Amabelz

Name: Amabelz

Description

Amabelz 1 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: copovidone, hypromellose, lactose monohydrate, magnesium stearate, starch (corn) and triacetin.

Amabelz 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: copovidone, hypromellose, lactose monohydrate, magnesium stearate, starch (corn) and triacetin.

Estradiol (E2), an estrogen, 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 C18H24O2, ½ H2O and a molecular weight of 281.4. The structural formula of E2 is as follows:

Norethindrone acetate (NETA), a progestin, 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 C22H28O3 and molecular weight of 340.46. The structural formula of NETA is as follows:

USP dissolution test is pending.

Indications

Treatment Of Moderate To Severe Vasomotor Symptoms Due To Menopause

Treatment Of Moderate To Severe Symptoms Of Vulvar And Vaginal Atrophy Due To Menopause

Limitation Of Use

When prescribing solely for the treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause, topical vaginal products should be considered.

Prevention Of Postmenopausal Osteoporosis Limitation Of Use

Limitation Of Use

When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medication should be carefully considered.

Clinical pharmacology

Mechanism Of Action

Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level.

The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone in the peripheral tissues. Thus, estrone and the sulfate-conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women.

Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue.

Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH), and FSH through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.

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.

Pharmacodynamics

There are no pharmacodynamic data known for Amabelz tablets.

Pharmacokinetics

Absorption

Estradiol:

Estradiol is absorbed through the gastrointestinal tract. Following oral administration of Amabelz tablets, peak plasma estradiol concentrations are reached within 5 to 8 hours. The oral bioavailability of estradiol following administration of Amabelz 1 mg/0.5 mg when compared to a combination oral solution is 53%. Administration of Amabelz 1 mg/0.5 mg with food did not modify the bioavailability of estradiol.

Norethindrone Acetate:

After oral administration, norethindrone acetate is absorbed and transformed to norethindrone. Norethindrone reaches a peak plasma concentration within 0.5 to 1.5 hours after the administration of Amabelz tablets. The oral bioavailability of norethindrone following administration of Amabelz 1 mg/0.5 mg when compared to a combination oral solution is 100%. Administration of Amabelz 1 mg/0.5 mg with food increases norethindrone AUC0 to 72 by 19% and decreases Cmax by 36%.

The pharmacokinetic parameters of estradiol (E ), estrone (E ), and norethindrone (NET) following oral administration of 1 Amabelz 1 mg/0.5 mg or 2 Amabelz 0.5 mg/0.1 mg tablet(s) to healthy postmenopausal women are summarized in Table 3.

TABLE 3: PHARMACOKINETIC PARAMETERS AFTER ADMINISTRATION OF 1 TABLET OF AMABELZ 1 MG/0.5 MG OR 2 TABLETS OF AMABELZ 0.5 MG/0.1 MG TO HEALTHY POSTMENOPAUSAL WOMEN

  1 x Amabelz
1 mg/0.5 mg
(n=24)
Mean* (%CV)†
2 x Amabelz
0.5 mg/0.1 mg
(n=24)
Mean* (%CV)†
Estradiol (E2)‡    
AUC0 to t (pg/mL*h) 766.5 (48) 697.3 (53)
Cmax (pg/mL) 26.8 (36) 26.5 (37)
tmax (h): median (range) 6 (0.5 to 16) 6.5 (0.5 to 16)
t1/2 (h)§ 14¶ (29) 14.5# (27)
Estrone‡ (E1)    
AUC0 to t (pg/mL*h) 4469.1 (48) 4506.4 (44)
Cmax (pg/mL) 195.5 (37) 199.5 (30)
tmax (h): median (range) 6 (1 to 9) 6 (2 to 9)
t1/2 (h)§ 10.7 (44)Þ 11.8 (25)Þ
Norethindrone (NET)    
AUC0 to t (pg/mL*h) 21043 (41) 8407.2 (43)
Cmax (pg/mL) 5249.5 (47) 2375.4 (41)
tmax (h): median (range) 0.7 (0.7 to 1.25) 0.8 (0.7 to 1.3)
t1/2 (h) 9.8 (32)ß 11.4 (36)á
AUC = area under the curve, 0 – last quantifiable sample
Cmax = maximum plasma concentration,
tmax = time at maximum plasma concentration,
t1/2 = half-life,
*geometric mean;
†geometric % coefficient of variation;
‡baseline unadjusted data;
§baseline unadjusted data;
¶n=18;
#n=16;
Þn=13;
ßn=22;
án=21

