estradiol and norgestimate
Dosage Form: tablets
Prefest® (estradiol/norgestimate) tablets
Rx only
Iss. 9/2010
11001719
PHYSICIAN’S PACKAGE INSERT
WARNING
Estrogens and 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 equine 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.
DESCRIPTION:
The Prefest regimen provides for a single oral tablet to be taken once daily. The peach tablet containing 1 mg estradiol is taken on days one through three of therapy; the white tablet containing 1 mg estradiol and 0.09 mg norgestimate is taken on days four through six of therapy. This pattern is then repeated continuously to produce the constant estrogen/intermittent progestogen regimen of Prefest.
The estrogenic component of Prefest is estradiol, USP. It is a white, crystalline solid, chemically described as estra-1,3,5(10)-triene-3,17β-diol. The structural formula is as follows:
C18H24O2 Molecular Weight: 272.39
The progestational component of Prefest is micronized norgestimate, a white powder which is chemically described as 18,19-dinor-17-pregn-4-en-20-yn-3-one, 17-(acetyloxy)-13-ethyl-,oxime,(17α)-(+)-. The structural formula is as follows:
C23H31NO3 Molecular Weight: 369.50
Each tablet for oral administration contains 1 mg estradiol alone or 1 mg estradiol and 0.09 mg of norgestimate. The inactive ingredients are as follows:
The estradiol tablet contains anhydrous lactose, croscarmellose sodium, FD&C yellow no. 6 aluminum lake, magnesium stearate and microcrystalline cellulose.
The estradiol and norgestimate tablet contains anhydrous lactose, croscarmellose sodium, magnesium stearate and microcrystalline cellulose.
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.
Norgestimate is a derivative of 19-nortestosterone and binds to androgen and progestogen receptors, similar to that of the natural hormone progesterone; it does not bind to estrogen receptors. Progestins counter the estrogenic effects by decreasing the number of nuclear estradiol receptors and suppressing epithelial DNA synthesis in endometrial tissue.
Pharmacokinetics:
Absorption:
Estradiol reaches its peak serum concentration (Cmax) at approximately 7 hours in postmenopausal women receiving Prefest (Table 1). Norgestimate is completely metabolized; its primary active metabolite, 17-deacetylnorgestimate, reaches Cmax at approximately 2 hours after dose (Table 1). Upon co-administration of Prefest with a high fat meal, the Cmax values for estrone and estrone sulfate were increased by 14% and 24%, respectively, and the Cmax for 17-deacetylnorgestimate was decreased by 16%. The AUC values for these analytes were not significantly affected by food.
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 albumin. 17-deacetylnorgestimate, the primary active metabolite of norgestimate, does not bind to SHBG, but to other serum proteins. The percent protein binding of 17-deacetylnorgestimate is approximately 99%.
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 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 portion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. Norgestimate is extensively metabolized by first-pass mechanisms in the gastrointestinal tract and/or liver. Norgestimate’s primary active metabolite is 17-deacetylnorgestimate.
Excretion:
Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Norgestimate metabolites are eliminated in the urine and feces. The half-life (t1/2) of estradiol and 17-deacetylnorgestimate in postmenopausal women receiving Prefest is approximately 16 and 37 hours, respectively.
Drug Interactions:
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.
Results of a subset population (n=24) from a clinical study conducted in 36 healthy postmenopausal women indicated that the steady state serum estradiol levels during the estradiol plus norgestimate phase of the regimen may be lower by 12-18% as compared with estradiol administered alone. The serum estrone levels may decrease by 4% and the serum estrone sulfate levels may increase by 17% during the estradiol plus norgestimate phase as compared with estradiol administered alone. The clinical relevance of these observations is unknown.
Special Populations:
Race and Body Weight:
The effects of race and body weight on the pharmacokinetics of estradiol, norgestimate, and their metabolites were evaluated in 164 healthy postmenopausal women (100 Caucasians, 61 Hispanics, 2 Blacks, and 1 Asian). No significant pharmacokinetic difference was observed between the Caucasian and the Hispanic postmenopausal women. No significant difference due to body weight was observed in women in the 60 to 80 kg weight range. Women with body weight higher than 80 kg, however, had approximately 40% lower peak serum levels of 17-deacetylnorgestimate, 30% lower AUC values for 17-deacetylnorgestimate and 30% lower Cmax values for norgestrel. The clinical relevance of these observations is unknown.
No pharmacokinetic studies were conducted in other special populations.
| ||||||
| Analyte | Parameter† | Units | First Dose E2 | First Dose E2/NGM | Multiple Dose E2 | Multiple Dose E2/NGM |
| E2 | C max | pg/mL | 27.4 | 39.3 | 49.7 | 46.2 |
| tmax | h | 7 | 7 | 7 | 7 | |
| AUC (0-24 h) | pg. h/mL | 424 | 681 | 864 | 779 | |
| E1 | Cmax | pg/mL | 210 | 285 | 341 | 325 |
| t max | h | 6 | 6 | 341 | 6 | |
| AUC (0-24 h) | pg. h/mL | 2774 | 4153 | 5429 | 4957 | |
| E1S | Cmax | ng/mL | 11.1 | 13.9 | 14.9 | 14.5 |
| tmax | h | 5 | 4 | 6 | 5 | |
| AUC (0-24 h) | ng. h/mL | 135 | 180 | 198 | 198 | |
| 17d-NGM | Cmax | pg/mL | NA‡ | 515 | NA | 643 |
| tmax | h | NA | 2 | NA | 2 | |
| AUC (0-24 h) | pg. h/mL | NA | 2146 | NA | 5322 | |
| t½ | h | NA | 37 | NA | NA | |
CLINICAL STUDIES:
Effects on Vasomotor Symptoms:
The effect of the estrogen component of Prefest on vasomotor symptoms was confirmed in a 12-week placebo-controlled trial of 168 healthy postmenopausal women between 28 and 66 years of age (87% Caucasian) with moderate to severe vasomotor symptoms (MSVS). The addition of norgestimate to estrogen (i.e., the Prefest regimen) was studied in two 12-month trials in 1212 healthy postmenopausal women between 40 and 65 years of age (85% Caucasian) for endometrial protection. Results from a subset population (n=119) of these 12-month trials (women with MSVS) are shown in Table 2.
