ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Most common adverse reactions (incidence >= percent) are back pain, headache, pain in the extremity, nausea, diarrhea, gastroenteritis, insomnia, emotional lability, upper respiratory tract infection, sinusitis, nasopharyngitis, weight increase, breast pain, post-menopausal bleeding, uterine fibroid vaginal hemorrhage, ovarian cyst, endometrial thickening, viral infection, moniliasis genital, and accidental injury. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The following serious adverse reactions are discussed elsewhere in the labeling: Cardiovascular Disorders [see BOXED WARNING, WARNINGS AND PRECAUTIONS (5.1)] Malignant Neoplasms [see BOXED WARNING, WARNINGS AND PRECAUTIONS, (5.2)] 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.Adverse reactions reported with Amabelz mg/0.5 mg by investigators in the Phase studies regardless of causality assessment are shown in Table 1.TABLE 1: ALL TREATMENT-EMERGENT ADVERSE REACTIONS REGARDLESS OF RELATIONSHIP REPORTED AT FREQUENCY OF >= PERCENT WITH AMABELZ MG/0.5 MGEndometrial Hyperplasia Study(12-Months)Vasomotor Symptoms Study(3-Months)Osteoporosis Study(2-years)Amabelz1 mg/0.5 mg(n=295)1 mg E2 (n=296)Amabelz1 mg/0.5 mg(n=29)Placebo (n=34)Amabelz1 mg/0.5 mg(n=47)Placebo (n=48)Body as WholeBack PainHeadache 6%16% 5%16% 3%17% 3%18% 6%11% 4%6% Digestive SystemNausea Gastroenteritis 3%2% 5%2% 10%0% 0%0% 11%6% 0%4% Nervous SystemInsomnia Emotional Lability 6%1% 4%1% 3%0% 3%0% 0%6% 8%0% Respiratory SystemUpper Respiratory Tract Infection Sinusitis 18%7% 15%11% 10%7% 6%0% 15%15% 19%10% Metabolic and NutritionalWeight Increase 0% 0% 0% 0% 9% 6% Urogenital SystemBreast PainPost-Menopausal BleedingUterine FibroidOvarian Cyst 24%5%5%3% 10%15%4%2% 21%10%0%7% 0%3%0%0% 17%11%4%0% 8%0%8%8% Resistance mechanismInfection ViralMoniliasis Genital 4%4% 6%7% 0%0% 3%0% 6%6% 6%0% Secondary TermsInjury AccidentalOther Events 4%2% 3%3% 3%3% 0%0% 17%including one upper extremity fracture in each group 6% 4% 4% Adverse reactions reported with Amabelz 0.5 mg/0.1 mg by investigators during the Phase study regardless of causality assessment are shown in Table 2.TABLE 2: ALL TREATMENT-EMERGENT ADVERSE REACTIONS REGARDLESS OF RELATIONSHIP REPORTED AT FREQUENCY OF >= PERCENT WITH AMABELZ 0.5 MG/0.1 MGAmabelz0.5 mg/0.1 mg(n=194)Placebo(n=200)Body as WholeBack PainHeadachePain in extremity 10%22%5% 4%19%4% Digestive SystemNauseaDiarrhea 5%6% 4%6% Respiratory SystemNasopharyngitis 21% 18% Urogenital SystemEndometrial thickeningVaginal hemorrhage 10%26% 4%12% 6.2 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of Amabelz. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Genitourinary SystemChanges in vaginal bleeding pattern and abnormal withdrawal bleeding or flow; breakthrough bleeding; spotting; dysmenorrhea, increase in size of uterine leiomyomata; vaginitis, including vaginal candidiasis; change in amount of cervical secretion; changes in cervical ectropion; pre-menstrual-like syndrome; cystitis- like syndrome; ovarian cancer; endometrial hyperplasia; endometrial cancer.BreastTenderness, enlargement, pain, nipple discharge, galactorrhea; fibrocystic breast changes; breast cancer.CardiovascularDeep and superficial venous thrombosis; pulmonary embolism; thrombophlebitis; myocardial infarction, stroke; increase in blood pressure.GastrointestinalNausea, vomiting; changes in appetite; cholestatic jaundice; abdominal pain/cramps, flatulence, bloating; increased incidence of gallbladder disease and pancreatitis.SkinChloasma or melasma that may persist when drug is discontinued; erythema multiforme; erythema nodosum; hemorrhagic eruption; loss of scalp hair; seborrhea; hirsutism; itching; skin rash; pruritus.EyesRetinal vascular thrombosis, intolerance to contact lenses.Central Nervous SystemHeadache; migraine; dizziness; mental depression; chorea; insomnia; nervousness; mood disturbances; irritability; exacerbation of epilepsy; dementia.MiscellaneousIncrease or decrease in weight; edema; leg cramps; changes in libido; fatigue; exacerbation of asthma; increased triglycerides; hypersensitivity; anaphylactoid/anaphylactic reactions.

BOXED WARNING SECTION.

