to be useful in the management of postmenopausal women with moderate to severe vasomotor symptoms.
Drug-Laboratory Test Interactions
Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of antifactor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.
Increased TBG levels leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 levels by radioimmunoassay. T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Women on thyroid replacement therapy may require higher doses of thyroid hormone.
Other binding proteins may be elevated in serum, for example, corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG), leading to increased total circulating corticosteroids and sex steroids, respectively. Free hormone concentrations, such as testosterone and estradiol, may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-l-antitrypsin, ceruloplasmin).
Increased plasma high-density lipoprotein (HDL) and HDL2 cholesterol subfraction concentrations, reduced low-density lipoprotein (LDL) cholesterol concentration, and in oral formulations increased triglycerides levels.
Impaired glucose tolerance.
The following serious adverse reactions are discussed elsewhere in the labeling:
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- Cardiovascular Disorders [see Boxed Warning, Warnings and Precautions ]
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- Malignant Neoplasms [see Boxed Warning, Warnings and Precautions ]
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The data described below is from a one-year, prospective, multicenter, double blind, double dummy, randomized, controlled trial investigating the effect of three different dosage combinations of E2/LNG versus E2 alone on the development of endometrial hyperplasia. All women were postmenopausal, had a serum estradiol level of less than 20 pg/mL, and the sample included both symptomatic and asymptomatic women. The data below includes all adverse reactions reported at a frequency of >3% in the E2/LNG 0.045 / 0.015 group (the approved dosage for Climara Pro, N=212) and the E2 alone group (N=204).
| ||
Body System
| Climara Pro | E2 |
N * = 212 | N = 204 | |
Body as a Whole | ||
| 9 (4.2) | 11 (5.4) |
| 7 (3.3) | 6 (2.9) |
| 13 (6.1) | 12 (5.9) |
| 10 (4.7) | 13 (6.4) |
| 7 (3.3) | 10 (4.9) |
| 11 (5.2) | 13 (6.4) |
Cardiovascular System | ||
| 7 (3.3) | 9 (4.4) |
Digestive System | ||
| 8 (3.8) | 11 (5.4) |
Metabolic and Nutritional | ||
| 8 (3.8) | 5 (2.5) |
| 6 (2.8) | 10 (4.9) |
Musculoskeletal System | ||
| 9 (4.2) | 10 (4.9) |
Nervous System | ||
| 12 (5.7) | 7 (3.4) |
| 11 (5.2) | 14 (6.9) |
Respiratory System | ||
| 9 (4.2) | 7 (3.4) |
| 8 (3.8) | 12 (5.9) |
| 28 (13.2) | 26 (12.7) |
Skin and Appendages | ||
| 86 (40.6) | 69 (33.8) |
| 40 (18.9) | 20 (9.8) |
| 5 (2.4) | 10 (4.9) |
Urogenital System | ||
| 7 (3.3) | 8 (3.9) |
| 78 (36.8) | 44 (21.6) |
| 4 (1.9) | 6 (2.9) |
Irritation potential of Climara Pro was assessed in a 3-week irritation study. The study compared the irritation of a Climara Pro placebo patch (22 cm2) to a placebo (25 cm2). Visual assessments of irritation were made on Day 7 of each wear period, approximately 30 minutes after patch removal using a 7-point scale (0 = no evidence of irritation; 1 = minimal erythema, barely perceptible; 2 = definite erythema, readily visible, or minimal edema, or minimal papular response; 3–7 = erythema and papules, edema, vesicles, strong extensive reaction).
The mean irritation scores were 0.13 (week 1), 0.12 (week 2), and 0.06 (week 3) for the Climara Pro. The mean scores for the placebo group were 0.2 (week 1), 0.26 (week 2), 0.12 (week 3). There were no irritation scores greater than 2 at any timepoint in any woman.
In controlled clinical trials, withdrawals due to application site reactions occurred in 6 (2.1 percent) of women in the 12-week symptom study and in 71 (8.5 percent) of subjects in the 1-year endometrial protection study.
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of Climara Pro. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Genitourinary System
Changes in bleeding patterns
Gastrointestinal
Abdominal distension,* abdominal pain,* nausea
Skin
Alopecia, night sweats, pruritus,* Rash,* hot flush*
Central Nervous System
Dizziness, headache, insomnia
Miscellaneous
Application site reaction,* weight increased, anaphylactic reaction
* Combined two or more similar ARs
In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4 such as St. John's wort (Hypericum perforatum) preparations, phenobarbital, carbamazepine, and rifampin may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may increase plasma concentrations of estrogens and may result in side effects.
