estradiol acetate
Dosage Form: tablet
Femtrace® (estradiol acetate tablets)
Rx Only
ESTROGENS INCREASE THE RISK OF ENDOMETRIAL CANCER
Close clinical surveillance of all women taking estrogens is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of “natural” estrogens results in a different endometrial risk profile than synthetic estrogens at equivalent estrogen doses. (See WARNINGS, Malignant neoplasms, Endometrial cancer.)
CARDIOVASCULAR AND OTHER RISKS
Estrogens with or without progestins should not be used for the prevention of cardiovascular disease. (See WARNINGS, Cardiovascular disorders.)
The Women’s Health Initiative (WHI) study 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 years of treatment with oral conjugated estrogens (CE 0.625 mg) combined with medroxyprogesterone acetate (MPA 2.5 mg) relative to placebo. (See CLINICAL PHARMACOLOGY, Clinical Studies.)
The Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, reported increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with oral conjugated estrogens plus medroxyprogesterone acetate relative to placebo. It is unknown whether this finding applies to younger postmenopausal women or to women taking estrogen alone therapy. (See CLINICAL PHARMACOLOGY, Clinical Studies.)
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 risks, 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.
Femtrace Description
Femtrace® (estradiol acetate tablets) for oral administration contains 0.45 mg, 0.9 mg or 1.8 mg estradiol acetate.
Femtrace contains the following inactive ingredients: ferric oxide, povidone, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, silicon dioxide, magnesium stearate and acetic acid; ferric oxide, a coloring agent, is not an ingredient in the 0.9 mg tablets.
Estradiol acetate is chemically described as estra-1,3,5(10)-triene-3,17β-diol-3-acetate. The molecular formula of estradiol acetate is C20H26O3 and the structural formula is:
The molecular weight of estradiol acetate is 314.42.
Femtrace - Clinical Pharmacology
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, secreted by the adrenal cortex, to estrone by 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 follicle stimulating hormone (FSH) through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.
Pharmacokinetics
In vitro studies suggest that within 5 minutes of administration, all estradiol acetate will be hydrolyzed to estradiol in vivo.
Absorption
Estradiol was rapidly absorbed following oral administration of estradiol acetate. Mean serum estradiol concentrations following multiple dosing are shown in Figure 1. Estradiol and estrone serum concentrations increased proportionally with increasing dose; the corresponding estradiol Cavg values were 23.5, 44.4 and 92.1 pg/mL for the 0.45, 0.9 and 1.8 mg doses, respectively (see Table 1).
Figure 1. Mean (± SD) Serum Estradiol Concentration Following Multiple-Dose Administration of Femtrace to Healthy Postmenopausal Women
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Estradiol Acetate Dose | Analyte | Cmax (pg/mL) | tmax† (hour) | AUC(0-τ) (pg·h/mL) | t½‡ (hour) |
| 0.45 mg | Estradiol | 56.7 (57) | 0.50 | 565.0 (26) | 25.9 |
| Estrone§ | 155.0 (40) | 6.0 | 2363.8 (34) | 15.9 | |
| 0.9 mg | Estradiol | 90.1 (51) | 0.43 | 1066.5 (25) | 22.2 |
| Estrone§ | 313.9 (25) | 5.0 | 4980.9 (32) | 16.1 | |
| 1.8 mg | Estradiol | 177.3 (55) | 0.75 | 2211.3 (26) | 21.4 |
| Estrone§ | 680.6 (25) | 6.0 | 11510.8 (32) | 17.6 | |
Cmax: Maximum serum concentration | |||||
Effect of Food
The maximum serum concentration (Cmax) of estradiol following administration of 1.8 mg estradiol acetate was 36% lower in the fed state compared to the fasted state. However, the area under the serum concentration versus time curve (AUC) was comparable among the fed and fasted states.
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 sex hormone binding globulin (SHBG) and to albumin.
Metabolism
Estradiol acetate is hydrolyzed in vivo to estradiol. 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 the 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 gut 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.
Excretion
Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates.
The estradiol apparent elimination half-life value is 21 to 26 hours.
Special Populations
No pharmacokinetic studies were conducted in special populations, including patients with renal or hepatic impairment.
Drug Interactions
No clinical drug-drug interaction studies with estradiol acetate have been performed. 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 preparations (Hypericum perforatum), 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.
Clinical Studies
Effects on vasomotor symptoms.