WARNING: CARDIOVASCULAR DISORDERS, BREAST CANCER, ENDOMETRIAL CANCER AND PROBABLE DEMENTIASee full prescribing information for complete boxed warningEstrogen Plus Progestin Therapy Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia (5.1, 5.3) The Womens Health Initiative (WHI) estrogen plus progestin substudy reported increased risks of deep vein thrombosis (DVT),pulmonary embolism (PE), stroke and myocardial infarction (MI) (5.1) The WHI estrogen plus progestin substudy reported increased risks of invasive breast cancer (5.2) The WHI Memory Study (WHIMS) estrogen plus progestin ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age and older (5.3)Estrogen-Alone Therapy There is an increased risk of endometrial cancer in woman with uterus who use unopposed estrogens (5.2) Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia (5.2, 5.3) The WHI estrogen-alone substudy reported increased risks of stroke and DVT (5.1) The WHIMS estrogen-alone ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age and older (5.3). WARNING: CARDIOVASCULAR DISORDERS, BREAST CANCER, ENDOMETRIAL CANCER AND PROBABLE DEMENTIAEstrogen Plus Progestin TherapyCardiovascular Disorders and Probable DementiaEstrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia [see WARNINGS AND PRECAUTIONS (5.1, 5.3), and CLINICAL STUDIES (14.5, 14.6)]. The Womens Health Initiative (WHI) estrogen plus progestin substudy reported increased risks of deep vein thrombosis (DVT), pulmonary embolism (PE), stroke and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral conjugated estrogen (CE) [0.625 mg] combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo [see WARNINGS AND PRECAUTIONS (5.1), and CLINICAL STUDIES (14.5)]. The WHI Memory Study (WHIMS) estrogen plus progestin ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see WARNINGS AND PRECAUTIONS (5.3), USE IN SPECIFIC POPULATIONS (8.5), and CLINICAL STUDIES (14.6)]. Breast CancerThe WHI estrogen plus progestin substudy also demonstrated an increased risk of invasive breast cancer [see WARNINGS AND PRECAUTIONS (5.2), and CLINICAL STUDIES (14.5)]. In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and MPA and other combinations and dosage forms of estrogens and progestins.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.Estrogen-Alone TherapyEndometrial CancerThere is an increased risk of endometrial cancer in woman with uterus who uses unopposed estrogens. Adding progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be precursor to endometrial cancer. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding [see WARNINGS AND PRECAUTIONS (5.2)]. Cardiovascular Disorders and Probable DementiaEstrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia [see WARNINGS AND PRECAUTIONS (5.1, 5.3), and CLINICAL STUDIES (14.5, 14.6)]. The WHI estrogen-alone substudy reported increased risks of stroke and DVT in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral CE (0.625 mg)-alone, relative to placebo [see WARNINGS AND PRECAUTIONS (5.1), and CLINICAL STUDIES (14.5)]. The WHIMS estrogen-alone ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 5.2 years of treatment with daily CE (0.625 mg)-alone, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see WARNINGS AND PRECAUTIONS (5.3), USE IN SPECIFIC POPULATIONS (8.5), and CLINICAL STUDIES (14.6)]. In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and other dosage forms of estrogens.Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 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 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 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.. 12.2 Pharmacodynamics. There are no pharmacodynamic data known for Amabelz tablets.. 12.3 Pharmacokinetics. AbsorptionEstradiol:Estradiol is absorbed through the gastrointestinal tract. Following oral administration of Amabelz tablets, peak plasma estradiol concentrations are reached within to hours. The oral bioavailability of estradiol following administration of Amabelz mg/0.5 mg when compared to combination oral solution is 53%. Administration of Amabelz 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 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 mg/0.5 mg when compared to combination oral solution is 100%. Administration of Amabelz mg/0.5 mg with food increases norethindrone AUC0 to 72 by 19% and decreases Cmax by 36%.The pharmacokinetic parameters of estradiol (E2), estrone (E1), and norethindrone (NET) following oral administration of Amabelz mg/0.5 mg or 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 TABLET OF AMABELZ MG/0.5 MG OR TABLETS OF AMABELZ 0.5 MG/0.1 MG TO HEALTHY POSTMENOPAUSAL WOMENAUC area under the curve, - last quantifiable sample Cm x maximum plasma concentration, tm x time at maximum plasma concentration, t1 2 half-life, x Amabelz1 mg/0.5 mg(n=24)Meangeometric mean; (%CV) geometric coefficient of variation;2 Amabelz0.5 mg/0.1 mg(n=24)Mean (%CV)Estradiol baseline unadjusted data; (E2 )AUC0 to (pg/mLh)Cm x (pg/mL)tm x (h): median (range)t1 2 (h) baseline unadjusted data; 766.5 (48)26.8 (36)6 (0.5 to 16)14n=18; (29) 697.3 (53)26.5 (37)6.5 (0.5 to 16)14.5n=16; (27) Estrone (E1 )AUC0 to (pg/mLh)Cm x (pg/mL)tm x (h): median (range)t1 2 (h) 4469.1 (48)195.5 (37)6 (1 to 9)10.7 (44) n=13; 4506.4 (44)199.5 (30)6 (2 to 9)11.8 (25) Norethindrone (NET)AUC0 to (pg/mLh)Cmax (pg/mL)tm x (h): median (range)t1 2 (h) 21043 (41)5249.5 (47)0.7 (0.7 to 1.25)9.8 (32) n=22; 8407.2 (43)2375.4 (41)0.8 (0.7 to 1.3)11.4 (36) n=21 Following continuous dosing with once-daily administration of Amabelz 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 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 mg/0.5 mg (N=24)Figure 1b: Mean Baseline-Uncorrected Norethindrone Serum Concentration-Time Profile Following Multiple Doses of AMABELZ 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 to 2% is unbound.Norethindrone Acetate:Norethindrone also binds to similar extent to SHBG (36%) and to albumin (61%).MetabolismEstradiol:Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in 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 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, significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as circulating reservoir for the formation of more active estrogens.Norethindrone Acetate:The most important metabolites of norethindrone are isomers of 5-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 mg/0.5 mg is 12 to 14 hours.Norethindrone Acetate:The terminal half-life of norethindrone is about to 11 hours.Use in Specific PopulationsNo pharmacokinetic studies were conducted in specific populations, including women with renal or hepatic impairment.. fig 1a. fig 1b.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Effects on Vasomotor Symptoms. In 12-week randomized clinical trial involving 92 subjects, Amabelz mg/0.5 mg was compared to mg of estradiol and to placebo. The mean number and intensity of hot flushes were significantly reduced from baseline to week and 12 in both the Amabelz mg/0.5 mg and the mg estradiol group compared to placebo (see Figure 2).Figure 2Mean Weekly Number of Moderate and Severe Hot Flushes in 12-Week StudyIn study conducted in Europe 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 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 3Mean Number of Moderate to Severe Hot Flushes for Weeks Through 12. 