Following continuous dosing with once-daily administration of Amabelz 1 mg/0.5 mg, serum concentrations of estradiol, estrone, and norethindrone reached steady-state within two weeks with an accumulation of 33 to 47% above concentrations following single dose administration. Unadjusted circulating concentrations of E2, E1, and NET during Amabelz 1 mg/0.5 mg treatment at steady state (dosing at time 0) are provided in Figures 1a and 1b.

Figure 1a: Mean Baseline-Uncorrected Estradiol and Estrone Serum Concentration-Time Profiles Following Multiple Doses of AMABELZ 1 mg/0.5 mg (N=24)

Figure 1b: Mean Baseline-Uncorrected Norethindrone Serum Concentration-Time Profile Following Multiple Doses of AMABELZ 1 mg/0.5 mg (N=24)

Distribution

Estradiol:

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 SHBG (37%) and to albumin (61%), while only approximately 1 to 2% is unbound.

Norethindrone Acetate:

Norethindrone also binds to a similar extent to SHBG (36%) and to albumin (61%).

Metabolism

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 a major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the intestine followed by reabsorption. In postmenopausal women, a significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.

Norethindrone Acetate:

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.

Excretion

Estradiol:

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 Amabelz 1 mg/0.5 mg is 12 to 14 hours.

Norethindrone Acetate:

The terminal half-life of norethindrone is about 8 to 11 hours.

Use In Specific Populations

No pharmacokinetic studies were conducted in specific populations, including women with renal or hepatic impairment.

Clinical Studies

Effects On Vasomotor Symptoms

In a 12-week randomized clinical trial involving 92 subjects, Amabelz 1 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 Amabelz 1 mg/0.5 mg and the 1 mg estradiol group compared to placebo (see Figure 2).

Figure 2 Mean Weekly Number of Moderate and Severe Hot Flushes in a 12-Week Study

In a study conducted in Europe a total of 577 postmenopausal women were randomly assigned to either Amabelz 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 Amabelz 0.5 mg/0.1 mg (see Figure 3) and 0.5 mg E /0.25 mg NETA groups compared to placebo.

Figure 3 Mean Number of Moderate to Severe Hot Flushes for Weeks 0 Through 12

Effects On The Endometrium

Amabelz 1 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 E2 + 0.1 mg NETA (n=294), 1 mg E2 + 0.25 mg NETA (n=291), and Amabelz 1 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 Amabelz 1 mg/0.5 mg are shown in Table 4.

TABLE 4: INCIDENCE OF ENDOMETRIAL HYPERPLASIA WITH UNOPPOSED ESTRADIOL AND AMABELZ 1 MG/0.5 MG IN A 12- MONTH STUDY

  1 mg E2
(n=296)
Amabelz
1 mg E2 /0.5 mg 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 %)

Effects On Uterine Bleeding Or Spotting

During the initial months of therapy, irregular bleeding or spotting occurred with Amabelz 1 mg/0.5 mg treatment. However, bleeding tended to decrease over time, and after 12 months of treatment with Amabelz 1 mg/0.5 mg, about 86 percent of women were amenorrheic (see Figure 4).

Figure 4 Patients Treated with AMABELZ 1 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). In the clinical trial with Amabelz 0.5 mg/0.1 mg, 88 percent of women were amenorrheic after 6 months of treatment (See Figure 5).

Figure 5 Patients Treated with AMABELZ 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

Effects On Bone Mineral Density

The results of two randomized, multicenter, calcium-supplemented (500-1000 mg per day), placebocontrolled, 2 year clinical trials have shown that Amabelz 1 mg/0.5 mg and estradiol 0.5 mg are effective in preventing bone loss in postmenopausal women. 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 (T-score > - 2) 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 percent and 67 percent of the randomized subjects in the two clinical trials, respectively, completed the two clinical trials. BMD was measured using dual-energy x-ray absorptiometry (DXA).

