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Estradiol/Norethindrone Acetate Tablets | Estradiol / Norethindrone Acetate

05:42 EDT 27th August 2014 | BioPortfolio
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1.0 mg/0.5 mg 0.5 mg/0.1 mg

Rx only

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.

Estradiol/Norethindrone Acetate Tablets 1.0 mg/0.5 mg is a single tablet for oral administration containing 1 mg of estradiol and 0.5 mg of norethindrone acetate and the following excipients: lactose monohydrate, starch (corn), copovidone, talc, magnesium stearate, hypromellose and triacetin.

Estradiol/Norethindrone Acetate Tablets 0.5 mg/0.1 mg is a single tablet for oral administration containing 0.5 mg of estradiol and 0.1 mg of norethindrone acetate and the following excipients: lactose monohydrate, starch (corn), copovidone, talc, magnesium stearate, hypromellose and triacetin.

Estradiol (E) is a white or almost white crystalline powder. Its chemical name is estra-1, 3, 5 (10)-triene-3, 17β-diol hemihydrate with the empirical formula of CHO, ½ HO and a molecular weight of 281.4. The structural formula of E is as follows:

Norethindrone acetate (NETA) is a white or yellowish-white crystalline powder. Its chemical name is 17β-acetoxy-19-nor-17α-pregn-4-en-20-yn-3-one with the empirical formula of CHO and molecular weight of 340.5. The structural formula of NETA is as follows:

IMAGE ena-01.jpgIMAGE ena-02.jpg

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.

Progestin compounds enhance cellular differentiation and generally oppose the actions of estrogens by decreasing estrogen receptor levels, increasing local metabolism of estrogens to less active metabolites, or inducing gene products that blunt cellular responses to estrogen. Progestins exert their effects in target cells by binding to specific progesterone receptors that interact with progesterone response elements in target genes. Progesterone receptors have been identified in the female reproductive tract, breast, pituitary, hypothalamus, and central nervous system. Progestins produce similar endometrial changes to those of the naturally occurring hormone progesterone.

Estradiol is well absorbed through the gastrointestinal tract. Following oral administration of Estradiol/Norethindrone Acetate tablets, peak plasma estradiol concentrations are reached slowly within 5-8 hours. When given orally, estradiol is extensively metabolized (first-pass effect) to estrone sulfate, with smaller amounts of other conjugated and unconjugated estrogens. After oral administration, norethindrone acetate is rapidly absorbed and transformed to norethindrone. It undergoes first-pass metabolism in the liver and other enteric organs, and reaches a peak plasma concentration within 0.5 - 1.5 hours after the administration of Estradiol/Norethindrone Acetate tablets. The oral bioavailability of estradiol and norethindrone following administration of Estradiol/Norethindrone Acetate Tablets 1.0 mg/0.5 mg when compared to a combination oral solution is 53% and 100%, respectively. Administration of Estradiol/Norethindrone Acetate Tablets 1.0 mg/0.5 mg with food did not modify the bioavailability of estradiol, although increases in AUC of 19% and decreases in C of 36% for norethindrone were seen. The pharmacokinetic parameters of estradiol (E), estrone (E), and norethindrone (NET) following oral administration of 1 Estradiol/Norethindrone Acetate Tablets 1.0 mg/0.5 mg or 2 Estradiol/Norethindrone Acetate 0.5 mg/0.1 mg tablet(s) to healthy postmenopausal women are summarized in Table 1.

Following continuous dosing with once-daily administration of Estradiol/Norethindrone Acetate Tablets 1.0 mg/0.5 mg, serum levels of estradiol, estrone, and norethindrone reached steady-state within two weeks with an accumulation of 33-47% above levels following single dose administration. Unadjusted circulating levels of E, E, and NET during Estradiol/Norethindrone Acetate Tablets 1.0 mg/0.5 mg treatment at steady state (dosing at time 0) are provided in Figures 1a and 1b.