| 1 mg E2 | Prefest | |||
| N | Mean | N | Mean | |
| Baseline | 29 | 11.0 | 26 | 10.9 |
| Week 4 | 29 | 3.3 | 26 | 2.6 |
| Week 8 | 29 | 1.1 | 23 | 0.9 |
| Week 12 | 29 | 1.1 | 23 | 0.7 |
The effects of the addition of norgestimate on steady state estrogen levels and the clinical relevance thereof have been discussed in CLINICAL PHARMACOLOGY (see Drug Interactions).
Effects on Vulvar and Vaginal Atrophy:
The effect of the estrogen component of Prefest on vulvar and vaginal atrophy was confirmed in a 12-week placebo-controlled trial of healthy postmenopausal women with moderate to severe vasomotor symptoms (MSVS). The addition of norgestimate to estrogen (i.e., the Prefest regimen) was studied in a 12-month trial in 143 healthy postmenopausal women between 42 and 65 years of age (92% Caucasian) for endometrial protection. Results from a subset population (n=69) with paired tests for maturation index of the vaginal mucosa are shown in Table 3.
| Pretreatment Mean | Month 7 Mean | Mean Change | |
| 1 mg Estradiol (N=37) | |||
| Parabasal Cells (%) | 25.1 | 2.7 | -22.4 |
| Intermediate Cells (%) | 69.2 | 76.4 | 7.2 |
| Superficial Cells (%) | 5.7 | 20.9 | 15.3 |
| Prefest (N=32) | |||
| Parabasal Cells (%) | 31.9 | 0.0 | -31.9 |
| Intermediate Cells (%) | 64.2 | 80.9 | 16.7 |
| Superficial Cells (%) | 3.9 | 19.1 | 15.2 |
Effects on the Endometrium:
The effect of Prefest on the endometrium was evaluated in two 12-month trials. The combined results are shown in Table 4.
Continuous 1 mg estradiol | Prefest | |
| Total No. Subjects | 265 | 242 |
| Total No. Evaluable Biopsies | 256 (97%) | 227 (94%) |
| Normal endometrium | 182 (71%) | 227 (100%) |
| Simple hyperplasia | 64 (25%) | 0 (0%) |
| Complex hyperplasia | 2 (0.8%) | 0 (0%) |
| Hyperplasia with cytological atypia | 8 (3%) | 0 (0%) |
In another 12-month controlled clinical trial for endometrial protection an additional 190 postmenopausal women were treated with Prefest. No subject had a diagnosis of endometrial hyperplasia after treatment.
Effects on Uterine Bleeding or Spotting:
The effects of Prefest on uterine bleeding or spotting, as recorded on daily diary cards, were evaluated in two 12-month trials. Combined results are shown in Figure 1.
Figure 1: Subjects with Cumulative Amenorrhea Over Time (Percentage of Women With No Bleeding or Spotting at a Given Month Through Month 12), Intent to treat Population
Effects on Lipids:
The effect of Prefest on lipids was evaluated in a 12-month metabolic trial of healthy postmenopausal women. Results are shown in Table 5.
| 1 mg E2 | Prefest | |||
| N | Change | N | Change | |
| Total Cholesterol | 36 | 1.2 | 31 | -1.9 |
| HDL | 36 | 12.0 | 31 | 9.7 |
| LDL | 31 | 1.7 | 30 | 1.2 |
| Triglycerides | 36 | 29.0 | 31 | 9.4 |
The Women’s Health Initiative (WHI) 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 6 below:
| |||
| Event† | Relative Risk CE/MPA vs placebo at 5.2 Years | Placebo n = 8102 | CE/MPA n = 8506 |
| (95% CI‡) | Absolute Risk per 10,000 Person-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 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 WARNINGS and WARNINGS, Dementia.)
INDICATIONS AND USAGE:
Prefest is indicated in women who have a uterus for the:
- Treatment of moderate to severe vasomotor symptoms associated with the menopause.
- Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause. When prescribed solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered.
- Prevention of postmenopausal osteoporosis. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and nonestrogen medications should be carefully considered.
The mainstays for decreasing the risk of postmenopausal osteoporosis are weight bearing exercise, adequate calcium and vitamin D intake, and when indicated, pharmacologic therapy. Postmenopausal women require an average of 1500 mg/day of elemental calcium. Therefore, when not contraindicated, calcium supplementation may be helpful for women with suboptimal dietary intake. Vitamin D supplementation of 400-800 IU/day may also be required to ensure adequate daily intake in postmenopausal women.
CONTRAINDICATIONS:
Prefest 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.
- Prefest should not be used in patients with known hypersensitivity to its ingredients.
- Known or suspected pregnancy. There is no indication for Prefest 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 nonfatal 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 become 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 patients age, risk factors, and prior mammogram results.
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