Hydroxylation of levonorgestrel is a conversion step, which is mediated by cytochrome P450 enzymes. Based on in-vitro and in-vivo studies, it can be assumed that CYP3A, CYP2E and CYP2C are involved in the metabolism of levonorgestrel. Likewise, inducers or inhibitors of these enzymes may either, respectively, decrease the therapeutic effects or result in adverse reactions.
Climara Pro (estradiol/levonorgestrel transdermal system) is an adhesive-based matrix transdermal patch designed to release both estradiol and levonorgestrel, a progestational agent, continuously upon application to intact skin. The 22 cm2 Climara Pro system contains 4.4 mg estradiol and 1.39 mg levonorgestrel and provides a nominal delivery rate (mg per day) of 0.045 estradiol and 0.015 levonorgestrel.
Estradiol USP has a molecular weight of 272.39 and the molecular formula is C18H24O2.
Levonorgestrel USP has a molecular weight of 312.4 and a molecular formula of C21H28O2.
The structural formulas for estradiol and levonorgestrel are:
The Climara Pro transdermal system comprises 3 layers. Proceeding from the visible surface towards the surface attached to the skin, these layers are:
- 1.
- A translucent polyethylene backing film.
- 2.
- An acrylate adhesive matrix containing estradiol and levonorgestrel.
- 3.
- A protective liner of either siliconized or fluoropolymer coated polyester film. The protective liner is attached to the adhesive surface and must be removed before the system can be used.
The active components of the transdermal system are estradiol and levonorgestrel. The remaining components of the transdermal system (acrylate copolymer adhesive and polyvinylpyrrolidone/vinyl acetate copolymer) are pharmacologically inactive.
Mechanism of Action
Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level.
The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, which is secreted by the adrenal cortex, to estrone in the peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women.
Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue.
Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and FSH, through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.
Levonorgestrel inhibits gonadotropin production resulting in retardation of follicular growth and inhibition of ovulation.
Studies to assess the potency of progestins using estrogen-primed postmenopausal endometrial biochemistry and morphologic features have shown that levonorgestrel counteracts the proliferative effects of estrogens on the endometrium.
Pharmacodynamics
Generally, a serum estrogen concentration does not predict an individual woman’s therapeutic response to Climara nor her risk for adverse outcomes. Likewise, exposure comparisons across different estrogen products to infer efficacy or safety for the individual woman may not be valid.
Pharmacokinetics
Absorption
Transdermal administration of Climara Pro produces mean maximum estradiol concentrations in serum in about 2 to 2.5 days. Estradiol concentrations equivalent to the normal ranges observed at the early follicular phase in premenopausal women are achieved within 12–24 hours after the first application.
In one study, steady state estradiol concentrations in serum were measured during week 4 in 44 healthy, postmenopausal women during four consecutive Climara Pro applications of two formulations (0.045 mg estradiol/0.03 mg levonorgestrel and 0.045 mg estradiol/0.015 mg levonorgestrel) to the abdomen (each dose was applied for four 7-day periods). Both formulations were bioequivalent in terms of estradiol and estrone Cmax and AUC parameters. A summary of Climara Pro single and multiple applications estradiol, estrone and levonorgestrel pharmacokinetic parameters is shown in Table 2.
Summary of Mean (± SD) Pharmacokinetic Parameters Following a Single Application | ||||
Parameter | Units | Estradiol | Estrone | Levonorgestrel |
Single application | ||||
Cave | Pg/mL | 37.7 ± 10.4 | 41 ± 15 | 136 ± 52.7 |
Cmax | Pg/mL | 54.3 ± 18.9 | 43.9 ± 14.9 | 138 ± 51.8 |
Tmax | Hours | 42 | 84 | 90 |
Cmin | Pg/mL | 27.2 ± 7.66 | 32.6 ± 14.3 | 110 ± 41.7 |
AUC | Pg.h/mL | 6340 ± 1740 | 6890 ± 2520 | 22900 ± 8860 |
Summary of Mean (± SD) Pharmacokinetic Parameters (Week 4) Following Four Consecutive Weekly Applications of Climara Pro in 44 Healthy Postmenopausal Women | ||||
Multiple application | ||||
Cave | Pg/mL | 35.7 ± 11.4 | 45.5 ± 62.6 | 166 ± 97.8 |
Cmax | Pg/mL | 50.7 ± 28.6 | 81.6 ± 252 | 194 ± 111 |
Tmax | Hours | 36 | 48 | 48 |
Cmin | Pg/mL | 33.8 ± 28.7 | 72.5 ± 253 | 153 ± 69.6 |
AUC | Pg.h/mL | 6002 ± 1919 | 7642 ± 10518 | 27948 ± 16426 |
All mean parameters are arithmetic means except Tmax which is expressed as the median.