TABLE 1 PHARMACOKINETIC PARAMETERS AFTER ADMINISTRATION OF 1 TABLET OF ESTRADIOL/NORETHINDRONE ACETATE 1.0 MG/0.5 MG OR 2 TABLETS OF ESTRADIOL/NORETHINDRONE ACETATE 0.5 MG/0.1 MG TO HEALTHY POSTMENOPAUSAL WOMEN
1 × Estradiol/Norethindrone       Acetate Tablets 2 × Estradiol/Norethindrone       Acetate Tablets
1.0 mg/0.5 mg 0.5 mg/0.1 mg
(n=24) (n=24)
Meangeometric mean;(%CV) geometric % coeffient of variation; Mean(%CV)
AUC = area under the curve, 0 – last quantifiable sample
C max = maximum plasma concentration,
tmax = time at maximum plasma concentration,
t1/2 = half-life,
Estradiol baseline unadjusted data;(E 2)
  AUC 0-t (pg/mL*h) 766.5 (48) 697.3 (53)
  C max (pg/mL) 26.8 (36) 26.5 (37)
  t max (h): median (range) 6.0 (0.5-16.0) 6.5 (0.5-16.0)
  t1/2 (h) baseline unadjusted data ; 14.0 n=18; (29) 14.5 n=16; (27)
Estrone (E 1)
  AUC 0-t(pg/mL*h) 4469.1 (48) 4506.4 (44)
  C max (pg/mL) 195.5 (37) 199.5 (30)
  t max (h): median (range) 6.0 (1.0-9.0) 6.0 (2.0-9.0)
  t 1/2 (h) 10.7 (44) n=13; 11.8 (25)
Norethindrone (NET)
  AUC 0-t (pg/mL*h) 21043 (41) 8407.2 (43)
  C max (pg/mL) 5249.5 (47) 2375.4 (41)
  t max (h): median (range) 0.7 (0.7-1.25) 0.8 (0.7-1.3)
  t 1/2 (h) 9.8 (32) n=22; 11.4 (36) n=21
Figure 1a Levels of Estradiol and Estrone at Steady State During Continuous Dosing with Estradiol/Norethindrone Acetate Tablets 1.0 mg/0.5 mg (n=24)
Figure 1b Levels of Norethindrone at Steady State During Continuous Dosing with Estradiol/Norethindrone Acetate Tablets 1.0 mg/0.5 mg (n=24)

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. Estradiol circulates in the blood bound to sex-hormone-binding globulin (SHBG) (37%) and to albumin (61%), while only approximately 1-2% is unbound. Norethindrone also binds to a similar extent to SHBG (36%) and to albumin (61%).

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 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 metabolites of norethindrone are isomers of 5α-dihydro-norethindrone and tetrahydro-norethindrone, which are excreted mainly in the urine as sulfate or glucuronide conjugates.

Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. The half-life of estradiol following single dose administration of Estradiol/Norethindrone Acetate Tablets 1.0 mg/0.5 mg is 12-14 hours. The terminal half-life of norethindrone is about 8-11 hours.

No pharmacokinetic studies were conducted in special populations, including patients with renal or hepatic impairment.

Coadministration of estradiol with norethindrone acetate did not elicit any apparent influence on the pharmacokinetics of norethindrone. Similarly, no relevant interaction of norethindrone on the pharmacokinetics of estradiol was found within the NETA dose range investigated in a single dose study.

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 result in side effects.

In a 12-week randomized clinical trial involving 92 subjects, Estradiol/Norethindrone Acetate Tablets 1.0 mg/0.5 mg was compared to 1 mg of estradiol and to placebo. The mean number and intensity of hot flushes were significantly reduced from baseline to week 4 and 12 in both the Estradiol/Norethindrone Acetate Tablets 1.0 mg/0.5 mg and the 1 mg estradiol group compared to placebo (see Figure 2).

In a study conducted in Europe a total of 577 postmenopausal women were randomly assigned to either Estradiol/Norethindrone Acetate Tablets 0.5 mg/0.1 mg, 0.5 mg E/0.25 mg NETA, or placebo for 24 weeks of treatment. The mean number and severity of hot flushes were significantly reduced at week 4 and week 12 in the Estradiol/Norethindrone Acetate Tablets 0.5 mg/0.1 mg (see Figure 3) and 0.5 mg E/0.25 mg NETA groups compared to placebo.