14.2 Effects on the Endometrium. Amabelz mg/0.5 mg reduced the incidence of estrogen-induced endometrial hyperplasia at year in randomized, controlled clinical trial. This trial enrolled 1,176 subjects who were randomized to one of arms: mg estradiol unopposed (n=296), mg E2 0.1 mg NETA (n=294), mg E2 0.25 mg NETA (n=291), and Amabelz mg/0.5 mg (n=295). At the end of the study, endometrial biopsy results were available for 988 subjects. The results of the mg estradiol unopposed arm compared to Amabelz mg/0.5 mg are shown in Table 4.TABLE 4: INCIDENCE OF ENDOMETRIAL HYPERPLASIA WITH UNOPPOSED ESTRADIOL AND AMABELZ MG/0.5 MG IN 12-MONTH STUDY1 mg E2 (n=296)Amabelz1 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 %) (0.4 %) (0.4 %) (0.8 %) 14.3 Effects on Uterine Bleeding or Spotting. During the initial months of therapy, irregular bleeding or spotting occurred with Amabelz mg/0.5 mg treatment. However, bleeding tended to decrease over time, and after 12 months of treatment with Amabelz mg/0.5 mg, about 86 percent of women were amenorrheic (see Figure 4).Figure 4Patients Treated with AMABELZ 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, LOCFNote: the percentage of patients who were amenorrheic in 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 months of treatment (See Figure 5).Figure 5Patients 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. 14.4 Effects on Bone Mineral Density. The results of two randomized, multicenter, calcium-supplemented (500-1000 mg per day), placebo-controlled, year clinical trials have shown that Amabelz mg/0.5 mg and estradiol 0.5 mg are effective in preventing bone loss in postmenopausal women. total of 462 postmenopausal women with intact uteri and baseline BMD values for lumbar spine within standard deviations of the mean in healthy young women (T-score - 2) were enrolled. In US trial, 327 postmenopausal women (mean time from menopause 2.5 to 3.1 years) with mean age of 53 years were randomized to groups (0.25 mg, 0.5 mg, and mg of estradiol alone, mg estradiol with 0.25 mg norethindrone acetate, mg estradiol with 0.5 mg norethindrone acetate, and mg estradiol with mg norethindrone acetate, and placebo.) In European trial (EU trial), 135 postmenopausal women (mean time from menopause 8.4 to 9.3 years) with mean age of 58 years were randomized to mg estradiol with 0.25 mg norethindrone acetate, 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 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 MG/0.5 MG AND 0.5 MG E2 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. (Intent to Treat Analysis, Last Observation Carried Forward)US= United States, EU European US TrialEU TrialPlacebo(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 spineFemoral neckFemoral trochanter -2.1 +- 2.9-2.3 +- 3.4-2.0 +- 4.3 2.3 +- 2.8Significantly (p<0.001) different from placebo 0.3 +- 2.9Significantly (p<0.007) different from placebo 1.7 +- 4.1Significantly (p<0.002) different from placebo 3.8 +- 3.0 1.8 +- 4.1 3.7 +- 4.3 -0.9 +- 4.0-1.0 +- 4.60.8 +- 6.9 5.4 +- 4.8 0.7 +- 6.16.3 +- 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 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 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 mg/0.5 mg and estradiol 0.5 mg is displayed in Figure 6.Figure 6Percentage Change in Bone Mineral Density (BMD) +- SEM of the Lumbar Spine (L1-L4) for AMABELZ mg/0.5 mg and Estradiol 0.5 mg(Intent to Treat Analysis with Last Observation Carried Forward). 14.5 Womens 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. 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 SubstudyThe 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 more CHD events, more strokes, 10 more PEs, and more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were fewer colorectal cancers and 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 YEARSAdapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. Results are based on centrally adjudicated data. Event Relative RiskCE/MPA vs. Placebo(95% nCINominal confidence intervals unadjusted for multiple looks and multiple comparisons. )CE/MPAn 8,506Placebon 8,102Absolute Risk per 10,000Women-YearsCHD events Non fatal MI CHD death All strokes Ischemic stroke Deep vein thrombosisNot included in global index. Pulmonary embolism Invasive breast cancerIncludes metastatic and non-metastatic breast cancer, with the exception of in situ breast cancer. Colorectal cancerEndometrial cancer Cervical cancer Hip fractureVertebral fractures Lower arm/wrist fractures Total fractures Overall MortalityAll deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. Global IndexA subset of the events was combined in 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. 1.23 (0.99-1.53) . 28 1 00 1 63 1 10 0 70 1 75 1.31 (1.02-1.68) . 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 33 26 261841106211114415252184 34 25 25 18 13833167116176219952165 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 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 SubstudyThe 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 WHIAdapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. EventRelative RiskCE vs. Placebo(95% nCINominal confidence intervals unadjusted for multiple looks and multiple comparisons. )CEn 5,310Placebon 5,429Absolute Risk per 10,000 Women-yearsCHD eventsResults are based on centrally adjudicated data for an average follow-up of 7.1 years. 0.95 (0.78-1.16) 54 57 Non-fatal MI 0.91 (0.73-1.14)4043 CHD death 1.01(0.71-1.43)1616All strokes 1.33 (1.05-1.68) 45 33 Ischemic stroke 1.55 (1.19 2.01)3825Deep 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 cancerResults are based on an average follow-up of 6.8 years. 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 All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. 1.08 (0.88-1.32) 53 50 Overall mortality 1.04 (0.88-1.22) 79 75 Global IndexA subset of the events was combined in 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. 1.02 (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 fewer hip fracture. The absolute excess risk of events included in the global index was non-significant 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 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)]. 14.6 Womens 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 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 Alzheimers 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)]. fig 2. fig 3. fig 4. fig 5. fig 6.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Undiagnosed abnormal genital bleeding (4) Known, suspected, or history of breast cancer (4, 5.2) Known or suspected estrogen-dependent neoplasia (4, 5.2) Active DVT, PE, or history of these conditions (4, 5.1) Active arterial thromboembolic disease (for example, stroke and MI), or history of these conditions (4, 5.1) Known anaphylactic reaction or angioedema or hypersensitivity to Amabelz (4) Known liver impairment or disease (4, 5.10) Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders (4) Known or suspected pregnancy (4, 8.1). Amabelz is contraindicated in women with any of the following conditions: Undiagnosed abnormal genital bleeding Known, suspected, or history of breast cancer Known, past or suspected estrogen-dependent neoplasia Active DVT, PE, or history of these conditions Active arterial thromboembolic disease (for example stroke and MI), or history of these conditions Known anaphylactic reaction or angioedema or hypersensitivity to Amabelz Known liver impairment or disease Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders Known or suspected pregnancy.

