BOX WARNING CARDIOVASCULAR AND OTHER RISKS
Estrogens with or without progestins should not be used for the prevention of cardiovascular disease or dementia. (See CLINICAL STUDIES and WARNINGS , Cardiovascular disorders and Dementia.)
The estrogen plus progestin substudy of the Women’s Health Initiative (WHI) reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with oral conjugated estrogens (CE 0.625 mg) combined with medroxyprogesterone acetate (MPA 2.5 mg) per day, relative to placebo. (See CLINICAL STUDIES and WARNINGS, Cardiovascular disorders and Malignant neoplasms, Breast cancer.)
The estrogen-alone substudy of the WHI reported increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 6.8 years and 7.1 years, respectively, of treatment with oral conjugated estrogens (CE 0.625 mg) per day, relative to placebo. (See CLINICAL STUDIES and WARNINGS , Cardiovascular disorders.)
The Women’s Health Initiative Memory Study (WHIMS), a substudy of the WHI study, reported increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with CE 0.625 mg combined with MPA 2.5 mg and during 5.2 years of treatment with CE 0.625 mg alone, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women. (See CLINICAL STUDIES, WARNINGS, Dementia and PRECAUTIONS, Geriatric Use.)
Other doses of oral conjugated estrogens with medroxyprogesterone acetate, and other combinations and dosage forms of estrogens and progestins were not studied in the WHI clinical trials and, in the absence of comparable data, these risks should be assumed to be similar. Because of these trials, estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.
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ACTIVELLA SUMMARY
CARDIOVASCULAR AND OTHER RISKS
Activella® is a single tablet containing an estrogen, estradiol (E2), and a progestin, norethindrone acetate (NETA), for oral administration. Each tablet contains 1 mg estradiol and 0.5 mg norethindrone acetate and the following excipients: lactose monohydrate, starch (corn), copovidone, talc, magnesium stearate, hypromellose and triacetin.
Activella® therapy is indicated in women with an intact uterus for the:
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Treatment of moderate to severe vasomotor symptoms associated with the menopause. There is no adequate evidence that estrogens are effective for nervous symptoms or depression that might occur during menopause and they should not be used to treat these conditions.
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Treatment of vulvar and vaginal atrophy.
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Prevention of postmenopausal osteoporosis.
Most prospective studies of efficacy for the osteoporosis prevention indication have been carried out in white postmenopausal women, without stratification by other risk factors, and tend to show a universally beneficial effect on bone. Since estrogen administration is associated with risk, patient selection must be individualized based on the balance of risks and benefits.
Case-control studies have shown an approximately 60-percent reduction in hip and wrist fractures in women whose estrogen replacement was begun within a few years after menopause. Studies also suggest that estrogen reduces the rate of vertebral fractures. When estrogen therapy is discontinued, bone mass declines at a rate comparable to the immediate postmenopausal period. White and Asian women are at higher risk for osteoporosis than black women, and thin women are at a higher risk than heavier women, who generally have higher endogenous estrogen levels. Early menopause is one of the strongest predictors for the development of osteoporosis. Other factors associated with osteoporosis include genetic factors (small build, family history), lifestyle (cigarette smoking, alcohol abuse, sedentary exercise habits) and nutrition (below average body weight and dietary calcium intake).
The mainstays of prevention and management of osteoporosis are weight-bearing exercise, adequate calcium intake, and, when indicated, estrogen. Postmenopausal women absorb dietary calcium less efficiently than premenopausal women and require an average of 1500 mg/day of elemental calcium to remain in neutral calcium balance. The average calcium intake in the USA is 400-600 mg/day. Therefore, when not contraindicated, calcium supplementation may be helpful for women with suboptimal dietary intake.
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NEWS HIGHLIGHTS
Published Studies Related to Activella (Estradiol)
The Prevention of Post-Partum Relapses with Progestin and Estradiol in Multiple Sclerosis (POPART'MUS) trial: rationale, objectives and state of advancement. [2009.11.15]
Multiple sclerosis (MS) affects 1 in 1000 people in western countries, mainly women in their childbearing years. It is an autoimmune disease of the central nervous system, which results in a chronic focal inflammatory response with subsequent demyelination and axonal loss... Assuming the results of the trial to be positive, this new treatment could be considered in the relapsing-remitting phase of the disease in women afar from pregnancy and post-partum.
A randomized controlled trial of a low-dose combined oral contraceptive containing 3 mg drospirenone plus 20 microg ethinylestradiol in the treatment of acne vulgaris: lesion counts, investigator ratings and subject self-assessment. [2009.09]
OBJECTIVE: To assess the efficacy of a combined oral contraceptive (COC) containing 3 mg drospirenone (drsp) plus 20 microg ethinylestradiol (EE) administered in 24 days of active treatment followed by a four-day hormone-free interval (24/4 regimen) compared with placebo for the treatment of moderate acne vulgaris... CONCLUSION: The 3 mg drsp/20 microg EE COC administered in a 24/4 regimen significantly reduced acne lesions.
Steady-state pharmacokinetics following application of a novel transdermal estradiol spray in healthy postmenopausal women. [2009.09]
This study was designed to evaluate the steady-state pharmacokinetics (PK) of estradiol and its metabolites, estrone and estrone sulfate, following application of a novel estradiol transdermal spray to healthy postmenopausal women. Participants were randomly assigned in parallel to receive 1-, 2-, or 3-spray doses (24 participants/dose level) of a 1.7% estradiol metered-dose transdermal spray (1.53 mg/spray) once daily for 14 days...
Lower-dose vs high-dose oral estradiol therapy of hormone receptor-positive, aromatase inhibitor-resistant advanced breast cancer: a phase 2 randomized study. [2009.08.19]
CONTEXT: Estrogen deprivation therapy with aromatase inhibitors has been hypothesized to paradoxically sensitize hormone-receptor-positive breast cancer tumor cells to low-dose estradiol therapy. OBJECTIVE: To determine whether 6 mg of estradiol (daily) is a viable therapy for postmenopausal women with advanced aromatase inhibitor-resistant hormone receptor-positive breast cancer... CONCLUSIONS: In women with advanced breast cancer and acquired resistance to aromatase inhibitors, a daily dose of 6 mg of estradiol provided a similar clinical benefit rate as 30 mg, with fewer serious adverse events. The efficacy of treatment with the lower dose should be further examined in phase 3 clinical trials. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00324259.
Evaluation of different add-back estradiol and progesterone treatments to gonadotropin-releasing hormone agonist treatment in patients with premenstrual dysphoric disorder. [2009.08]
OBJECTIVE: The aim of this study was to investigate which add-back hormone replacement therapy would be most beneficial in terms of mood effects for patients with premenstrual dysphoric disorder who are receiving gonadotropin-releasing hormone agonist therapy... CONCLUSION: Based on the findings of the present study, long-cycle add-back treatment to avoid frequent progestagen use appears to be most beneficial for patients with premenstrual dysphoric disorder.
Clinical Trials Related to Activella (Estradiol)
Efficacy and Tolerability Study of Progesterone Vaginal Tablets (Endometrin®) in Menopausal Women Treated by Estrogen [Not yet recruiting]
A Study to Characterize Epidemiology, Clinical and Genetic Features of Kallmann Syndrome in Finland [Enrolling by invitation]
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Page last updated: 2009-10-20
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