Two 12-week double-blind, placebo-controlled clinical trials were conducted to evaluate the efficacy of Femtrace in the treatment of moderate to severe vasomotor symptoms in postmenopausal women who had at least 7 moderate to severe hot flushes daily or at least 60 moderate to severe hot flushes per week before randomization. In one study, 289 postmenopausal women (mean age 53.4 years [range 41 to 68 years], 78% Caucasian) were randomized to receive either placebo, Femtrace 0.9 mg/day or Femtrace 1.8 mg/day. In the second study, 221 postmenopausal women (mean age 52.2 years [range 36 to 80 years], 80% Caucasian) were randomized to receive either placebo or Femtrace 0.45 mg/day. The results in Tables 2a and 3a indicate that compared with placebo, Femtrace 0.9 mg/day and Femtrace 1.8 mg/day produced a reduction in both the frequency and severity of moderate to severe vasomotor symptoms at weeks 4 and 12. The results in Tables 2b and 3b indicate that compared with placebo, Femtrace 0.45 mg/day produced a reduction in the frequency of moderate to severe vasomotor symptoms at weeks 4 and 12, and a reduction in the severity of moderate to severe vasomotor symptoms at weeks 7 and 12.
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| Visit | Placebo (n = 94) | Femtrace 0.9 mg/day (n = 100) | Femtrace 1.8 mg/day (n = 95) |
| Baseline* | |||
| Mean (SD) | 86.1 (40.2) | 78.5 (24.9) | 82.4 (39.1) |
| Week 4† | |||
| Mean (SD) | 51.5 (47.2) | 24.3 (28.4) | 21.9 (25.9) |
| Mean (SE) Change from Baseline | -30.1 (3.3) | -56.5 (3.2) | -59.3 (3.4) |
| p value vs. Placebo‡ | - | <0.001 | <0.001 |
| Week 12† | |||
| Mean (SD) | 46.8 (54.6) | 17.5 (28.9) | 7.3 (15.2) |
| Mean (SE) Change from Baseline | -36.3 (3.5) | -63.9 (3.4) | -74.8 (3.6) |
| p value vs. Placebo‡ | - | <0.001 | <0.001 |
| ITT = intent to treat; LOCF = last observation carried forward; SD = standard deviation; SE = standard error | |||
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| Visit | Placebo (n = 108) | Femtrace 0.45 mg/day (n = 113) |
| Baseline† | ||
| Mean (SD) | 85.8 (37.8) | 86.2 (34.8) |
| Week 4‡ | ||
| Mean (SD) | 51.5 (37.1) | 44.1 (39.5) |
| Mean (SE) Change from Baseline | -33.8 (3.5) | -41.5 (3.5) |
| p value vs. Placebo§ | - | 0.014 |
| Week 12‡ | ||
| Mean (SD) | 43.1 (38.1) | 34.1 (40.9) |
| Mean (SE) Change from Baseline | -41.5 (3.5) | -51.2 (3.5) |
| p value vs. Placebo§ | - | 0.005 |
ITT = intent to treat; LOCF = last observation carried forward; SD = standard deviation; SE = standard error | ||
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| Visit | Placebo (n = 94) | Femtrace 0.9 mg/day (n = 100) | Femtrace 1.8 mg/day (n = 95) |
| Baseline* | |||
| Mean (SD) | 2.5 (0.2) | 2.5 (0.2) | 2.5 (0.2) |
| Week 4† | |||
| Mean (SD) | 2.3 (0.6) | 1.8 (1.0) | 1.9 (1.0) |
| Mean (SE) Change from Baseline | -0.2 (1.0) | -0.7 (0.1) | -0.7 (0.1) |
| p value vs. Placebo‡ | - | 0.001 | 0.002 |
| Week 12† | |||
| Mean (SD) | 2.2 (0.8) | 1.4 (1.2) | 1.0 (1.2) |
| Mean (SE) Change from Baseline | -0.3 (0.1) | -1.1 (0.1) | -1.5 (0.1) |
| p value vs. Placebo‡ | - | <0.001 | <0.001 |
Note: Hot flush severity was scored using the following scale: 1 = Mild, 2 = Moderate, 3 = Severe ITT = intent to treat; LOCF = last observation carried forward; SD = standard deviation; SE = standard error | |||
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| Visit | Placebo (n = 108) | Femtrace 0.45 mg/day (n = 113) |
| Baseline† | ||
| Mean (SD) | 2.6 (0.2) | 2.5 (0.2) |
| Week 4‡ | ||
| Mean (SD) | 2.4 (0.5) | 2.3 (0.7) |
| Mean (SE) Change from Baseline | -0.2 (0.1) | -0.3 (0.06) |
| p value vs. Placebo§ | - | 0.787 |
| Week 12‡ | ||
| Mean (SD) | 2.3 (0.8) | 1.9 (1.1) |
| Mean (SE) Change from Baseline | -0.3 (0.1) | -0.7 (0.1) |
| p value vs. Placebo§ | - | 0.016 |
Note: Hot flush severity was scored using the following scale: 1 = Mild, 2 = Moderate, 3 = Severe ITT = intent to treat; LOCF = last observation carried forward; SD = standard deviation; SE = standard error | ||
Women’s Health Initiative Studies
The Women’s Health Initiative (WHI) study enrolled a total of 27,000 predominantly healthy postmenopausal women to assess the risks and benefits of either the use of oral 0.625 mg conjugated estrogens (CE) per day alone or the use of oral 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate (MPA) per day compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome studied. A “global index” included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture or death due to other cause. The study did not evaluate the effects of CE or CE/MPA on menopausal symptoms.