At steady state, Climara Pro maintains during the application period an average serum estradiol concentration of 35.7 pg/mL as depicted in Figure 1.
Figure 1: Mean Estradiol Concentration Profile (Week 4) Following Four Consecutive Weekly Applications of Climara Pro
Following the application of the Climara Pro transdermal system, levonorgestrel concentrations are maximum in about 2.5 days. At steady state, Climara Pro maintains during the application period an average serum levonorgestrel concentration of 166 pg/mL as depicted in Figure 2. The mean levonorgestrel pharmacokinetic parameters of Climara Pro are summarized in Table 2.
Figure 2: Mean Levonorgestrel Concentration Profile (Week 4) Following Four Consecutive Weekly Applications of Climara Pro
Adhesion
A study of the adhesion potential of Climara Pro was conducted in 104 healthy women of 45–75 years of age. Each woman applied a placebo patch, containing only the Climara Pro adhesive without active ingredient, to the upper outer abdominal areas weekly for three weeks. The adhesion assessment was done visually on Days 2, 4, 5, 6 and 7 of each of the three weeks using a four-point scale. The mean scores ranked in the highest category possible on the 0 to 4 scale demonstrating clinically acceptable adhesion performance
Excretion
Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Following patch removal, serum estradiol concentrations decline with a mean (± SD) terminal half-life of 3± 0.67 hours.
Levonorgestrel and its metabolites are primarily excreted in the urine. Mean (± SD) terminal half-life for levonorgestrel was determined to be 28 ± 6.4 hours.
Metabolism
Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is a major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the intestine followed by reabsorption. In postmenopausal women, a significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.
The most important metabolic pathway for levonorgestrel occurs in the reduction of the Δ4- and the 3-oxo-group as well as hydroxylations at positions 2α, 1β, and 16β, followed by conjugation. Most of the metabolites that circulate in the blood are sulfates of 3α, 5β-tetrahydro-levonorgestrel, while excretion occurs predominantly in the form of glucuronides. Some of the parent levonorgestrel also circulates as the 17β-sulfate. In-vitro studies on the biotransformation of levonorgestrel in human skin did not indicate any significant metabolism of levonorgestrel during skin penetration.
Distribution
The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to SHBG and albumin.
Levonorgestrel in serum is bound to both SHBG and albumin. Following four consecutive weekly applications of Climara Pro mean (± SD) SHBG concentrations declined from a predose value of 47.5 (25.8) to 41.2 (22.4) nmol/L at week 4.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.
Effects on Vasomotor Symptoms in Postmenopausal Women
The efficacy of 0.045 mg estradiol/0.03 mg levonorgestrel administered weekly versus placebo in the relief of moderate to severe vasomotor symptoms in postmenopausal women was studied in one 12-week clinical trial (n=183, average age 52.1 ± 4.93, 82 percent Caucasian). The 0.045 mg estradiol/0.03 mg levonorgestrel dosage strength was shown to be statistically better than placebo at weeks 4 and 12 for relief of both the number and severity of moderate to severe hot flushes. See Tables 3 and 4. Climara Pro and the 0.045 mg estradiol/0.03 mg levonorgestrel dosage strength are bioequivalent in terms of estradiol delivery [See Clinical Pharmacology ].