Figure 2 Mean Weekly Number of Moderate and Severe Hot Flushes in a 12-Week Study
Figure 3 Mean Number of Moderate to Severe Hot Flushes for Weeks 0 Through 12

Estradiol/Norethindrone Acetate Tablets 1.0 mg/0.5 mg reduced the incidence of estrogen-induced endometrial hyperplasia at 1 year in a randomized, controlled clinical trial. This trial enrolled 1,176 subjects who were randomized to one of 4 arms: 1 mg estradiol unopposed (n=296), 1 mg E + 0.1 mg NETA (n=294), 1 mg E + 0.25 mg NETA (n=291), and Estradiol/Norethindrone Acetate Tablets 1.0 mg/0.5 mg (n=295). At the end of the study, endometrial biopsy results were available for 988 subjects. The results of the 1 mg estradiol unopposed arm compared to Estradiol/Norethindrone Acetate Tablets 1.0 mg/0.5 mg are shown in Table 2.

TABLE 2 INCIDENCE OF ENDOMETRIAL HYPERPLASIA WITH UNOPPOSED ESTRADIOL AND ESTRADIOL/ NORETHINDRONE ACETATE TABLETS 1.0 MG/0.5 MG IN A 12-MONTH STUDY
1 mg E 2
(n=296)
Estradiol/Norethindrone Acetate Tablets
1 mg E2/0.50mg NETA (n=295)
1 mg E2/0.25 mg NETA
(n=291 )
1 mg E2/0.1 mg
NETA (n=294 )
No. of subjects with histological evaluation at the end of the study 247 241 251 249

No. (%) of subjects with endometrial hyperplasia at the end of the study 36 (14.6%) 1 (0.4%) 1 (0.4%) 2 (0.8%)

During the initial months of therapy, irregular bleeding or spotting occurred with Estradiol/Norethindrone Acetate Tablets 1.0 mg/0.5 mg treatment. However, bleeding tended to decrease over time, and after 12 months of treatment with Estradiol/Norethindrone Acetate Tablets 1.0 mg/0.5 mg, about 86% of women were amenorrheic (see Figure 4).

In the clinical trial with Estradiol/Norethindrone Acetate Tablets 0.5 mg/0.1 mg, 88% of women were amenorrheic after 6 months of treatment (see Figure 5).

Figure 4 Patients Treated with Estradiol/Norethindrone Acetate Tablets 1.0 mg/0.5 mg with Cumulative Amenorrhea over Time Percentage of Women with no Bleeding or Spotting at any Cycle Through Cycle 13 Intent to Treat Population, LOCF
Note: the percentage of patients who were amenorrheic in a given cycle and through cycle 13 is shown. If data were missing, the bleeding value from the last reported day was carried forward (LOCF).
Figure 5 Patients Treated with Estradiol/Norethindrone Acetate Tablets 0.5 mg/0.1 mg with Cumulative Amenorrhea over Time Percentage of Women with no Bleeding or Spotting at any Cycle Through Cycle 6, Intent to Treat Population, LOCF

The results of two randomized, multicenter, calcium-supplemented (500-1000 mg/day), placebo-controlled, 2 year clinical trials have shown that Estradiol/Norethindrone Acetate Tablets 1.0 mg/0.5 mg and estradiol 0.5 mg are effective in preventing bone loss in postmenopausal women. While Estradiol/Norethindrone Acetate Tablets 0.5 mg/0.1 mg was not directly studied in these trials, the US trial showed that addition of NETA to estradiol enhances the effect on BMD, therefore the BMD changes expected from treatment with Estradiol/Norethindrone Acetate Tablets 0.5 mg/0.1 mg should be at least as great as observed with estradiol 0.5 mg. A total of 462 postmenopausal women with intact uteri and baseline BMD values for lumbar spine within 2 standard deviations of the mean in healthy young women were enrolled. In a US trial, 327 postmenopausal women (mean time from menopause 2.5 to 3.1 years) with a mean age of 53 years were randomized to 7 groups (0.25 mg, 0.5 mg, and 1 mg of estradiol alone, 1 mg estradiol with 0.25 mg norethindrone acetate, 1 mg estradiol with 0.5 mg norethindrone acetate, and 2 mg estradiol with 1 mg norethindrone acetate, and placebo.) In a European trial (EU trial), 135 postmenopausal women (mean time from menopause 8.4 to 9.3 years) with a mean age of 58 years were randomized to 1 mg estradiol with 0.25 mg norethindrone acetate, 1 mg estradiol with 0.5 mg norethindrone acetate, and placebo. Approximately 58% and 67% of the randomized subjects in the two clinical trials, respectively, completed the two clinical trials. BMD was measured using dual-energy x-ray absorptiometry (DEXA).