The CE/MPA substudy was stopped early because, according to the predefined stopping rule, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the “global index”. Results of the CE/MPA substudy, which included 16,608 women (average age of 63 years, range 50 to 79; 83.9% White, 6.5% Black, 5.5% Hispanic), after an average follow-up of 5.2 years are presented in Table 4 below.
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| Event† | Relative Risk CE/MPA vs Placebo at 5.2 Years (95% CI‡) | Placebo n = 8102 | CE/MPA n = 8506 |
| Absolute Risk per 10,000 Women-years | |||
CHD events Non-fatal MI CHD death | 1.29 (1.02 – 1.63) 1.32 (1.02 – 1.72) 1.18 (0.70 – 1.97) | 30 23 6 | 37 30 7 |
| Invasive breast cancer§ | 1.26 (1.00 – 1.59) | 30 | 38 |
| Stroke | 1.41 (1.07 – 1.85) | 21 | 29 |
| Pulmonary embolism | 2.13 (1.39 – 3.25) | 8 | 16 |
| Colorectal cancer | 0.63 (0.43 – 0.92) | 16 | 10 |
| Endometrial cancer | 0.83 (0.47 – 1.47) | 6 | 5 |
| Hip fracture | 0.66 (0.45 – 0.98) | 15 | 10 |
| Death due to causes other than the events above | 0.92 (0.74 – 1.14) | 40 | 37 |
| Global Index† | 1.15 (1.03 – 1.28) | 151 | 170 |
| Deep vein thrombosis¶ | 2.07 (1.49 – 2.87) | 13 | 26 |
| Vertebral fractures¶ | 0.66 (0.44 – 0.98) | 15 | 9 |
| Other osteoporotic fractures¶ | 0.77 (0.69 – 0.86) | 170 | 131 |
For those outcomes included in the “global index”, the absolute excess risks per 10,000 women-years in the group treated with CE/MPA were 7 more CHD events, 8 more strokes, 8 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. The absolute excess risk of events included in the “global index” was 19 per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality. (See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.)
Women’s Health Initiative Memory Study
The Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47% were age 65 to 69 years, 35% were 70 to 74 years, and 18% were 75 years of age and older) to evaluate the effects of CE/MPA (0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate) on the incidence of probable dementia (primary outcome) compared with placebo.
After an average follow-up of 4 years, 40 women in the estrogen/progestin group (45 per 10,000 women-years) and 21 in the placebo group (22 per 10,000 women-years) were diagnosed with probable dementia. The relative risk of probable dementia in the hormone therapy group was 2.05 (95% CI, 1.21 to 3.48) compared to placebo. Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNING and WARNINGS, Dementia.)
Indications and Usage for Femtrace
Femtrace therapy is indicated in the treatment of moderate to severe vasomotor symptoms associated with the menopause.
Contraindications
Femtrace should not be used in women with any of the following conditions:
- Undiagnosed abnormal genital bleeding.
- Known, suspected, or history of cancer of the breast.
- Known or suspected estrogen-dependent neoplasia.
- Active deep vein thrombosis, pulmonary embolism or history of these conditions.
- Active or recent (e.g., within the past year) arterial thromboembolic disease (e.g., stroke, myocardial infarction).
- Liver dysfunction or disease.
- Femtrace should not be used in patients with known hypersensitivity to its ingredients.
- Known or suspected pregnancy. There is no indication for Femtrace in pregnancy. There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins from oral contraceptives inadvertently during early pregnancy. (See PRECAUTIONS.)
Warnings
See BOXED WARNINGS.
1. Cardiovascular disorders
Estrogen and estrogen/progestin therapy has been associated with an increased risk of cardiovascular events such as myocardial infarction and stroke, as well as venous thrombosis and pulmonary embolism (venous thromboembolism or VTE). Should any of these occur or be suspected, estrogens should be discontinued immediately.