DESCRIPTION SECTION.

11 DESCRIPTION. Amabelz mg/0.5 mg is single tablet for oral administration containing 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 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 white or almost white crystalline powder. Its chemical name is estra-1, 3, (10)-triene-3, 17-diol hemihydrate with the empirical formula of C18H24O2, 1/2 H2O and molecular weight of 281.4. The structural formula of E2 is as follows:Norethindrone acetate (NETA), progestin, is white or yellowish-white crystalline powder. Its chemical name is 17-acetoxy-19-nor-17-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.. estradiol. norethindrone acetate.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. One tablet to be taken once daily (2). Use of estrogen-alone, or in combination with progestin, should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary.. 2.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause. Amabelz(TM) therapy consists of single tablet to be taken once daily for the treatment of moderate to severe vasomotor symptoms due to menopause. Amabelz mg/0.5 mg Amabelz 0.5 mg/0.1 mg. 2.2 Treatment of Moderate to Severe Symptoms of Vulvar and Vaginal Atrophy due to Menopause. Amabelz therapy consists of single tablet to be taken once daily for the treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause. Amabelz mg/0.5 mg. 2.3 Prevention of Postmenopausal Osteoporosis. Amabelz therapy consists of single tablet to be taken once daily for the prevention of postmenopausal osteoporosis. Amabelz mg/0.5 mg Amabelz 0.5 mg/0.1 mg.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Amabelz (estradiol and norethindrone acetate tablets USP) mg/0.5 mg (3) Amabelz (estradiol and norethindrone acetate tablets USP) 0.5 mg/0.1 mg (3). Amabelz tablets are available in two strengths: Each tablet of Amabelz mg/ 0.5 mg contains 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 SECTION.

7 DRUG INTERACTIONS. Inducers and/or inhibitors of CYP3A4 may affect estrogen drug metabolism (7.1). 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 single dose study.. 7.1 Metabolic Interactions. EstradiolIn-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. Johns wort (Hypericum perforatum) preparations, phenobarbital, carbamazepine, and rifampin may reduce plasma concentrations of estrogens, possibly resulting in 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 AcetateDrugs or herbal products that induce or inhibit cytochrome P-450 enzymes, including CYP3A4, may decrease or increase the serum concentrations of norethindrone.

GERIATRIC USE SECTION.

8.5 Geriatric Use. There have not been sufficient numbers of geriatric women involved in clinical studies utilizing Amabelz to determine whether those over 65 years of age differ from younger subjects in their response to Amabelz.The Womens Health Initiative StudiesIn the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age [see CLINICAL STUDIES (14.5)]. In the WHI estrogen-alone substudy (daily CE [0.625 mg]-alone versus placebo), there was higher relative risk of stroke in women greater than 65 years of age [see CLINICAL STUDIES (14.5)]. The Womens Health Initiative Memory StudyIn the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen plus progestin or estrogen-alone when compared to placebo. It is unknown whether this finding applies to younger postmenopausal women [see WARNINGS AND PRECAUTIONS (5.3), and CLINICAL STUDIES (14.6)]. Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women8 [see WARNINGS AND PRECAUTIONS (5.3), and CLINICAL STUDIES (14.6)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1 How Supplied. Amabelz mg/0.5 mg is white to off-white, round shaped film-coated tablet debossed with M54 on one side and LU on other side. Amabelz mg/0.5 mg is available in wallet (NDC 68180-830-11) containing 28 tablets enclosed in pouch, such pouches are packed in carton (NDC 68180-830-13).Amabelz 0.5 mg/0.1 mg is white to off-white, round shaped film-coated tablet debossed with M53 on one side and LU on other side.Amabelz 0.5 mg/0.1 mg is available in wallet (NDC 68180-829-11) containing 28 tablets enclosed in pouch, such pouches are packed in carton (NDC 68180-829-13).. 16.2 Storage and Handling. Store in dry place protected from light. Store at 25C (77F), excursions permitted to 15 to 30C (59 to 86F). [See USP Controlled Room Temperature.].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Amabelz is an estrogen and progestin combination indicated in woman with uterus for:Amabelz mg/0.5 mg and 0.5 mg/0.1 mg are indicated in woman with uterus for: Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause (1.1) Prevention of Postmenopausal Osteoporosis (1.3)Amabelz mg/0.5 mg is also indicated in woman with uterus for: Treatment of Moderate to Severe Symptoms of Vulvar and Vaginal Atrophy due to Menopause (1.2). 1.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause. 1.2 Treatment of Moderate to Severe Symptoms of Vulvar and Vaginal Atrophy due to Menopause. Limitation of UseWhen prescribing solely for the treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause, topical vaginal products should be considered.. 1.3 Prevention of Postmenopausal Osteoporosis Limitation of Use. Limitation of UseWhen 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.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. See FDA-approved patient labeling (Patient Information) 17.1 Abnormal Vaginal Bleeding. Inform postmenopausal women of the importance of reporting abnormal vaginal bleeding to their healthcare provider as soon as possible [see WARNINGS AND PRECAUTIONS (5.2)]. 17.2 Possible Serious Adverse Reactions with Estrogen Plus Progestin Therapy. Inform postmenopausal women of possible serious adverse reactions of estrogen plus progestin therapy including Cardiovascular Disorders, Malignant Neoplasms, and Probable Dementia [see WARNINGS AND PRECAUTIONS (5.1, 5.2, 5.3)]. 17.3 Possible Less Serious but Common Adverse Reactions with Estrogen Plus Progestin Therapy. Inform postmenopausal women of possible less serious but common adverse reactions of estrogen plus progestin therapy such as headache, breast pain and tenderness, nausea and vomiting.Rx onlyAmabelz(TM) is trademark of Lupin Pharmaceuticals, Inc.Manufactured for:Lupin Pharmaceuticals, Inc.Baltimore, Maryland 21202United StatesManufactured by:Lupin LimitedPithampur (M.P.) 454 775IndiaMay 2017 ID: 251298.