A summary of the results comparing Amabelz 1 mg/0.5 mg and estradiol 0.5 mg to placebo from the two prevention trials is shown in Table 5.

TABLE 5: PERCENTAGE CHANGE (MEAN ± SD) IN BONE MINERAL DENSITY (BMD) FOR AMABELZ 1 MG/0.5 MG AND 0.5 MG E (Intent to Treat Analys is , Las t Obs ervation Carried Forward)

  US Trial EU Trial
Placebo
(n=37)
0.5 mg E2*
(n=31)
Amabelz
1.0 mg/0.5 mg
(n=37)
Placebo
(n=40)
Amabelz
1.0 mg/0.5 mg
(n=38)
Lumbar spine -2.1 ± 2.9 2.3 ± 2.8† 3.8 ± 3.0† -0.9 ± 4.0 5.4 ± 4.8†
Femoral neck -2.3 ± 3.4 0.3 ± 2.9‡ 1.8 ± 4.1† -1.0 ± 4.6 0.7 ± 6.1
Femoral trochanter -2.0 ± 4.3 1.7 ± 4.1§ 3.7 ± 4.3† 0.8 ± 6.9 6.3 ± 7.6†
US= United States, EU = European
*While Amabelz 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 Amabelz 0.5 mg/0.1 mg should be at least as great as observed with estradiol 0.5 mg.
†Significantly (p<0.001) different from placebo
‡Significantly (p<0.007) different from placebo
§Significantly (p<0.002) different from placebo

The overall difference in mean percentage change in BMD at the lumbar spine in the US trial (1000 mg per day calcium) between Amabelz 1 mg/0.5 mg and placebo was 5.9 percent and between estradiol 0.5 mg and placebo was 4.4 percent. In the European trial (500 mg per day calcium), the overall difference in mean percentage change in BMD at the lumbar spine was 6.3 percent. Amabelz 1 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 Amabelz 1 mg/0.5 mg and estradiol 0.5 mg is displayed in Figure 6.

Figure 6 Percentage Change in Bone Mineral Density (BMD) ± SEM of the Lumbar Spine (L1-L4) for AMABELZ 1 mg/0.5 mg and Estradiol 0.5 mg
(Intent to Treat Analysis with Last Observation Carried Forward)

Women’s Health Initiative Studies

The WHI enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of daily oral CE (0.625 mg)-alone or in combination with MPA (2.5 mg) compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of CHD (defined as nonfatal MI, silent MI and CHD death), with invasive breast cancer as the primary adverse outcome. A "global index" included the earliest occurrence of CHD, invasive breast cancer, stroke, PE, endometrial cancer (only in the CE plus MPA substudy), colorectal cancer, hip fracture, or death due to other cause. These substudies did not evaluate the effects of CE plus MPA or CE-alone on menopausal symptoms.

WHI Estrogen Plus Progestin Substudy

The WHI estrogen plus progestin substudy was stopped early. According to the predefined stopping rule, after an average follow-up of 5.6 years of treatment, the increased risk of invasive breast cancer and cardiovascular events exceeded the specified benefits included in the "global index." The absolute excess risk of events included in the "global index" was 19 per 10,000 women-years.

For those outcomes included in the WHI "global index," that reached statistical significance after 5.6 years of follow-up, the absolute excess risks per 10,000 women-years in the group treated with CE plus MPA were 7 more CHD events, 8 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures.

Results of the CE plus MPA substudy, which included 16,608 women (average 63 years of age, range 50 to 79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other) are presented in Table 6. These results reflect centrally adjudicated data after an average follow-up of 5.6 years.