Risk factors for arterial vascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia and obesity) and/or venous thromboembolism (e.g., personal history or family history of VTE, obesity and systemic lupus erythematosus) should be managed appropriately.
a. Coronary heart disease and stroke
In the Women’s Health Initiative (WHI) study, an increase in the number of myocardial infarctions and strokes has been observed in women receiving CE compared to placebo. These observations are preliminary. (See CLINICAL PHARMACOLOGY, Clinical Studies.)
In the CE/MPA substudy of WHI, an increased risk of coronary heart disease (CHD) events (defined as non-fatal myocardial infarction and CHD death) was observed in women receiving CE/MPA compared to women receiving placebo (37 vs 30 per 10,000 women-years). The increase in risk was observed in year one and persisted.
In the same substudy of WHI, an increased risk of stroke was observed in women receiving CE/MPA compared to women receiving placebo (29 vs 21 per 10,000 women-years). The increase in risk was observed after the first year and persisted.
In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years) a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study; HERS), treatment with CE/MPA (0.625 mg/2.5 mg per day) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE/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 CE/MPA-treated group than in the placebo group in year 1 but not during the subsequent years. Two thousand three hundred and twenty one women from the original HERS trial agreed to participate in an open label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the CE/MPA group and the placebo group in HERS, HERS II and overall.
Large doses of estrogen (5 mg conjugated estrogens per day), comparable to those used to treat cancer of the prostate and breast, have been shown in a large prospective clinical trial in men to increase the risks of nonfatal myocardial infarction, pulmonary embolism and thrombophlebitis.
b. Venous thromboembolism (VTE)
In the Women’s Health Initiative (WHI) study, an increase in VTE has been observed in women receiving CE compared to placebo. These observations are preliminary. (See CLINICAL PHARMACOLOGY, Clinical Studies.)
In the CE/MPA substudy of WHI, a 2-fold greater rate of VTE, including deep venous thrombosis and pulmonary embolism, was observed in women receiving CE/MPA compared to women receiving placebo. The rate of VTE was 34 per 10,000 women-years in the CE/MPA group compared to 16 per 10,000 women-years in the placebo group. The increase in VTE risk was observed during the first year and persisted.
If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism or during periods of prolonged immobilization.
2. Malignant neoplasms
a. Endometrial cancer
The use of unopposed estrogens in women with intact uteri has been associated with an increased risk of endometrial cancer. The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12-fold greater than in non-users, 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 one year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for five to ten years or more, and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.
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. 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 progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia which may be a precursor to endometrial cancer.
b. Breast cancer
The use of estrogens and progestins by postmenopausal women has been reported to increase the risk of breast cancer. The most important randomized clinical trial providing information about this issue is the Women’s Health Initiative (WHI) substudy of CE/MPA (See CLINICAL PHARMACOLOGY, Clinical Studies). The results from observational studies are generally consistent with those of the WHI clinical trial and report no significant variation in the risk of breast cancer among different estrogens or progestins, doses, or routes of administration.
The CE/MPA substudy of WHI reported an increased risk of breast cancer in women who took CE/MPA for a mean follow-up of 5.6 years. Observational studies have also reported an increased risk for estrogen/progestin combination therapy and a smaller increased risk for estrogen alone therapy after several years of use. In the WHI trial and from observational studies, the excess risk increased with duration of use. From observational studies, the risk appeared to return to baseline in about five years after stopping treatment. In addition, observational studies suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen/progestin combination therapy as compared to estrogen alone therapy.
In the CE/MPA substudy, 26% of the women reported prior use of estrogen alone and/or estrogen/progestin combination hormone therapy. After a mean follow-up of 5.6 years during the clinical trial, the overall relative risk of invasive breast cancer was 1.24 (95% confidence interval 1.01-1.54) and the overall absolute risk was 41 vs 33 cases per 10,000 women-years, for CE/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 vs 25 cases per 10,000 women-years for CE/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 vs 36 cases per 10,000 women-years for CE/MPA compared with placebo. In the same substudy, invasive breast cancers were larger and diagnosed at a more advanced stage in the CE/MPA 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 groups.
The use of 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.
3. Dementia
In the Women’s Health Initiative Memory Study (WHIMS), 4,532 generally healthy postmenopausal women 65 years of age and older were studied of whom 35% were 70 to 74 years of age and 18% were 75 or older. After an average follow-up of 4 years, 40 women being treated with CE/MPA (1.8%, n = 2,229) and 21 w
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