LABORATORY TESTS SECTION.

5.17 Laboratory Tests. Serum follicle stimulating hormone (FSH) and estradiol levels have not been shown to be useful in the management of moderate to severe vasomotor symptoms and moderate to severe symptoms of vulvar and vaginal atrophy.

MECHANISM OF ACTION SECTION.

12.1 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 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 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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 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.

NURSING MOTHERS SECTION.

8.3 Nursing Mothers. Amabelz should not be used during lactation. Estrogen administration to nursing women has been shown to decrease the quantity and quality of the breast milk. Detectable amounts of estrogen and progestin have been identified in the breast milk of women receiving estrogen plus progestin therapy. Caution should be exercised when Amabelz is administered to nursing woman.

OVERDOSAGE SECTION.

10 OVERDOSAGE. Overdosage of estrogen plus progestin may cause nausea, vomiting, breast tenderness, abdominal pain, drowsiness and fatigue, and withdrawal bleeding may occur in women. Treatment of overdose consists of discontinuation of Amabelz therapy with institution of appropriate symptomatic care.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

AMABELZ(TM) (estradiol and norethindrone acetate tablets USP) 1 mg/0.5 mg Carton Pack:NDC: 681810-830-133 Pouches of 28 Tablets EachRx onlyAMABELZ(TM) (estradiol and norethindrone acetate tablets USP) 1 mg/0.5 mg Pouch Pack: NDC: 681810-830-111 Wallet of 28 TabletsRx onlyPharmacist: Each unit contains information intended for the patients. See enclosed information for the patient including boxed warning. This informational piece is to be provided to the patient with each prescription.AMABELZ(TM) (estradiol and norethindrone acetate tablets USP) 1 mg/0.5 mg 28 Day Regimen Wallet Pack: NDC: 681810-830-1128 TabletsRx onlyAMABELZ(TM) (estradiol and norethindrone acetate tablets USP) 0.5 mg 0.1 mgCarton Pack:NDC: 681810-829-133 Pouches of 28 Tablets EachRx onlyAMABELZ(TM) (estradiol and norethindrone acetate tablets USP) 0.5 mg 0.1 mgPouch Pack: NDC: 681810-829-111 Wallet of 28 TabletsRx onlyPharmacist: Each unit contains information intended for the patients. See enclosed information for the patient including boxed warning. This informational piece is to be provided to the patient with each prescription.AMABELZ(TM) (estradiol and norethindrone acetate tablets USP) 0.5 mg 0.1 mg28 Day Regimen Wallet Pack: NDC: 681810-829-1128 TabletsRx only. carton 1mg-0.5mg. pouch 1mg-0.5mg. wallet 1mg-0.5mg. carton 0.5 mg-0.1 mg. pouch 0.5mg-0.1mg. wallet 0.5 mg-0.1 mg.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Amabelz is not indicated in children. Clinical studies have not been conducted in the pediatric population.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. There are no pharmacodynamic data known for Amabelz tablets.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionEstradiol:Estradiol is absorbed through the gastrointestinal tract. Following oral administration of Amabelz tablets, peak plasma estradiol concentrations are reached within to hours. The oral bioavailability of estradiol following administration of Amabelz mg/0.5 mg when compared to combination oral solution is 53%. Administration of Amabelz 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 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 mg/0.5 mg when compared to combination oral solution is 100%. Administration of Amabelz mg/0.5 mg with food increases norethindrone AUC0 to 72 by 19% and decreases Cmax by 36%.The pharmacokinetic parameters of estradiol (E2), estrone (E1), and norethindrone (NET) following oral administration of Amabelz mg/0.5 mg or 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 TABLET OF AMABELZ MG/0.5 MG OR TABLETS OF AMABELZ 0.5 MG/0.1 MG TO HEALTHY POSTMENOPAUSAL WOMENAUC area under the curve, - last quantifiable sample Cm x maximum plasma concentration, tm x time at maximum plasma concentration, t1 2 half-life, x Amabelz1 mg/0.5 mg(n=24)Meangeometric mean; (%CV) geometric coefficient of variation;2 Amabelz0.5 mg/0.1 mg(n=24)Mean (%CV)Estradiol baseline unadjusted data; (E2 )AUC0 to (pg/mLh)Cm x (pg/mL)tm x (h): median (range)t1 2 (h) baseline unadjusted data; 766.5 (48)26.8 (36)6 (0.5 to 16)14n=18; (29) 697.3 (53)26.5 (37)6.5 (0.5 to 16)14.5n=16; (27) Estrone (E1 )AUC0 to (pg/mLh)Cm x (pg/mL)tm x (h): median (range)t1 2 (h) 4469.1 (48)195.5 (37)6 (1 to 9)10.7 (44) n=13; 4506.4 (44)199.5 (30)6 (2 to 9)11.8 (25) Norethindrone (NET)AUC0 to (pg/mLh)Cmax (pg/mL)tm x (h): median (range)t1 2 (h) 21043 (41)5249.5 (47)0.7 (0.7 to 1.25)9.8 (32) n=22; 8407.2 (43)2375.4 (41)0.8 (0.7 to 1.3)11.4 (36) n=21 Following continuous dosing with once-daily administration of Amabelz 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 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 mg/0.5 mg (N=24)Figure 1b: Mean Baseline-Uncorrected Norethindrone Serum Concentration-Time Profile Following Multiple Doses of AMABELZ 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 to 2% is unbound.Norethindrone Acetate:Norethindrone also binds to similar extent to SHBG (36%) and to albumin (61%).MetabolismEstradiol:Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in 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 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, significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as circulating reservoir for the formation of more active estrogens.Norethindrone Acetate:The most important metabolites of norethindrone are isomers of 5-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 mg/0.5 mg is 12 to 14 hours.Norethindrone Acetate:The terminal half-life of norethindrone is about to 11 hours.Use in Specific PopulationsNo pharmacokinetic studies were conducted in specific populations, including women with renal or hepatic impairment.

PREGNANCY SECTION.