TABLE 6: RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN PLUS PROGESTIN SUBSTUDY OF WHI AT AN AVERAGE OF 5.6 YEARS

Event Relative Risk
CE/MPA vs . Placebo
(95% nCI‡)
CE/MPA
n = 8,506
Placebo
n = 8,102
    Absolute Risk per 10,000 Women-Years
CHD events 1.23 (0.99-1.53) 41 34
  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) 33 25
  Ischemic stroke 1.44 (1.09–1.90) 26 18
Deep vein thrombosis§ 1.95 (1.43–2.67) 26 13
Pulmonary embolism 2.13 (1.45–3.11) 18 8
Invasive breast cancer¶ 1.24 (1.01–1.54) 41 33
Colorectal cancer 0.61 (0.42–0.87) 10 16
Endometrial cancer§ 0.81 (0.48–1.36) 6 7
Cervical cancer§ 1.44 (0.47–4.42) 2 1
Hip fracture 0.67 (0.47–0.96) 11 16
Vertebral fractures§ 0.65 (0.46–0.92) 11 17
Lower arm/wrist fractures§ 0.71 (0.59–0.85) 44 62
Total fractures§ 0.76 (0.69–0.83) 152 199
Overall Mortality# 1.00 (0.83-1.19) 52 52
Global IndexÞ 1.13 (1.02-1.25) 184 165
*Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi.
†Results are based on centrally adjudicated data.
‡Nominal confidence intervals unadjusted for multiple looks and multiple comparisons.
§Not included in “global index”.
¶Includes metastatic and non-metastatic breast cancer, with the exception of in situ breast cancer.
#All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease.
ÞA 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.

Timing of the initiation of estrogen plus progestin therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen plus progestin substudy, stratified by age, showed in women 50 to 59 years of age a non-significant trend toward reduced risk for overall mortality [hazard ratio (HR) 0.69 (95 percent CI, 0.44 to 1.07)].

WHI Estrogen-Alone Substudy

The WHI estrogen-alone substudy was stopped early because an increased risk of stroke was observed, and it was deemed that no further information would be obtained regarding the risks and benefits of estrogen-alone in predetermined primary endpoints.

Results of the estrogen-alone substudy, which included 10,739 women (average 63 years of age, range 50 to 79; 75.3 percent White, 15.1 percent Black, 6.1 percent Hispanic, 3.6 percent Other), after an average follow-up of 7.1 years, are presented in Table 7.

Table 7: Relative and Absolute Risk Seen in the Estrogen-Alone Substudy of WHI

Event Relative Risk
CE vs . Placebo
(95% nCI†)
CE
n = 5,310
Placebo
n = 5,429
Absolute Risk per 10,000 Women-years
CHD events‡ 0.95 (0.78–1.16) 54 57
  Non-fatal MI‡ 0.91 (0.73–1.14) 40 43
  CHD death‡ 1.01(0.71–1.43) 16 16
All strokes‡ 1.33 (1.05-1.68) 45 33
  Ischemic stroke† 1.55 (1.19 – 2.01) 38 25
Deep vein thrombosis‡,§ 1.47 (1.06–2.06) 23 15
Pulmonary embolism‡ 1.37 (0.90–2.07) 14 10
Invasive breast cancer‡ 0.80 (0.62–1.04) 28 34
Colorectal cancer¶ 1.08 (0.75–1.55) 17 16
Hip fracture‡ 0.65 (0.45–0.94) 12 19
Vertebral fractures‡,§ 0.64 (0.44-0.93) 11 18
Lower arm/wrist fractures‡,§ 0.58 (0.47-0.72) 35 59
Total fractures‡,§ 0.71 (0.64-0.80) 144 197
Death due to other causes¶,# 1.08 (0.88–1.32) 53 50
Overall mortality‡,§ 1.04 (0.88–1.22) 79 75
Global IndexÞ 1.02 (0.92–1.13) 206 201
*Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi.
†Nominal confidence intervals unadjusted for multiple looks and multiple comparisons.
‡Results are based on centrally adjudicated data for an average follow-up of 7.1 years.
§Not included in “global index”.
¶Results are based on an average follow-up of 6.8 years.
#All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease.
ÞA 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.

For those outcomes included in the WHI "global index" that reached statistical significance, the absolute excess risk per 10,000 women-years in the group treated with CE-alone was 12 more strokes, while the absolute risk reduction per 10,000 women-years was 7 fewer hip fracture.9 The absolute excess risk of events included in the "global index" was a non-significant 5 events per 10,000 womenyears. There was no difference between the groups in terms of all-cause mortality.