| |||||
Baseline † | Week 4 | Week 8 | Week 12 | ||
Placebo | n ‡ | 88 | 82 | 73 | 69 |
Mean (SD) § | 10.8 (5.803) | 6.13 (4.311) | 5.35 (4.095) | 5.59 (4.93) | |
Mean Change from baseline (SD) | NA | -4.23 (4.374) | -4.8 (4.448) | -4.55 (5.407) | |
0.045/.03 | n ‡ | 92 | 88 | 80 | 73 |
Mean (SD) § | 10.13 (3.945) | 2.69 (4.455) | 1.22 (2.804) | 1.06 (3.187) | |
Mean Change from baseline (SD) § | NA | -7.4 (4.715) | -8.68 (4.146) | -8.82 (4.336) | |
p-Value ¶ | NA | <0.001 # | NA | <0.001 # | |
| |||||
Baseline † | Week 4 (day 7) | Week 8 (day 7) | Week 12 (day 7) | ||
Placebo | n ‡ | 89 | 76 | 68 | 57 |
Mean (SD)d | 2.42 (0.282) | 1.99 (0.875) | 1.93 (0.955) | 1.8 (1.034) | |
Mean Change from baseline (SD) ‡ | NA | -0.4 (0.865) | -0.48 (0.922) | -0.57 (1.044) | |
0.045/.03 | n ‡ | 92 | 83 | 72 | 55 |
Mean (SD) ‡ | 2.48 (0.295) | 1.1 (1.191) | 0.82 (1.226) | 0.44 (0.96) | |
Mean Change from baseline (SD) ‡ | NA | -1.4 (1.164) | -1.67 (1.245) | -2.06 (1.005) | |
p-value § | NA | <0.001 ¶ | NA | <0.001 ¶ | |
Effects on the Endometrium in Postmenopausal Women
In a 1-year clinical trial of 412 postmenopausal women (with intact uteri) treated with a continuous regimen of Climara Pro or with an continuous estradiol-only transdermal system, results of evaluable endometrial biopsies show that no hyperplasia was seen with Climara Pro. Table 5 below summarizes these results (Intent-to-Treat populations).
| ||
Climara Pro E2 0.045 mg / LNG 0.015 mg | Estradiol E2 0.045 mg | |
n † = 210 | na = 202 | |
No. of Patients with Biopsies at >6 months ‡ | 124 | 139 |
No. of Patients with Biopsies at 1 year § | 102 | 110 |
No. (%) of Patients with Hyperplasia ¶ | 0 (0%) # | 19 (17.3%) |
95% Confidence Interval | 0-3.55% | 9.75–24.79% |
Effects on Uterine Bleeding or Spotting in Postmenopausal Women
The effects of Climara Pro on uterine bleeding or spotting, as recorded using an interactive voice response system, were evaluated in one 12-month clinical trial. Results are shown in Figure 3.
Figure 3: Cumulative Proportion of Subjects at Each Cycle with No Bleeding/Spotting Through the End of Cycle 13 Last Observation Carried Forward
- •
- Percent based upon the number of participating women with data
- •
- Last non-missing cycle carried forward through cycle 13
- •
- Bleeding associated with endometrial biopsies not included
Effects on Bone Mineral Density in Postmenopausal Women
The effects on bone mineral density (BMD) were studied in a randomized, double-blind, placebo-controlled clinical trial of transdermal systems (patches) containing only estradiol (E2). Participants were postmenopausal women with hysterectomies, 40–83 years of age (mean=51.4 years), and 77.3 percent Caucasian. Women received calcium supplements if they appeared deficient on a questionnaire. Vitamin D supplements were not given.
A total of 154 women were randomized in a 2:2:3 ratio to weekly application of 22 cm2 patches containing 2.2 mg E2, 4.4 mg E2, or placebo, for 728 days of continuous treatment (26 28-day cycles). Only the results for the estradiol dose in Climara Pro (4.4 mg E2) and for placebo are presented.
Statistically significant increases in the primary efficacy variable, BMD of the lumbar spine (A-P view, L2-L4), were seen for 4.4 mg E2 compared to placebo (see Table 5 and Figure 4). BMD was also measured at the hip (total, non-dominant side) and radius (midshaft, non-dominant side) with statistically significant treatment effects only observed for the hip (see Table 6).
| ||
4.4 mg E2 † | Placebo | |
Total Lumbar Spine Baseline (g/cm2) | n=36 1.1 (0.2) | n=46 1.1 (0.2) |
% Change from baseline LOCF | +1.7% (4.4) | -2.9% (3.8) |
P-value compared to placebo | <0.0001 | |
Total Hip Baseline (g/cm2) | n=36 0.97 (0.1) | n=48 0.94 (0.1) |
% Change from baseline LOCF | +1.3% (4.2) | -0.9% (5.2) |
P-value compared to placebo | 0.05 | |
Figure 4: Percent Change From Baseline in Bone Mineral Density (g/cm2) of Lumbar Spine (A-P View, L2–L4) by Treatment Group and Cycle (Mean ± SE)*
* Data in the figure is for 21 patients on 4.4 mg E2 and 27 placebo patients who completed the study; approximately 44 percent of randomized patients.