8.1 Pregnancy. Amabelz should not be used during pregnancy [see CONTRAINDICATIONS (4)]. There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins as an oral contraceptive inadvertently during early pregnancy.

RECENT MAJOR CHANGES SECTION.

RECENT MAJOR CHANGES. Contraindications (4) 10/2013Warnings and Precautions, Hereditary Angioedema (5.15) 10/2013.

REFERENCES SECTION.

15 REFERENCES. 1. Rossouw JE, et al. Postmenopausal Hormone Therapy and Risk of Cardiovascular Disease by Age and Years Since Menopause. JAMA. 2007;297:1465-1477. 2. Hsia J, et al. Conjugated Equine Estrogens and Coronary Heart Disease. Arch Int Med. 2006;166:357- 365. 3. Cushman M, et al. Estrogen Plus Progestin and Risk of Venous Thrombosis. JAMA. 2004;292:1573- 1580. 4. Curb JD, et al. Venous Thrombosis and Conjugated Equine Estrogen in Women Without Uterus. Arch Int Med. 2006;166:772-780. 5. Chlebowski RT, et al. Influence of Estrogen Plus Progestin on Breast Cancer and Mammography in Healthy Postmenopausal Women. JAMA. 2003;289:3234-3253. 6. Stefanick ML, et al. Effects of Conjugated Equine Estrogens on Breast Cancer and Mammography Screening in Postmenopausal Women With Hysterectomy. JAMA. 2006;295:1647-1657. 7. Anderson GL, et al. Effects of Estrogen Plus Progestin on Gynecologic Cancers and Associated Diagnostic Procedures. JAMA. 2003;290:1739-1748. 8. Shumaker SA, et al. Conjugated Equine Estrogens and Incidence of Probable Dementia and Mild Cognitive Impairment in Postmenopausal Women. JAMA. 2004;291:2947-2958. 9. Jackson RD, et al. Effects of Conjugated Equine Estrogen on Risk of Fractures and BMD in Postmenopausal Women With Hysterectomy: Results From the Womens Health Initiative Randomized Trial. Bone Miner Res. 2006;21:817-828. 10. Hendrix SL, et al. Effects of Conjugated Equine Estrogen on Stroke in the Womens Health Initiative. Circulation. 2006;113:2425-2434.

SPL PATIENT PACKAGE INSERT SECTION.

AMABELZ(TM) (AM-ah-bells)(estradiol and norethindrone acetate tablets USP)Read this Patient Information before you start taking Amabelz and each time you get refill. There may be new information. This information does not take the place of talking to your healthcare provider about your menopausal symptoms or your treatment.

SPL UNCLASSIFIED SECTION.

WARNING: CARDIOVASCULAR DISORDERS, BREAST CANCER, ENDOMETRIAL CANCER AND PROBABLE DEMENTIAEstrogen Plus Progestin TherapyCardiovascular Disorders and Probable DementiaEstrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia [see WARNINGS AND PRECAUTIONS (5.1, 5.3), and CLINICAL STUDIES (14.5, 14.6)]. The Womens Health Initiative (WHI) estrogen plus progestin substudy reported increased risks of deep vein thrombosis (DVT), pulmonary embolism (PE), stroke and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral conjugated estrogen (CE) [0.625 mg] combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo [see WARNINGS AND PRECAUTIONS (5.1), and CLINICAL STUDIES (14.5)]. The WHI Memory Study (WHIMS) estrogen plus progestin ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see WARNINGS AND PRECAUTIONS (5.3), USE IN SPECIFIC POPULATIONS (8.5), and CLINICAL STUDIES (14.6)]. Breast CancerThe WHI estrogen plus progestin substudy also demonstrated an increased risk of invasive breast cancer [see WARNINGS AND PRECAUTIONS (5.2), and CLINICAL STUDIES (14.5)]. In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and MPA and other combinations and dosage forms of estrogens and progestins.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.Estrogen-Alone TherapyEndometrial CancerThere is an increased risk of endometrial cancer in woman with uterus who uses unopposed estrogens. Adding progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be precursor to endometrial cancer. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding [see WARNINGS AND PRECAUTIONS (5.2)]. Cardiovascular Disorders and Probable DementiaEstrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia [see WARNINGS AND PRECAUTIONS (5.1, 5.3), and CLINICAL STUDIES (14.5, 14.6)]. The WHI estrogen-alone substudy reported increased risks of stroke and DVT in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral CE (0.625 mg)-alone, relative to placebo [see WARNINGS AND PRECAUTIONS (5.1), and CLINICAL STUDIES (14.5)]. The WHIMS estrogen-alone ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 5.2 years of treatment with daily CE (0.625 mg)-alone, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see WARNINGS AND PRECAUTIONS (5.3), USE IN SPECIFIC POPULATIONS (8.5), and CLINICAL STUDIES (14.6)]. In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and other dosage forms of estrogens.Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment.

STORAGE AND HANDLING SECTION.