No overall difference for primary CHD events (nonfatal MI, silent MI and CHD death) and invasive breast cancer incidence in women receiving CE-alone compared with placebo was reported in final centrally adjudicated results from the estrogen-alone substudy, after an average follow up of 7.1 years.

Centrally adjudicated results for stroke events from the estrogen-alone substudy, after an average follow-up of 7.1 years, reported no significant difference in distribution of stroke subtype or severity, including fatal strokes, in women receiving CE-alone compared to placebo. Estrogen-alone increased the risk for ischemic stroke, and this excess risk was present in all subgroups of women examined.10

Timing of the initiation of estrogen-alone therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen-alone substudy, stratified by age, showed in women 50 to 59 years of age a non-significant trend toward reduced risk for CHD [HR 0.63 (95 percent CI, 0.36 to 1.09)] and overall mortality [HR 0.71 (95 percent CI, 0.46 to 1.11)].

Women’s Health Initiative Memory Study

The WHIMS estrogen plus progestin ancillary study of WHI enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47 percent were 65 to 69 years of age, 35 percent were 70 to 74 years of age, 18 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia (primary outcome) compared to placebo.

After an average follow-up of 4 years, the relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21-3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years. Probable dementia as defined in this study included Alzheimer's disease (AD), vascular dementia (VaD) and mixed types (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women [see WARNINGS AND PRECAUTIONS, and Use In Specific Populations].

The WHIMS estrogen-alone ancillary study of WHI study enrolled 2,947 predominantly healthy hysterectomized postmenopausal women 65 to 79 years of age (45 percent were 65 to 69 years of age, 36 percent were 70 to 74 years of age, 19 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg)-alone on the incidence of probable dementia (primary outcome) compared to placebo.

After an average follow-up of 5.2 years, the relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83-2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years. Probable dementia as defined in this study included AD, VaD and mixed types (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women [see WARNINGS AND PRECAUTIONS, and Use In Specific Populations].

When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 percent CI, 1.19-2.60). Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women [see WARNINGS AND PRECAUTIONS, and Use In Specific Populations].

REFERENCES

9. Jackson RD, et al. Effects of Conjugated Equine Estrogen on Risk of Fractures and BMD in Postmenopausal Women With Hysterectomy: Results From the Women's Health Initiative Randomized Trial. J Bone Miner Res. 2006;21:817-828.

10. Hendrix SL, et al. Effects of Conjugated Equine Estrogen on Stroke in the Women's Health Initiative. Circulation. 2006;113:2425-2434.

Dosage Forms and Strengths

Amabelz tablets are available in two strengths:

    •    Each tablet of Amabelz 1 mg/ 0.5 mg contains 1 mg of estradiol and 0.5 mg of norethindrone acetate. The tablets are white to off-white, round shaped film-coated tablet debossed with "M54" on one side and "LU" on other side.

    •    Each tablet of Amabelz 0.5 mg/ 0.1 mg contains 0.5 mg of estradiol and 0.1 mg of norethindrone acetate. The tablets are white to off-white, round shaped film-coated tablet debossed with "M53" on one side and "LU" on other side.

Drug Interactions

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

Metabolic Interactions

Estradiol

In-vitro and in-vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4 such as St. John's wort (Hypericum perforatum) preparations, phenobarbital, carbamazepine, and rifampin may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may increase plasma concentrations of estrogens and result in side effects.

Norethindrone Acetate

Drugs or herbal products that induce or inhibit cytochrome P-450 enzymes, including CYP3A4, may decrease or increase the serum concentrations of norethindrone.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.

Clinical Studies

Effects on Vasomotor Symptoms

In a 12-week randomized clinical trial involving 92 subjects, Amabelz 1 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 Amabelz 1 mg/0.5 mg and the 1 mg estradiol group compared to placebo (see Figure 2).

Figure 2

Mean Weekly Number of Moderate and Severe Hot Flushes in a 12-Week Study

In a study conducted in Europe a total of 577 postmenopausal women were randomly assigned to either Amabelz 0.5 mg/0.1 mg, 0.5 mg E2/0.25 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 Amabelz 0.5 mg/0.1 mg (see Figure 3) and 0.5 mg E2/0.25 mg NETA groups compared to placebo.