Women's Health Initiative Studies
The WHI enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of daily oral CE (0.625 mg)-alone or in combination with MPA (2.5 mg) compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of CHD (defined as nonfatal MI, silent MI and CHD death), with invasive breast cancer as the primary adverse outcome. A "global index" included the earliest occurrence of CHD, invasive breast cancer, stroke, PE, endometrial cancer (only in the CE plus MPA substudy), colorectal cancer, hip fracture, or death due to other cause. These substudies did not evaluate the effects of CE plus MPA or CE-alone on menopausal symptoms.
WHI Estrogen Plus Progestin Substudy
The WHI estrogen plus progestin substudy was stopped early. According to the predefined stopping rule, after an average follow-up of 5.6 years of treatment, the increased risk of invasive breast cancer and cardiovascular events exceeded the specified benefits included in the "global index". The absolute excess risk of events included in the “global index” was 19 per 10,000 women-years.
For those outcomes included in the WHI “global index” that reached statistical significance after 5.6 years of follow-up, the absolute excess risks per 10,000 women-years in the group treated with CE plus MPA were 7 more CHD events, 8 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures.
Results of the CE plus MPA substudy, which included 16,608 women (average 63 years of age, range 50 to 79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other) are presented in Table 7. These results reflect centrally adjudicated data after an average follow-up of 5.6 years.
| |||
Event | Relative Risk | CE/MPA | Placebo n = 8,102 |
Absolute Risk per 10,000 Women-Years | |||
CHD events | 1.23 (0.99-1.53) | 41 | 34 |
31 | 25 | ||
8 | 8 | ||
All strokes | 1.31 (1.03-1.68) | 33 | 25 |
Ischemic stroke | 1.44 (1.09-1.90) | 26 | 18 |
Deep vein thrombosis § | 1.95 (1.43-2.67) | 26 | 13 |
Pulmonary embolism | 2.13 (1.45-3.11) | 18 | 8 |
Invasive breast cancer ¶ | 1.24 (1.01-1.54) | 41 | 33 |
Colorectal cancer | 0.61 (0.42-0.87) | 10 | 16 |
Endometrial cancer § | 0.81 (0.48-1.36) | 6 | 7 |
Cervical cancer § | 1.44 (0.47-4.42) | 2 | 1 |
Hip fracture ‡ | 0.67 (0.47-0.96) | 11 | 16 |
Vertebral fractures § | 0.65 (0.46-0.92) | 11 | 17 |
Lower arm/wrist fractures § | 0.71 (0.59-0.85) | 44 | 62 |
Total fractures § | 0.76 (0.69-0.83) | 152 | 199 |
Overall Mortality # | 1.00 (0.83-1.19) | 52 | 52 |
Global Index Þ | 1.13 (1.02-1.25) | 184 | 165 |
Timing of the initiation of estrogen-alone therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen-alone substudy, stratified by age, showed in women 50 to 59 years of age, a non-significant trend toward reduced risk for overall mortality [hazard ratio (HR) 0.69 (95 percent CI, 0.44–1.07)].
WHI Estrogen-Alone Substudy
The WHI estrogen-alone substudy was stopped early because an increased risk of stroke was observed, and it was deemed that no further information would be obtained regarding the risks and benefits of estrogen-alone in predetermined primary endpoints.
Results of the estrogen-alone substudy, which included 10,739 women (average age of 63 years, range 50 to 79; 75.3 percent White, 15.1 percent Black, 6.1 percent Hispanic, 3.6 percent Other), after an average follow-up of 7.1 years are presented in Table 8.