A summary of the results comparing Estradiol/Norethindrone Acetate Tablets 1.0 mg/0.5 mg and estradiol 0.5 mg to placebo from the two prevention trials is shown in Table 3.

The overall difference in mean percentage change in BMD at the lumbar spine in the US trial (1000 mg/day calcium) between Estradiol/Norethindrone Acetate Tablets 1.0 mg/0.5 mg and placebo was 5.9% and between estradiol 0.5 mg and placebo was 4.4%. In the European trial (500 mg/day calcium), the overall difference in mean percentage change in BMD at the lumbar spine was 6.3%. Estradiol/Norethindrone Acetate Tablets 1.0 mg/0.5 mg and estradiol 0.5 mg also increased BMD at the femoral neck and femoral trochanter compared to placebo. The increase in lumbar spine BMD in the US and European clinical trials for Estradiol/Norethindrone Acetate Tablets 1.0 mg/0.5 mg and estradiol 0.5 mg is displayed in Figure 6.

TABLE 3 PERCENTAGE CHANGE (MEAN ± SD) IN BONE MINERAL DENSITY (BMD) FOR ESTRADIOL/ NORETHINDRONE ACETATE TABLETS 1.0 MG/0.5 MG AND 0.5 MG E2 While Estradiol/Norethindrone Acetate Tablets 0.5 mg/0.1 mg was not directly studied in these trials, the US trial showed that addition of NETA to estradiol enhances the effect on BMD, therefore the BMD changes expected from treatment with Estradiol/Norethindrone Acetate Tablets 0.5 mg/0.1 mg should be at least as great as observed with estradiol 0.5 mg. (Intent to Treat Analysis, Last Observation Carried Forward)
US Trial EU Trial
Estradiol/Norethindrone Estradiol/Norethindrone
Placebo
(n=37)
0.5 mg E 2
(n=31)
Acetate Tablets
1.0 mg/0.5 mg
(n=37)
Placebo
(n=40)
Acetate Tablets
1.0 mg/0.5 mg
(n=38)
US= United States, EU = European
Lumbar spine -2.1 ± 2.9 2.3 ± 2.8 Significantly (p<0.001) different from placebo 3.8 ± 3.0 -0.9 ± 4.0 5.4 ± 4.8
Femoral neck -2.3 ± 3.4 0.3 ± 2.9 Significantly (p<0.007) different from placebo 1.8 ± 4.1 -1.0 ± 4.6 0.7 ± 6.1
Femoral trochanter -2.0 ± 4.3 1.7 ± 4.1 Significantly (p<0.002) different from placebo 3.7 ± 4.3 0.8 ± 6.9 6.3 ± 7.6
Figure 6 Percentage Change in Bone Mineral Density (BMD) ± SEM of the Lumbar Spine (L1-L4) for Estradiol/Norethindrone Acetate Tablets 1.0 MG/0.5 MG and Estradiol 0.5 MG While Estradiol/Norethindrone Acetate Tablets 0.5mg/0.1mg were not directly studied in these trials, the US trial showed that addition of NETA to estradiol enhances the effect on BMD, therefore BMD changes expected from treatment with Estradiol/Norethindrone Acetate Tablets 0.5 mg/0.1 mg should be at least as great as observed with estradiol 0.5 mg. (Intent to Treat Analysis with Last Observation Carried Forward)

Estradiol/Norethindrone Acetate Tablets 1.0 mg/0.5 mg reduced serum and urine markers of bone turnover with a marked decrease in bone resorption markers (e.g., urinary pyridinoline crosslinks Type 1 collagen C- telopeptide, pyridinoline, deoxypyridinoline) and to a lesser extent in bone formation markers (e.g., serum osteocalcin, bone-specific alkaline phosphatase, C-terminal propetide of type 1 collagen). The suppression of bone turnover markers was evident by 3 months and persisted throughout the 24-month treatment period.

Treatment with 0.5 mg estradiol decreased biochemical markers of bone resorption (urinary pyridinoline, urinary deoxypyridinoline) and bone formation (bone-specific alkaline phosphatase) compared to placebo. These decreases occurred by 6 months of treatment after which the levels were maintained throughout the 24 months.

The WHI enrolled a total of 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of either the use of oral conjugated estrogens (CE 0.625 mg per day) alone or the use of oral conjugated estrogens (CE 0.625 mg) plus medroxyprogesterone acetate (MPA 2.5 mg 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 (MI), silent MI 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 estrogen-plus-progestin substudy was stopped early. According to the predefined stopping rule, after an average follow-up of 5.2 years of treatment, the increased risk of 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 (RR 1.15, 95% nCI 1.03-1.28).