Figure 3

Mean Number of Moderate to Severe Hot Flushes for Weeks 0 Through 12

Effects on the Endometrium

Amabelz 1 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 E2 + 0.1 mg NETA (n=294), 1 mg E2 + 0.25 mg NETA (n=291), and Amabelz 1 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 Amabelz 1 mg/0.5 mg are shown in Table 4.

TABLE 4: INCIDENCE OF ENDOMETRIAL HYPERPLASIA WITH UNOPPOSED ESTRADIOL AND Amabelz 1 MG/0.5 MG IN A 12-MONTH STUDY

1 mg E2
(n=296)
Amabelz
1 mg E2/0.5 mg 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 %)

Effects on Uterine Bleeding or Spotting

During the initial months of therapy, irregular bleeding or spotting occurred with Amabelz 1 mg/0.5 mg treatment.  However, bleeding tended to decrease over time, and after 12 months of treatment with Amabelz 1 mg/0.5 mg, about 86 percent of women were amenorrheic (see Figure 4).

Figure 4

Patients Treated with Amabelz 1 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).

In the clinical trial with Amabelz 0.5 mg/0.1 mg, 88 percent of women were amenorrheic after 6 months of treatment (See Figure 5).

Figure 5

Patients Treated with Amabelz 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

Effects on Bone Mineral Density

The results of two randomized, multicenter, calcium-supplemented (500-1000 mg per day), placebo-controlled, 2 year clinical trials have shown that Amabelz 1 mg/0.5 mg and estradiol 0.5 mg are effective in preventing bone loss in postmenopausal women. 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 (T-score > - 2) 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 percent and 67 percent of the randomized subjects in the two clinical trials, respectively, completed the two clinical trials.  BMD was measured using dual-energy x-ray absorptiometry (DXA).

A summary of the results comparing Amabelz 1 mg/0.5 mg and estradiol 0.5 mg to placebo from the two prevention trials is shown in Table 5.

TABLE 5: PERCENTAGE CHANGE (MEAN ± SD) IN BONE MINERAL DENSITY (BMD) FOR Amabelz 1 MG/0.5 MG AND 0.5 MG E2*(Intent to Treat Analysis, Last Observation Carried Forward)

US= United States, EU = European

* While Amabelz 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 Amabelz 0.5 mg/0.1 mg should be at least as great as observed with estradiol 0.5 mg. † Significantly (p<0.001) different from placebo ‡ Significantly (p<0.007) different from placebo § Significantly (p<0.002) different from placebo


US Trial

EU Trial


Placebo
(n=37)
0.5 mg E2*
(n=31)
Amabelz 
1.0 mg/0.5 mg
(n=37)
Placebo
(n=40)
Amabelz 
1.0 mg/0.5 mg
(n=38)
Lumbar spine
Femoral neck
Femoral trochanter
-2.1 ± 2.9
-2.3 ± 3.4
-2.0 ± 4.3
2.3 ± 2.8†
0.3 ± 2.9‡
1.7 ± 4.1§
3.8 ± 3.0†
1.8 ± 4.1†
3.7 ± 4.3†
-0.9 ± 4.0
-1.0 ± 4.6
0.8 ± 6.9
5.4 ± 4.8†
0.7 ± 6.1
6.3 ± 7.6†

The overall difference in mean percentage change in BMD at the lumbar spine in the US trial (1000 mg per day calcium) between Amabelz 1 mg/0.5 mg and placebo was 5.9 percent and between estradiol 0.5 mg and placebo was 4.4 percent. In the European trial (500 mg per day calcium), the overall difference in mean percentage change in BMD at the lumbar spine was 6.3 percent. Amabelz 1 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 Amabelz 1 mg/0.5 mg and estradiol 0.5 mg is displayed in Figure 6.

Figure 6

Percentage Change in Bone Mineral Density (BMD) ± SEM of the Lumbar Spine (L1-L4) for Amabelz 1 mg/0.5 mg and Estradiol 0.5 mg

(Intent to Treat Analysis with Last Observation Carried Forward)

Women’s Health Initiative Studies

The WHI enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of daily oral CE (0.625 mg)-alone or in combination with MPA (2.5 mg) compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of CHD (defined as nonfatal MI, silent MI and CHD death), with invasive breast cancer as the primary adverse outcome. A "global index" included the earliest occurrence of CHD, invasive breast cancer, stroke, PE, endometrial cancer (only in the CE plus MPA substudy), colorectal cancer, hip fracture, or death due to other cause. These substudies did not evaluate the effects of CE plus MPA or CE-alone on menopausal symptoms.