16.2 Storage and Handling. Store in dry place protected from light. Store at 25C (77F), excursions permitted to 15 to 30C (59 to 86F). [See USP Controlled Room Temperature.].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Nursing Mothers: Estrogen administration to nursing women has been shown to decrease the quantity and quality of breast milk (8.3) Geriatric Use: An increase risk of probable dementia in women over 65 years of age was reported in the Womens Health Initiative Memory ancillary studies of the Womens Health Initiative (5.3, 8.5). 8.1 Pregnancy. Amabelz should not be used during pregnancy [see CONTRAINDICATIONS (4)]. There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins as an oral contraceptive inadvertently during early pregnancy.. 8.3 Nursing Mothers. Amabelz should not be used during lactation. Estrogen administration to nursing women has been shown to decrease the quantity and quality of the breast milk. Detectable amounts of estrogen and progestin have been identified in the breast milk of women receiving estrogen plus progestin therapy. Caution should be exercised when Amabelz is administered to nursing woman.. 8.4 Pediatric Use. Amabelz is not indicated in children. Clinical studies have not been conducted in the pediatric population.. 8.5 Geriatric Use. There have not been sufficient numbers of geriatric women involved in clinical studies utilizing Amabelz to determine whether those over 65 years of age differ from younger subjects in their response to Amabelz.The Womens Health Initiative StudiesIn the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age [see CLINICAL STUDIES (14.5)]. In the WHI estrogen-alone substudy (daily CE [0.625 mg]-alone versus placebo), there was higher relative risk of stroke in women greater than 65 years of age [see CLINICAL STUDIES (14.5)]. The Womens Health Initiative Memory StudyIn the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen plus progestin or estrogen-alone when compared to placebo. It is unknown whether this finding applies to younger postmenopausal women [see WARNINGS AND PRECAUTIONS (5.3), and CLINICAL STUDIES (14.6)]. Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women8 [see WARNINGS AND PRECAUTIONS (5.3), and CLINICAL STUDIES (14.6)]. 8.6 Renal Impairment. The effect of renal impairment on the pharmacokinetics of Amabelz has not been studied.. 8.7 Hepatic Impairment. The effect of hepatic impairment on the pharmacokinetics of Amabelz has not been studied.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Estrogens increase the risk of gall bladder disease (5.4) Discontinue estrogen if severe hypercalcemia, loss of vision, severe hypertriglyceridemia or cholestatic jaundice occurs (5.5, 5.6, 5.9, 5.10) Monitor thyroid function in women on thyroid replacement therapy (5.11, 5.18). 5.1 Cardiovascular Disorders. An increased risk of PE, DVT, stroke and MI has been reported with estrogen plus progestin therapy. An increased risk of stroke and DVT has been reported with estrogen-alone therapy. Should any of these occur or be suspected, estrogen with or without progestin therapy should be discontinued immediately.Risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (for example, personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately.StrokeIn the WHI estrogen plus progestin substudy, statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women in the same age group receiving placebo (33 versus 25 per 10,000 women-years) [see CLINICAL STUDIES (14.5)]. The increase in risk was demonstrated after the first year and persisted.1Should stroke occur or be suspected, estrogen plus progestin therapy should be discontinued immediately.In the WHI estrogen-alone substudy, statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg)-alone compared to women in the same age group receiving placebo (45 versus 33 per 10,000 women-years). The increase in risk was demonstrated in year and persisted [see CLINICAL STUDIES (14.5)]. Should stroke occur or be suspected, estrogen-alone therapy should be discontinued immediately.Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving CE (0.625 mg)-alone versus those receiving placebo (18 versus 21 per 10,000 women-years). Coronary Heart DiseaseIn the WHI estrogen plus progestin substudy, there was statistically non-significant increase risk of coronary heart disease (CHD) events (defined as nonfatal MI, silent MI, or CHD death) reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (41 versus 34 per 10,000 women-years) 1An increase in relative risk was demonstrated in year 1, and trend toward decreasing relative risk was reported in years through [see CLINICAL STUDIES (14.5)]. In the WHI estrogen-alone substudy, no overall effect on CHD events was reported in women receiving estrogen-alone compared to placebo [see CLINICAL STUDIES (14.5)]. Subgroup analyses of women 50 to 59 years of age suggest statistically non-significant reduction in CHD events (CE [0.625 mg]-alone compared to placebo) in women with less than 10 years since menopause (8 versus 16 per 10,000 women-years). In postmenopausal women with documented heart disease (n=2,763), average 66.7 years of age, in controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study [HERS]), treatment with daily CE (0.625 mg plus MPA (2.5 mg) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE plus MPA did not reduce the overall rate of CHD events in postmenopausal women with established CHD. There were more CHD events in the CE plus MPA- treated group than in the placebo group in year 1, but not during the subsequent years. Two thousand, three hundred and twenty-one (2,321) 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 total of 6.8 years overall. Rates of CHD events were comparable among women in the CE plus MPA group and the placebo group in HERS, HERS II, and overall.Venous ThromboembolismIn the WHI estrogen plus progestin substudy, statistically significant 2-fold greater rate of VTE (DVT and PE), was reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (35 versus 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 versus 13 per 10,000 women-years) and PE (18 versus per 10,000 women-years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted [see CLINICAL STUDIES (14.5)]. Should VTE occur or be suspected, estrogen plus progestin therapy should be discontinued immediately.In the WHI estrogen-alone substudy, the risk of VTE was increased for women receiving daily CE (0.625 mg)-alone compared to placebo (30 versus 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 versus 15 per 10,000 women-years). The increase in VTE risk was demonstrated during the first years [see CLINICAL STUDIES (14.5)]. Should VTE occur or be suspected, estrogen-alone therapy should be discontinued immediately.If feasible, estrogens should be discontinued at least to weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.. 5.2 Malignant Neoplasms. Breast CancerThe most important randomized clinical trial providing information about breast cancer in estrogen plus progestin users is the WHI substudy of daily CE (0.625 mg) plus MPA (2.5 mg). After mean follow-up of 5.6 years, the estrogen plus progestin substudy reported an increased risk of invasive breast cancer in women who took daily CE plus MPA. In this substudy, prior use of estrogen-alone or estrogen plus progestin therapy was reported by 26 percent of the women. The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years, for CE plus MPA compared with placebo [see CLINICAL STUDIES (14.5)]. 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 versus 25 cases per 10,000 women-years, for CE plus 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 versus 36 cases per 10,000 women-years, for CE plus MPA compared with placebo. In the same substudy, invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at more advanced stage in the CE (0.625 mg) plus MPA (2.5 mg) 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 groups5 [see CLINICAL STUDIES (14.5)]. The most important randomized clinical trial providing information about breast cancer in estrogen-alone users is the WHI substudy of daily CE (0.625 mg)-alone. In the WHI estrogen-alone substudy, after an average follow-up of 7.1 years, daily CE-alone was not associated with an increased risk of invasive breast cancer [relative risk (RR) 0.806 [see CLINICAL STUDIES (14.5)]. Consistent with the WHI clinical trials, observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and smaller increased risk for estrogen-alone therapy, after several years of use. The risk increased with duration of use, and appeared to return to baseline over about years after stopping treatment (only the observational studies have substantial data on risk after stopping). Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen plus progestin therapy as compared to estrogen-alone therapy. However, these studies have not found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, doses, or routes of administration.The use of estrogen-alone and estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation.In one-year trial among 1,176 women who received either unopposed mg estradiol or combination of mg estradiol plus one of three different doses of NETA (0.1, 0.25, 0.5 mg), seven new cases of breast cancer were diagnosed, two of which occurred among the group of 295 women treated with Amabelz mg/0.5 mg and two of which occurred among the group of 294 women treated with mg estradiol/0.1 mg NETA.All women should receive yearly breast examinations by healthcare provider and perform monthly breast self- examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results.Endometrial CancerEndometrial hyperplasia (a possible precursor of endometrial cancer) has been reported to occur at rate of approximately percent or less with Amabelz.An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in woman with uterus. The reported endometrial cancer risk among unopposed estrogen users is about to 12 times greater than in nonusers, 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 year. The greatest risk appears to be associated with prolonged use, with increased risks of 15- to 24-fold for to 10 years or more. This risk has been shown to persist for at least to 15 years after estrogen therapy is discontinued.Clinical surveillance of all women using estrogen-alone or estrogen plus progestin therapy is important. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding.There is no evidence that the use of natural estrogens results in different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding progestin to estrogen therapy in postmenopausal women has been shown to reduce the risk of endometrial hyperplasia, which may be precursor to endometrial cancer.Ovarian CancerThe WHI estrogen plus progestin substudy reported statistically non-significant increased risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE plus MPA versus placebo was 1.58 (95 percent CI, 0.77 to 3.24]. The absolute risk for CE plus MPA versus placebo was versus cases per 10,000 women-years.7In some epidemiologic studies, the use of estrogen plus progestin and estrogen-only products, in particular for or more years, has been associated with an increased risk of ovarian cancer. However, the duration of exposure associated with increased risk is not consistent across all epidemiologic studies, and some report no association.. 5.3 Probable Dementia. In the WHIMS estrogen plus progestin ancillary study of WHI, population of 4,532 postmenopausal women 65 to 79 years of age was randomized to daily CE (0.625 mg) plus MPA (2.5 mg) or placebo.After an average follow-up of years, 40 women in the CE plus MPA and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for the CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21 to 3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years [see USE IN SPECIFIC POPULATIONS (8.5), and CLINICAL STUDIES (14.6)]. In the WHIMS estrogen-alone ancillary study of WHI, population of 2,947 hysterectomized women 65 to 79 years of age was randomized to daily CE (0.625 mg)-alone or placebo. After an average follow-up of 5.2 years, 28 women in the estrogen-alone group and 19 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83 to 2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years8 [see USE IN SPECIFIC POPULATIONS (8.5), and CLINICAL STUDIES (14.6)]. When data from the two populations in the WHIMS estrogen-alone and estrogen plus progestin ancillary studies were pooled as planned in the WHIMS protocol, the reported overall relative risk of probable dementia was 1.76 (95 percent CI, 1.19 to 2.60). Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women [see USE IN SPECIFIC POPULATIONS (8.5), and CLINICAL STUDIES (14.6)]. 5.4 Gallbladder Disease. 2- to fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.. 5.5 Hypercalcemia. Estrogen administration may lead to severe hypercalcemia in patients with breast cancer and bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken to reduce the serum calcium level.. 5.6 Vision Abnormalities. Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, estrogens should be permanently discontinued.. 5.7 Addition of Progestin When Woman Has Not Had Hysterectomy. Studies of the addition of progestin for 10 or more days of cycle of estrogen administration, or daily with estrogen in continuous regimen, have reported lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be precursor to endometrial cancer. There are, however, possible risks that may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include an increased risk of breast cancer.. 5.8 Elevated Blood Pressure. In small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In large, randomized, placebo-controlled clinical trial, generalized effect of estrogen therapy on blood pressure was not seen.. 5.9 Hypertriglyceridemia. In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Consider discontinuation of treatment if pancreatitis occurs.. 5.10 Hepatic Impairment and/or Past History of Cholestatic Jaundice. Estrogens may be poorly metabolized in women with impaired liver function. For women with history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised, and in the case of recurrence, medication should be discontinued.. 5.11 Hypothyroidism. Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Women with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Women dependent on thyroid hormone replacement therapy who are also receiving estrogen may require increased doses of their thyroid replacement therapy. These women should have their thyroid function monitored to maintain their free thyroid hormone levels in an acceptable range.. 5.12 Fluid Retention. Estrogens plus progestins may cause some degree of fluid retention. Women with conditions that might be influenced by this factor, such as cardiac or renal impairment, warrant careful observation when estrogens plus progestins are prescribed.. 5.13 Hypocalcemia. Estrogen therapy should be used with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur.. 5.14 Exacerbation of Endometriosis. few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen-alone therapy. For women known to have residual endometriosis post- hysterectomy, the addition of progestin should be considered.. 5.15 Hereditary Angioedema. Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema.. 5.16 Exacerbation of Other Conditions. Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions.. 5.17 Laboratory Tests. Serum follicle stimulating hormone (FSH) and estradiol levels have not been shown to be useful in the management of moderate to severe vasomotor symptoms and moderate to severe symptoms of vulvar and vaginal atrophy.. 5.18 Drug-Laboratory Test Interactions. Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, and beta- thromboglobulin; decreased levels of anti-factor Xa and antithrombin III, decreased antithrombin III activity, increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.Increased TBG levels leading to increased circulating total thyroid hormone levels as measured by protein- bound iodine (PBI), T4 levels (by column or by radioimmunoassay), or T3 levels by radioimmunoassay. T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Women on thyroid replacement therapy may require higher doses of thyroid hormone.Other binding proteins may be elevated in serum, for example, corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG), leading to increased total circulating corticosteroids and sex steroids, respectively. Free hormone concentrations, such as testosterone and estradiol, may be decreased. Other plasma proteins may be increased (angiotensinogen/rennin substrate, alpha-1 antitrypsin, ceruloplasmin).Increased plasma high-density lipoprotein (HDL) and HDL2 cholesterol subfraction concentration, reduced low-density lipoprotein (LDL) cholesterol concentration, increased triglyceride levels.Impaired glucose tolerance.