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/MPA were six more CHD events, seven more strokes, ten more PEs, and eight more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were seven fewer colorectal cancers and five fewer hip fractures. (See BOXED WARNINGS, WARNINGS, and PRECAUTIONS .)

Results of the estrogen-plus-progestin substudy, which included 16,608 women (average age of 63 years, range 50 to 79; 83.9 % White, 6.8 % Black, 5.4 % Hispanic, 3.9% Other) are presented in Table 4 below:

The estrogen-alone substudy was also 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 % White, 15.1 % Black, 6.1 % Hispanic, 3.6% Other), after an average follow-up of 6.8 years are presented in Table 5 below.

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 estrogen-alone was 12 more strokes, while the absolute risk reduction per 10,000 women-years was six fewer hip fractures. The absolute excess risk of events included in the "global index" was a nonsignificant two events per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality. (See BOXED WARNINGS, WARNINGS, and PRECAUTIONS .)

Final adjudicated results for CHD events from the estrogen-alone substudy, after an average follow-up of 7.1 years, reported no overall difference for primary CHD events (nonfatal MI, silent MI and CHD death) in women receiving CE alone compared with placebo (see Table 5).

TABLE 4 RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN-PLUS-PROGESTIN SUBSTUDY OF WHI AT AN AVERAGE OF 5.6 YEARSResults are based on centrally adjudicated data. Mortality data was not part of the adjudicated data; however, data at 5.2 years of follow-up showed no difference between the groups in terms of all-cause mortality (RR 0.98, 95% nCI 0.82-1.18).
Event Relative Risk
CE/MPA vs. Placebo
(95% nCINominal confidence intervals unadjusted for multiple looks and multiple comparisons.)
CE/MPA
n = 8,506
Placebo
n = 8,102
Absolute Risk per 10,000 Women-years
CHD events 1.24 (1.00-1.54) 39 33
  Non-fatal MI 1.28 (1.00-1.63) 31 25
  CHD death 1.10 (0.70-1.75) 8 8
All strokes 1.31 (1.02–1.68) 31 24
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 cancerIncludes metastatic and non-metastatic breast cancer, with the exception of in situ breast cancer. 1.24 (1.01–1.54) 41 33
Invasive colorectal cancer 0.56 (0.38–0.81) 9 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
TABLE 5 RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN-ALONE SUBSTUDY OF WHINominal confidence intervals unadjusted for multiple looks and multiple comparisons.
Event Relative Risk
CE vs. Placebo
CE
n = 5,310
Placebo
n = 5,429
(95% nCI) Absolute Risk per 10,000 Women-years
CHD events Results are based on centrally adjudicated data for an average follow-up of 7.1 years. 0.95 (0.79–1.16) 53 56
  Non-fatal MI 0.91 (0.73–1.14) 40 43
  CHD death 1.01(0.71–1.43) 16 16
  Stroke Results are based on an average follow-up of 6.8 years. 1.39 (1.10-1.77) 44 32
  Deep vein thrombosis , Not included in Global Index. 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 0.61 (0.41–0.91) 11 17
  Vertebral fractures , 0.62 (0.42-0.93) 11 17
  Total fractures , 0.70 (0.63-0.79) 139 195
  Death due to other causes , All deaths, except from breast or colorectal cancer, definite/probable CHD, PE or cerebrovascular disease. 1.08 (0.88–1.32) 53 50
  Overall mortality , 1.04 (0.88–1.22) 81 78
  Global Index , A subset of the events was combined in a "global index," defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, or death due to other causes. 1.01 (0.91–1.12) 192 190

The estrogen plus progestin Women's Health Initiative Memory Study (WHIMS) substudy of WHI enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47 %, age 65 to 69 years, 35 %, age 70 to 74 years, 18 %, 75 years of age and older) to evaluate the effects of CE 0.625 mg plus MPA 2.5 mg daily on the incidence of probable dementia (primary outcome) compared with placebo.

After an average follow-up of four years, 40 women in the estrogen-plus-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, 1.21-3.48) compared to placebo. It is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNINGS, WARNINGS, Dementia, and PRECAUTIONS, Geriatric Use .)