WHI Estrogen Plus Progestin Substudy

The WHI estrogen plus progestin substudy was stopped early. According to the predefined stopping rule, after an average follow-up of 5.6 years of treatment, the increased risk of invasive breast cancer and cardiovascular events exceeded the specified benefits included in the "global index." The absolute excess risk of events included in the "global index" was 19 per 10,000 women-years.

For those outcomes included in the WHI "global index," that reached statistical significance after 5.6 years of follow-up, the absolute excess risks per 10,000 women-years in the group treated with CE plus MPA were 7 more CHD events, 8 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures.

Results of the CE plus MPA substudy, which included 16,608 women (average 63 years of age, range 50 to 79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other) are presented in Table 6. These results reflect centrally adjudicated data after an average follow-up of 5.6 years.

TABLE 6: RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN PLUS PROGESTIN SUBSTUDY OF WHI AT AN AVERAGE OF 5.6 YEARS*,†
* Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. † Results are based on centrally adjudicated data. ‡ Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. § Not included in “global index”. ¶ Includes metastatic and non-metastatic breast cancer, with the exception of in situ breast cancer. # All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. Þ 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.
Event
Relative Risk
CE/MPA vs. Placebo
(95% nCI‡)
CE/MPA
n = 8,506
Placebo
n = 8,102


Absolute Risk per 10,000
Women-Years
CHD events 
   Non-fatal MI 
   CHD death 
All strokes
    Ischemic stroke 
Deep vein thrombosis§
Pulmonary embolism 
Invasive breast cancer¶
Colorectal cancer
Endometrial cancer§
Cervical cancer§
Hip fracture
Vertebral fractures§
Lower arm/wrist fractures§
Total fractures§
Overall Mortality#
Global IndexÞ
1.23 (0.99-1.53)
1.28 (1.00-1.63) 
1.10(0.70-1.75)
1.31 (1.02–1.68)
1.44 (1.09–1.90)
1.95 (1.43–2.67)
2.13 (1.45–3.11)
1.24 (1.01–1.54)
0.61 (0.42–0.87)
0.81 (0.48–1.36)
1.44 (0.47–4.42)
0.67 (0.47–0.96)
0.65 (0.46–0.92)
0.71 (0.59–0.85)
0.76 (0.69–0.83)
1.00 (0.83-1.19)
1.13 (1.02-1.25)
41
31
8
33
26
26
18
41
10
6
2
11
11
44
152
52
184
34
25
8
25
18
13
8
33
16
7
1
16
17
62
199
52
165

Timing of the initiation of estrogen plus progestin therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen plus progestin substudy, stratified by age, showed in women 50 to 59 years of age a non-significant trend toward reduced risk for overall mortality [hazard ratio (HR) 0.69 (95 percent CI, 0.44 to 1.07)].

WHI Estrogen-Alone Substudy

The WHI estrogen-alone substudy was stopped early because an increased risk of stroke was observed, and it was deemed that no further information would be obtained regarding the risks and benefits of estrogen-alone in predetermined primary endpoints.

Results of the estrogen-alone substudy, which included 10,739 women (average 63 years of age, range 50 to 79; 75.3 percent White, 15.1 percent Black, 6.1 percent Hispanic, 3.6 percent Other), after an average follow-up of 7.1 years, are presented in Table 7.