| |||
Event | Relative Risk | CE | Placebo |
Absolute Risk per 10,000 Women-Years | |||
CHD events † | 0.95 (0.78-1.16) | 54 | 57 |
| 0.91 (0.73-1.14) | 40 | 43 |
| 1.01 (0.71-1.43) | 16 | 16 |
All strokes † | 1.33 (1.05-1.68) | 45 | 33 |
Ischemic stroke † | 1.55 (1.19-2.01) | 38 | 25 |
Deep vein thrombosis †, ‡ | 1.47 (1.06-2.06) | 23 | 15 |
Pulmonary embolism † | 1.37 (0.90-2.07) | 14 | 10 |
Invasive breast cancer † | 0.80 (0.62-1.04) | 28 | 34 |
Colorectal cancer † | 1.08 (0.75-1.55) | 17 | 16 |
Hip fracture † | 0.65 (0.45-0.94) | 12 | 19 |
Vertebral fractures †, ‡ | 0.64 (0.44-0.93) | 11 | 18 |
Lower arm/wrist fractures †, ‡ | 0.58 (0.47-0.72) | 35 | 59 |
Total fractures †, ‡ | 0.71 (0.64-0.80) | 144 | 197 |
Death due to other causes §, ¶ | 1.08 (0.88-1.32) | 53 | 50 |
Overall Mortality †, ‡ | 1.04 (0.88-1.22) | 79 | 75 |
Global Index # | 1.02 (0.92-1.13) | 206 | 201 |
For those outcomes included in the WHI "global index" that reached statistical significance, the absolute excess risk per 10,000 women-years in the group treated with CE- alone was 12 more strokes, while the absolute risk reduction per 10,000 women-years was 7 fewer hip fractures.9 The absolute excess risk of events included in the "global index" was a non-significant 5 events per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality.
No overall difference for primary CHD events (nonfatal MI, silent MI and CHD death) and invasive breast cancer incidence in women receiving CE-alone compared with placebo was reported in final centrally adjudicated results from the estrogen-alone substudy, after an average follow-up of 7.1 years.
Centrally adjudicated results for stroke events from the estrogen-alone substudy, after an average follow-up of 7.1 years, reported no significant difference in distribution of stroke subtype or severity, including fatal strokes, in women receiving CE-alone compared to placebo. Estrogen-alone increased the risk for ischemic stroke, and this excess risk was present in all subgroups of women examined.10
Timing of the initiation of estrogen-alone therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen-alone substudy stratified by age showed in women 50 to 59 years of age, a non-significant trend toward reduced risk for CHD [HR 0.63 (95 percent CI, 0.36-1.09)] and overall mortality [HR 0.71 (95 percent CI, 0.46-1.11)].
Women's Health Initiative Memory Study
The WHIMS estrogen plus progestin ancillary study of WHI enrolled 4,532 predominantly healthy postmenopausal women 65 to 79 years of age and older (47 percent were 65 to 69 years of age, 35 percent were 70 to 74 years of age, and 18 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia (primary outcome) compared to placebo.
After an average follow-up of 4 years, the relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21-3.48). The absolute risk of probable dementia for CE plus MPA was 45 versus 22 cases per 10,000 women-years. Probable dementia as defined in this study included Alzheimer’s disease (AD), vascular dementia (VaD) and mixed type (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women [see Warnings and Precautions , and Use in Specific Populations ].
The WHIMS estrogen-alone ancillary study of WHI enrolled 2,947 predominantly healthy hysterectomized postmenopausal women 65 years of age and older (45 percent were age 65 to 69 years of age, 36 percent were 70 to 74 years of age, and 19 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg)-alone on the incidence of probable dementia (primary outcome) compared to placebo.
After an average follow-up of 5.2 years, the relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83-2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years. Probable dementia as defined in this study included Alzheimer’s disease (AD), vascular dementia (VaD) and mixed type (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo groups was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women [see Warnings and Precautions , and Use in Specific Populations ].
When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 percent CI, 1.19-2.60). Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women [see Warnings and Precautions , and Use in Specific Populations ].
How Supplied
Individual Carton of 4 systems
Climara Pro (estradiol/levonorgestrel transdermal system) 0.045 mg/day estradiol and 0.015 mg/day levonorgestrel – each 22 cm2 system contains 4.4 mg of estradiol and 1.39 mg of levonorgestrel. NDC 50419-491-04
Storage and Handling
Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP controlled Room Temperature].
Do not store unpouched. Apply immediately upon removal from the protective pouch.
Used transdermal systems still contain active hormones. To discard, fold the sticky side of the transdermal system together, place it in a sturdy child-proof container, and place this container in the trash. Used transdermal systems should not be flushed in the toilet
Mechanism of Action
Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level.
The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, which is secreted by the adrenal cortex, to estrone in the peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women.
Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue.
Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and FSH, through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.
Levonorgestrel inhibits gonadotropin production resulting in retardation of follicular growth and inhibition of ovulation.
Studies to assess the potency of progestins using estrogen-primed postmenopausal endometrial biochemistry and morphologic features have shown that levonorgestrel counteracts the proliferative effects of estrogens on the endometrium.