The estrogen-alone WHIMS, a substudy of the WHI study, enrolled 2,947 predominantly healthy postmenopausal women 65 years of age and older (45 %, age 65 to 69 years, 36 %, age 70 to 74 years, 19 %, 75 years of age and older) to evaluate the effects of conjugated estrogens (CE 0.625 mg) on the incidence of probable dementia (primary outcome) compared with placebo.

After an average follow-up of 5.2 years, 28 women in the estrogen-alone group (37 per 10,000 women-years) and 19 in the placebo group (25 per 10,000 women-years) were diagnosed with probable dementia. The relative risk of probable dementia in the estrogen-alone group was 1.49 (95% CI 0.83-2.66) compared to placebo.

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% 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 BOXED WARNINGS, WARNINGS, Dementia, and PRECAUTIONS, Geriatric Use .)

Estradiol/Norethindrone Acetate Tablets 1.0 mg/0.5 mg and 0.5 mg/0.1 mg are indicated in women who have a uterus for the:

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.

Estradiol/Norethindrone Acetate Tablets 1.0 mg/0.5 mg is also indicated in women who have a uterus for the:

Estradiol/Norethindrone Acetate Tablets should not be used in women with any of the following conditions:

See BOXED WARNINGS.

Estrogen-plus-progestin therapy has been associated with an increased risk of myocardial infarction as well as stroke, venous thrombosis and pulmonary embolism.

Estrogen-alone therapy has been associated with an increased risk of stroke and deep vein thrombosis (DVT). Should any of these events 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.

In the estrogen plus progestin substudy of the Women's Health Initiative (WHI), a statistically significant increased risk of stroke was reported in women receiving CE/MPA 0.625 mg/2.5 mg daily compared to women receiving placebo (31 vs. 24 per 10,000 women-years). The increase in risk was demonstrated after the first year and persisted. (See CLINICAL STUDIES .)

In the estrogen-alone substudy of the WHI, a statistically significant increased risk of stroke was reported in women receiving CE 0.625 mg daily compared to women receiving placebo (44 vs. 32 per 10,000 women-years). The increase in risk was demonstrated in year one and persisted.

In the estrogen-plus progestin sub-study of WHI, no statistically significant increase in CHD events (defined as non-fatal, MI, silent MI, or death, due to CHD) was reported in women receiving CE/MPA compared to women receiving placebo (39 vs. 33 per 10,000 women years). An increase in relative risk was demonstrated in year one, and a trend toward decreasing relative risk was reported in years 2 through 5. (See CLINICAL STUDIES .)

In the estrogen-alone substudy of WHI, no overall effect on coronary disease (CHD) events was reported in women receiving estrogen alone compared to placebo. (See CLINICAL STUDIES .)

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 (0.625mg/2.5mg 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. Participation in an open-label extension of the original HERS trial (HERS II) was agreed to by 2,321 women. 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 risk of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis.

In the estrogen-plus-progestin substudy of the Women's Health Initiative (WHI), a statistically significant 2-fold greater rate of VTE (DVT and pulmonary embolism [PE]), was reported in women receiving CE/MPA compared to women receiving placebo (35 vs. 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 vs. 13 per 10,000 women-years) and PE (18 vs. 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted. (See CLINICAL STUDIES .) In the estrogen-alone substudy of WHI, the risk of VTE was reported to be increased for women taking conjugated estrogens (30 vs. 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 vs. 15 per 10,000 women-years). The increase in VTE risk was demonstrated during the first two years.

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.

In some studies, 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 CE/MPA substudy of the WHI study (see CLINICAL STUDIES ). The results from observational studies are generally consistent with those of the WHI clinical trial.

Observational studies have also reported an increased risk of breast cancer for estrogen-plus-progestin combination therapy, and a smaller increased risk for estrogen-alone therapy, after several years of use. For both findings, the excess risk increased with duration of use, and appeared to return to baseline over about five years after stopping treatment (only the observational studies have substantial data on risk after stopping). In these studies, the risk of breast cancer was greater, and became apparent earlier, with estrogen-plus-progestin combination therapy as compared to estrogen-alone therapy. However, these studies have not found significant variation in the risk of breast cancer among different estrogens or among different estrogen-plus-progestin combinations, doses, or routes of administration.