Table 7: Relative and Absolute Risk Seen in the Estrogen-Alone Substudy of WHI*
* Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. † Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. ‡ Results are based on centrally adjudicated data for an average follow-up of 7.1 years. § Not included in “global index”. ¶ Results are based on an average follow-up of 6.8 years. # All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. Þ 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.
Event
Relative Risk
CE vs. Placebo
(95% nCI†)
CE
n = 5,310
Placebo
n = 5,429


Absolute Risk per 
10,000 Women-years
CHD events‡
0.95 (0.78–1.16)
54

57
   Non-fatal MI‡ 
0.91 (0.73–1.14)
40
43
   CHD death‡
1.01(0.71–1.43)
16
16
All strokes‡
1.33 (1.05-1.68)
45
33
   Ischemic stroke†
1.55 (1.19 – 2.01)
38
25
Deep vein thrombosis‡,§
1.47 (1.06–2.06)
23
15
Pulmonary embolism‡
1.37 (0.90–2.07)
14
10
Invasive breast cancer‡
0.80 (0.62–1.04)
28
34
Colorectal cancer¶
1.08 (0.75–1.55)
17
16
Hip fracture‡
0.65 (0.45–0.94)
12
19
Vertebral fractures‡,§
0.64 (0.44-0.93)
11
18
Lower arm/wrist fractures‡,§
0.58 (0.47-0.72)
35
59
Total fractures‡,§
0.71 (0.64-0.80)
144
197
Death due to other causes¶,#
1.08 (0.88–1.32)
53
50
Overall mortality‡,§
1.04 (0.88–1.22)
79
75
Global IndexÞ
1.02 (0.92–1.13)
206
201

For those outcomes included in the WHI "global index" that reached statistical significance, the absolute excess risk per 10,000 women-years in the group treated with CE-alone was 12 more strokes, while the absolute risk reduction per 10,000 women-years was 7 fewer hip fracture. 9 The absolute excess risk of events included in the "global index" was a non-significant 5 events per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality.

No overall difference for primary CHD events (nonfatal MI, silent MI and CHD death) and invasive breast cancer incidence in women receiving CE-alone compared with placebo was reported in final centrally adjudicated results from the estrogen-alone substudy, after an average follow up of 7.1 years.

Centrally adjudicated results for stroke events from the estrogen-alone substudy, after an average follow-up of 7.1 years, reported no significant difference in distribution of stroke subtype or severity, including fatal strokes, in women receiving CE-alone compared to placebo. Estrogen-alone increased the risk for ischemic stroke, and this excess risk was present in all subgroups of women examined. 10

Timing of the initiation of estrogen-alone therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen-alone substudy, stratified by age, showed in women 50 to 59 years of age a non-significant trend toward reduced risk for CHD [HR 0.63 (95 percent CI, 0.36 to 1.09)] and overall mortality [HR 0.71 (95 percent CI, 0.46 to 1.11)].

Women’s Health Initiative Memory Study

The WHIMS estrogen plus progestin ancillary study of WHI enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47 percent were 65 to 69 years of age, 35 percent were 70 to 74 years of age, 18 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia (primary outcome) compared to placebo.

After an average follow-up of 4 years, the relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21-3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years. Probable dementia as defined in this study included Alzheimer's disease (AD), vascular dementia (VaD) and mixed types (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women [see WARNINGS AND PRECAUTIONS (5.3), and USE IN SPECIFIC POPULATIONS (8.5)].

The WHIMS estrogen-alone ancillary study of WHI study enrolled 2,947 predominantly healthy hysterectomized postmenopausal women 65 to 79 years of age (45 percent were 65 to 69 years of age, 36 percent were 70 to 74 years of age, 19 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg)-alone on the incidence of probable dementia (primary outcome) compared to placebo.

After an average follow-up of 5.2 years, the relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83-2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years. Probable dementia as defined in this study included AD, VaD and mixed types (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women [see WARNINGS AND PRECAUTIONS (5.3), and USE IN SPECIFIC POPULATIONS (8.5)].

When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 percent CI, 1.19-2.60). Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women [see WARNINGS AND PRECAUTIONS (5.3), and USE IN SPECIFIC POPULATIONS (8.5)].

  • Cenestin
  • Climara
  • Climara Pro
  • Divigel
  • Estrace
  • Estrace Vaginal Cream
  • Evista
  • Fosamax
  • Fosamax Plus D
  • Menest
  • Premarin
  • Premarin Injection
  • Premarin Vaginal Cream
  • Provera

© Amabelz Patient Information is supplied by Cerner Multum, Inc. and Amabelz Consumer information is supplied by First Databank, Inc., used under license and subject to their respective copyrights.

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