In the estrogen-plus-progestin substudy, after a mean follow-up of 5.6 years, the WHI substudy reported an increased risk of breast cancer. In this substudy, prior use of estrogen alone or estrogen-plus-progestin combination hormone therapy was reported by 26% of the women. The relative risk of invasive breast cancer was 1.24 (95% nCI 1.01-1.54), and the absolute risk was 41 vs 33 cases per 10,000 women-years, for estrogen plus progestin compared with placebo, respectively. 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 estrogen plus progestin 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 of estrogen plus progestin compared with placebo. In the WHI trial, invasive breast cancers were larger and diagnosed at a more advanced stage in the estrogen-plus-progestin 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.

I

Manufacturer

Breckenridge Pharmaceutical, Inc.

Active Ingredients

Source

Drugs and Medications [892 Associated Drugs and Medications listed on BioPortfolio]

Combipatch [Novartis Pharmaceuticals Corporation]

Combipatch

Mimvey [TEVA Pharmaceuticals USA Inc]

Mimvey (estradiol and norethindrone acetate tablets)

Norethindrone acetate [Glenmark Generics Inc., USA]

Norethindrone Acetate Tablets USP, 5 mg

Jinteli [Physicians Total Care, Inc.]

Jinteli (northindrone acetate and ethinyl estradiol tablets, USP)

Jinteli [TEVA Pharmaceuticals USA Inc]

Jinteli (northindrone acetate and ethinyl estradiol tablets, USP)

Clinical Trials [842 Associated Clinical Trials listed on BioPortfolio]

Safety and Efficacy in Premenopausal Women With Heavy Menstrual Bleeding (HMB) Associated With Uterine Fibroids (UF)

This is a Phase 2b randomized, double-blind, placebo-controlled study evaluating the safety and efficacy of elagolix alone and in combination with add-back therapy versus placebo on heavy ...

Efficacy and Safety of Elagolix in Combination With Estradiol/Norethindrone Acetate for the Management of Heavy Menstrual Bleeding Associated With Uterine Fibroids in Premenopausal Women (Replicate Study)

This study seeks to evaluate the efficacy, safety and tolerability of elagolix alone and in combination with estradiol/norethindrone acetate for the management of heavy menstrual bleeding ...

Ovulation Incidence in Oral Contraceptive Users

Since the introduction of the combined hormonal contraceptive pill, dosages of ethinyl estradiol (EE) have steadily decreased from more than 150mcg to 20mcg in an attempt to improve the ri...

Efficacy and Safety of Elagolix in Combination With Estradiol/Norethindrone Acetate for the Management of Heavy Menstrual Bleeding Associated With Uterine Fibroids in Premenopausal Women

This study seeks to evaluate the efficacy, safety and tolerability of elagolix alone and in combination with estradiol/norethindrone acetate for the management of heavy menstrual bleeding ...

Study of Safety and Efficacy of an Oral Contraceptive

This is a comparative study. The primary objective of the study is to assess the efficacy of a low dose oral contraceptive in the prevention of pregnancy. The secondary objectives are to a...

PubMed Articles [1002 Associated PubMed Articles listed on BioPortfolio]

Efficacy and acceptability of long-term norethindrone acetate for the treatment of rectovaginal endometriosis.

To study the efficacy of long-term treatment with norethindrone acetate (NETA) in patients with rectovaginal endometriosis.

Disk-based solid phase extraction for the determination of diclofenac and steroidal estrogens E1, E2 and EE2 listed in the WFD watch list by GC-MS.

The aim of this study was to develop and validate an analytical method for determining estrone, 17β-estradiol, 17α-ethynyl estradiol and diclofenac in whole surface water samples at or below the lim...

Ultra performance liquid chromatography-tandem mass spectrometry assay for determination of plasma nomegestrol acetate and estradiol in healthy postmenopausal women.

A highly sensitive and selective ultra-performance liquid chromatography-tandem mass spectrometry method is described for the simultaneous determination of nomegestrol acetate (NOMAC), a highly select...

Concentration of sulfated glycosaminoglycans in the mammary tissue of female rats with the aging and about hormonal influence.

It was to evaluate the concentration of sulfate glycosaminoglycans (GAG) in mammary tissue of the young and adult female rats and ovariectomized females rats after hormonal stimulation. For this purpo...

Diffusion-weighted MRS of acetate in the rat brain.

Acetate has been proposed as an astrocyte-specific energy substrate for metabolic studies in the brain. The determination of the relative contribution of the intracellular and extracellular compartmen...

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